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 A Figure S2 Figure Lesssimilar Moresimilar 1076.87 488.48 762.59 0.00 N4 1048.81 488.48 808.24 0.00 N30 762.59 808.24 849.63 0.00 B31 1076.87 849.63 1048.81 0.00 B27 N4 N30 B31 B27 B 335.97 230.85 1 17.59 0.00 N30 1 349.73 239.66 17.59 0.00 N4 244.83 230.85 239.66 0.00 B31 335.97 349.73 244.83 0.00 B27 N30 N4 B31 B27 Figure S3A

Respiration !!! ! ! ! ! ! ! Membrane Transport ! ! ! ! Iron acquisition and metabolism ! ! ! ! ! ! ! !! ! ! ! ! ! Carbohydrates ! ! ! ! !!! !!! ! ! ! ! subsys1

!! Purines ! !

!! !!! ! ! ! !!! ! Protein biosynthesis !!!!!! !!!

! !! Folate and pterines ! absolute

!!! Di− and oligosaccharides ! ! ! ! ! ! ! ! CRISPs ! ! ! !

! ! ! subsys2 Capsular and extracellular polysaccharides !! Branched−chain amino acids !!

! Transport of Zinc ! ! ! ! ! ! ! ! Sugar utilization in Thermotogales ! ! absolute! ! Sialic Acid Metabolism !! ! !

!! ! Restriction−Modification System ! ! !

!! Purine conversions ! !

!! ! ! Mannose Metabolism !

! ! !! ! ! ! Maltose and Maltodextrin Utilization !!! ! ! ! Iron−sulfur cluster assembly subsys3

! Heme, hemin uptake and utilization systems in GramPositives !!

! ! ! Glycerol and Glycerol−3−phosphate Uptake and Utilization ! ! ! Folate Biosynthesis ! !

! ! !! ! !! !! ! ! COG0523 !

−10 −5 0 5 10 Median Absolute Log2 Difference absolute All mapped reads Top 10% exp. genes DE genes DE genes (reads) (reads) (reads) (number) 1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4 Fraction reads Fraction Fraction genes Fraction

0.2 0.2

0.0 0.0 N B N4 N4 N4 B27 B31 B27 B31 B27 B31 N30 N30 N30 0

none no COG hits U Intracellular trafficking and secretion V Defense mechanisms S Function unknown R General function prediction only Q Secondary metabolites biosynthesis, transport and catabolism I Lipid metabolism H Coenzyme metabolism F Nucleotide transport and metabolism E Amino Acid transport and metabolism G Carbohydrate transport and metabolism C Energy production and conversion T Signal transduction mechanisms P Inorganic ion transport and metabolism N Cell motility and secretion M Cell enelope biogenesis, outer membrane

5 O Post−translational modification, protein turnover, chaperones − D Cell division and chromosome partitioning L DNA replication, recombination and repair K Transcription J Translation, ribosomal structure and biogenesis 10 − 15 − 20 − N4 N30 B27 B31 ! ! ! ! !! ! ! ! ! ! !!! ! !! ! ! ! ! ! ! ! ! Virulence, Disease and Defense ! ! ! !!! ! ! ! ! !

! ! Sulfur Metabolism ! ! ! ! ! ! ! ! ! ! ! ! ! ! !! ! ! ! ! ! ! ! Stress Response ! ! ! !!!! !! ! ! ! ! Secondary Metabolism ! ! ! !!!! !!!!!!!!! ! !! ! ! ! ! !!!! ! !!!!!!! ! !! ! ! RNA Metabolism !! !! !! !! ! !!!!!! ! !!! ! !! ! ! ! ! ! ! ! ! ! ! ! ! ! !! ! !!!!!!!!!! ! Respiration ! ! ! ! ! ! !!! ! !! ! !!! ! ! ! ! ! ! ! Regulation and Cell signaling ! !! ! ! !!!! !!!!!!!!!!!!! ! ! ! ! ! ! ! !!!!! !!!! !!!!!!!!! !! !! ! ! ! !!!!! ! Protein Metabolism ! !!! !!!!!!!!!!!!!!!! ! ! ! ! !! !

! ! Potassium metabolism ! ! ! ! ! Phosphorus Metabolism !!! ! ! ! ! ! ! ! ! ! ! Phages, Prophages, Transposable elements, Plasmids ! ! ! ! ! ! ! !! !!!! ! ! !! ! ! !! !!!! ! ! Nucleosides and Nucleotides ! ! ! ! ! !!! ! ! ! ! ! ! ! Nitrogen Metabolism !! ! ! ! ! ! ! Motility and Chemotaxis ! ! !! !!!! !!!!! ! !!! !!!!! ! ! ! !! !!! ! ! ! !! ! ! !! ! !!! !!!!! !! ! ! ! !! ! ! !!!! !! ! ! !! Miscellaneous ! ! !!! ! !!!!!!!!!!!!!!!!!!!! ! ! !! ! !! ! !! !

! ! ! Metabolism of Aromatic Compounds ! ! ! ! ! ! ! ! ! ! !!! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Membrane Transport ! ! !!! !!! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Iron acquisition and metabolism ! ! ! ! ! ! ! ! ! ! ! !! ! ! ! ! !! ! ! ! Fatty Acids, Lipids, and Isoprenoids !!!! !!! ! ! ! ! ! !! ! ! ! Dormancy and Sporulation ! !! !!!! ! !!! ! ! !!!!! ! !!! !! !!! !!!! ! ! ! ! ! ! DNA Metabolism ! ! !! !!!!! !!!! ! !! ! ! ! ! !! ! ! ! ! !! ! ! !! ! !!! !! ! ! !! ! !! !!! ! ! ! ! !! !!!! ! Cofactors, Vitamins, Prosthetic Groups, Pigments ! ! ! ! !! ! ! ! ! ! !! !! ! !! ! ! ! !!!! !! ! !!!! !! !! !! ! ! ! ! !!!! !! ! ! ! ! ! ! ! Clustering−based subsystems !!!! !!!!!!! ! !! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !!!! ! ! !! !! !! ! ! !!! ! ! ! !! !!! !!!!! ! !! ! !!!!!! !!! ! !! ! ! Cell Wall and Capsule ! !!! ! ! ! !!!! ! !! !! !! ! !!! !!! ! !! ! ! ! ! ! ! ! !!!! ! ! Cell Division and Cell Cycle !! ! ! !! !! ! !! ! ! ! ! ! ! !!!! !!!!!!! !! !! ! ! ! ! ! !! !! !! !!!! !! !! ! !! !! ! ! ! !! !!! !!!!! !!!!!!! !!! !! ! ! ! ! ! ! !!! ! !! Carbohydrates !! ! ! !! ! !! !!! !!! !! !!! ! ! !! ! !! !! !!! !! ! ! ! !!! ! !! !! !!! ! !! ! !!! ! !! !! ! ! !! !! ! !! !! ! !!! !!!! !! ! Amino Acids and Derivatives ! !!!!! ! !! ! ! ! !!! !!! ! ! ! ! !

−10 −5 0 5 10 Median Absolute Log2 Difference Triacylglycerols ! Transposable elements !! ! ! ! ! ! Transcription ! ! ! Toxins and superantigens

! ! Tetrapyrroles ! ! Sugar Phosphotransferase Systems, PTS ! ! ! Sugar alcohols ! ! ! !

Sodium Ion−Coupled Energetics ! !

Siderophores ! Selenoproteins ! !! ! ! ! ! ! ! !! !! !!! ! !! RNA processing and modification ! ! ! !! ! ! ! !! ! ! ! Riboflavin, FMN, FAD ! ! ! ! ! ! ! !! ! ! Resistance to antibiotics and toxic compounds ! ! ! ! ! !

Regulation of virulence ! Quorum sensing and biofilm formation

! ! Quinone cofactors ! ! ! Pyrimidines ! Pyridoxine ! ! ! ! ! ! ! !!! ! ! Purines ! ! ! !! ! ! proteosome related Proteolytic pathway Protein translocation across cytoplasmic membrane ! Protein secretion system, Type V Protein secretion system, Type II

! ! !! ! ! ! Protein processing and modification ! ! ! ! ! ! Protein folding ! !! ! ! ! ! Protein degradation !! ! ! ! ! ! ! ! !! ! !!! ! ! ! ! ! ! ! ! !!!!! !!!! ! Protein biosynthesis !!!! !!!! ! ! !!

! ! Protein and nucleoprotein secretion system, Type IV ! ! Proline and 4−hydroxyproline ! Programmed Cell Death and Toxin−antitoxin Systems ! ! !! ! ! Polysaccharides ! ! ! ! ! ! ! ! !! !!! !! !!!!! ! ! !! ! ! ! !!! ! !!! !! !!! !!!!!! ! ! ! ! !! ! !! Plant−Prokaryote DOE project ! ! ! ! !!! !!!!!!! !! ! Plant Hormones ! ! ! Phospholipids ! !! ! ! !

! ! Phages, Prophages ! !

! Peripheral pathways for catabolism of aromatic compounds ! Pathogenicity islands ! ! ! ! ! ! Oxidative stress ! ! ! ! ! !

! ! ! Osmotic stress ! ! ! ! Organic sulfur assimilation ! ! ! ! Organic acids ! ! ! ! ! One−carbon Metabolism !! ! ! ! NAD and NADP ! ! ! ! ! ! !! ! !! ! ! ! ! ! ! ! ! Monosaccharides ! ! !!! ! ! ! ! ! ! ! ! Metabolism of central aromatic intermediates ! ! ! !! ! ! ! ! Lysine, threonine, methionine, and cysteine ! ! Lipoic acid

! ! ! ! ! Isoprenoids ! ! !

Invasion and intracellular resistance !

Inorganic sulfur assimilation !

Histidine Metabolism ! ! ! Heat shock ! ! ! ! ! ! Gram−Positive cell wall components ! !! !! ! ! ! ! ! ! !!!! ! ! ! Gram−Negative cell wall components ! ! !! ! ! Glycoside hydrolases ! ! ! ! Glutamine, glutamate, aspartate, asparagine; ammonia assimilation ! ! ! ! ! ! ! ! ! ! !! ! ! ! ! ! Folate and pterines ! ! !! ! ! ! Flagellar motility in Prokaryota ! !

! ! ! ! Fermentation ! ! ! Fatty acids ! ! ! ! ! Fatty acid metabolic cluster !! ! ! ! ! ! !!! ! !! Electron donating reactions ! ! ! !! ! !! ! ! ! Electron accepting reactions ! ! ! !!!!! ! ! !! ! ! DNA replication ! ! !!!! ! ! ! ! ! ! ! !!!! ! ! ! !!! !! ! ! ! DNA repair !!!! !! !! DNA recombination ! DNA polymerase III epsilon cluster ! ! ! ! ! ! ! ! ! ! Di− and oligosaccharides ! !! ! ! ! ! ! ! ! Detoxification ! ! ! ! CRISPs ! !! ! Coenzyme F420 !

Coenzyme A ! !! !

! ! ! ! CO2 fixation ! ! Clustering−based subsystems ! ! ! ! ! ! ! !! ! ! Central carbohydrate metabolism ! ! ! ! ! ! !

Carbohydrates ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Capsular and extracellular polysacchrides ! ! ! ! ! ! !!

! ! ! Branched−chain amino acids ! ! Biotin Bacteriocins, ribosomally synthesized antibacterial peptides

! ATP synthases !! !! ! ! ! !! Aromatic amino acids and derivatives ! ! ! ! ! ! ! ! ! Arginine; urea cycle, polyamines ! ! ! !

! Aminosugars ! ! ! ! ! ! ! ! ! Alanine, serine, and glycine ! ! ! ! Adhesion ! ! ! ABC transporters ! !! !

−10 −5 0 5 10 Median Absolute Log2 Difference ! ZZ gjo need homes ! ! ! !

Zinc resistance ! !! ! YrdC−YciO−Sua5 protein family ! ! ! ! YjeE ! YhgI, YhgH ! YgjD and YeaZ ! ! YggW !

YgfZ−Iron ! ! ! ! ! ! ! ! ! !! YgfZ ! !! ! !! Yfa cluster YeiH ! ! ! ! !! YebC ! ! ! ! YcfH ! Ycd cluster (putative 2−hydroxyacid dehydrogenase) ! YbbK ! YaaA

! Xylose utilization ! ! Xyloglucan Utilization ! Xanthosine utilization (xap region) ! ! ! Xanthine MetabolismZZ gjo need in Bacteria homes ! ! ! !

Zinc resistance ! ! Wyeosine−MimG Biosynthesis ! !! ! YrdCWidespread−YciO−Sua5 colonization protein familyisland ! ! ! ! ! YjeE ! Valine degradation ! ! V−Type ATPYhgI, synthase YhgH ! ! ! Utilization of glutathione as a YgjDsulphur and source YeaZ ! Urea decompositionYggW ! ! Unspecified monosaccharide transportYgfZ cluster−Iron ! ! !! !! ! ! ! ! ! ! ! !! Unknown sugar utilization (cluster yphABCDEFG)YgfZ ! !! ! !! Unknown carbohydrate utilization containing Fructose−bisphosphateYfa aldolase cluster

Unknown carbohydrate utilization (cluster YeiHYeg) ! ! ! ! ! !! Unknown carbohydrate utilization (clusterYebC Ydj) ! ! ! ! ! ! Universal stress protein familyYcfH ! Ycd cluster (putative 2−hydroxyacid dehydrogenase) ! ! ! Universal GTPases ! ! !! !! ! ! YbbK ! Uncharacterized sugar kinase cluster (ygc) ! ! YaaA ! ! ! UDP−N−acetylmuramate from Fructose−6−phosphate Biosynthesis ! ! ! Ubiquinone Menaquinone−cytochrome c reductaseXylose complexes utilization ! ! UbiquinoneXyloglucan Biosynthesis Utilization ! ! Xanthosine utilizationType (xap IVregion) pilus ! ! Two−component regulatoryXanthine systems Metabolism in Campylobacter in Bacteria ! ! Two partnerWyeosine secretion−MimG pathway Biosynthesis (TPS) ! ! Widespread colonization island ! ! Two cell division clusters relating to chromosome partitioning ! ! ! ! Twin−arginine translocationValine degradation system ! ! ! VTryptophan−Type ATP synthesissynthase ! Utilization of glutathione as a sulphur source ! ! tRNAmodification position 34 ! ! ! ! ! Urea decomposition ! ! ! tRNA processing ! ! Unspecified monosaccharidetRNA nucleotidyltransferase transport cluster ! ! ! ! !! ! ! Unknown sugar utilization (cluster yphABCDEFG) ! ! ! tRNA modification yeast mitochondrial ! ! ! Unknown carbohydrate utilization containing Fructose−bisphosphate aldolase ! ! tRNA modification yeast cytoplasmic !!

! ! ! !! ! ! ! !! Unknown carbohydrate utilization (cluster Yeg) ! ! ! ! ! ! ! tRNA modification Bacteria ! !!! ! ! ! ! !! ! Unknown carbohydrate utilization (cluster Ydj) ! !! tRNA modification Archaea ! !

! tRNAUniversal aminoacylation, stress protein Glu and family Gln ! ! ! ! ! ! ! ! ! ! tRNA aminoacylation,Universal Asp GTPases and Asn !! ! !! Uncharacterized Triacylglycerolsugar kinase cluster metabolism (ygc) ! ! ! ! ! ! UDP−N−acetylmuramate from FructoseTrehalose−6−phosphate Uptake and Biosynthesis Utilization ! ! Ubiquinone Menaquinone−cytochrome Trehalosec reductase Biosynthesis complexes ! !! ! UbiquinoneTransport Biosynthesis of Zinc ! ! Transport of NickelType and IV Cobalt pilus ! Two−component regulatory systemsTransport in ofCampylobacter Molybdenum ! Two partner secretion pathway (TPS) Transport of Manganese ! ! ! ! Two cell division clusters relating to chromosome partitioning ! ! ! ! ! ! ! ! Transport of Iron ! ! Translation initiationTwin factors−arginine eukaryotic translocation and archaeal system !

Translation elongation factors eukaryoticTryptophan and synthesis archaeal ! ! ! ! ! tRNAmodification position 34 ! ! ! ! ! Translation elongation factor G family ! ! ! ! Transcription initiation, bacterialtRNA sigma processing factors ! ! ! tRNA nucleotidyltransferase ! Transcription factors cyanobacterial RpoD−like sigma factors ! ! ! ! ! ! ! ! ! ! ! ! tRNA modificationTranscription yeast factors mitochondrial bacterial ! ! ! ! ! ! TranstRNA−translation modification by yeaststalled cytoplasmic ribosomes !! ! ! ! !! ! ! !! ! ! ! ! ! ! ! Toxin−antitoxin replicontRNA modificationstabilization Bacteriasystems ! !!! ! ! ! ! ! ! ! ! ! ! ! tRNA modification Archaea ! ! ! Ton and Tol transport systems ! !! ! tRNA aminoacylation, Glu and Gln ! ! Tn552 ! ! tRNA aminoacylation,Threonine Asp degradation and Asn ! ! ! ! Threonine andTriacylglycerol Homoserine Biosynthesis metabolism ! ! Trehalose Uptake and Utilization ! Threonine anaerobic catabolism gene cluster ! ! ! ! ! Trehalose Biosynthesis ! Thioredoxin−disulfide reductase ! ! ! ! ! ! ! ThiaminTransport biosynthesis of Zinc ! !! ! ! TransportTetrathionate of Nickel andrespiration Cobalt TerminalTransport cytochrome of Molybdenum oxidases Terminal cytochromeTransport d ubiquinol of Manganese oxidases ! ! ! ! ! ! Terminal cytochromeTransport C oxidases of Iron ! Translation initiation factorsTeichuronic eukaryotic acid and biosynthesis archaeal ! !

Translation elongation factors eukaryotic and archaeal ! ! ! ! !!! Teichoic and lipoteichoic acids biosynthesis ! !! ! ! ! Translation elongation factor G family ! ! TCA Cycle ! ! ! Transcription initiation, bacterialTaurine sigma Utilization factors !

Transcription factors cyanobacterialSynechocystis RpoD−like sigmaexperimental factors ! ! ! ! ! ! ! Transcription factorsSulfur oxidationbacterial ! ! ! ! ! ! ! ! ! ! Trans−translation by stalled ribosomes ! ! ! ! !! !! ! ! ! Sugar utilization in Thermotogales ! ! !!! ! !! ! Toxin−antitoxinSucrose replicon utilization stabilization Shewanella systems ! ! ! Ton and Tol Sucrosetransport utilization systems ! ! ! !! ! Tn552 ! ! ! Succinate dehydrogenase ! ! Stringent Response,Threonine (p)ppGpp degradationmetabolism ! ! ! StreptolysinThreonine and S Biosynthesis Homoserine and Biosynthesis Transport ! ! ! Threonine anaerobic catabolism gene cluster ! ! Streptococcus pyogenes Virulome ! ! ! ! ! StreptococcusThioredoxin pyogenes recombinatorial−disulfide reductase zone ! ! ! ! ! Streptococcus pneumoniae VancomycinThiamin Tolerance biosynthesis Locus ! !! ! Tetrathionate respiration Streptococcal Mga Regulon ! Terminal cytochromeSteroid oxidases sulfates StaphylococcalTerminal cytochrome phi−Mu50B d ubiquinol−like prophages oxidases ! ! ! StaphylococcalTerminal pathogenicity cytochrome islands C oxidases SaPI ! ! Staphylococcal accessoryTeichuronic gene acidregulator biosynthesis system ! ! ! ! ! ! Teichoic and lipoteichoic acids biosynthesis ! !! ! ! Sporulation gene orphans ! ! SporeTCA Cycle Coat ! ! ! SpeB−SpeF Taurineextended Utilization regulon Synechocystis experimental ! Sortase ! Soluble cytochromes and functionally related electronSulfur oxidation carriers ! ! ! ! ! ! ! ! ! ! ! !! !! ! ! ! Sugar utilization in Thermotogales ! ! !!! ! !! ! Signal peptidase ! SigmaBSucrose stress utilization responce Shewanella regulation ! SiderophoreSucrose Pyoverdine utilization ! ! ! ! SuccinateSiderophore dehydrogenase Enterobactin ! Stringent Response,Siderophore (p)ppGpp metabolism Aerobactin ! ! Streptolysin S Biosynthesis and Transport ! ! Sialic Acid Metabolism ! ! ! ! ! ! ! ! ! ! ! Sex pheromones in EnterococcusStreptococcus faecalis and pyogenes other Firmicutes Virulome ! ! ! ! Serotype determining Capsular polysaccharideStreptococcus pyogenesbiosynthesis recombinatorial in Staphylococcus zone !! ! ! ! ! Streptococcus pneumoniae Vancomycin Tolerance Locus ! !! ! Serine−glyoxylate cycle ! ! ! StreptococcalSerine Mga Biosynthesis Regulon ! ! SelenocysteineSteroid metabolism sulfates ! Staphylococcal phi−Mu50B−like prophages ! ! Scaffold proteins for [4Fe−4S] cluster assembly (MRP family) ! ! ! ! StaphylococcalSalicylate pathogenicity ester islands degradation SaPI ! ! StaphylococcalSalicylate accessory and gene gentisate regulator catabolism system !

Sporulation gene orphans ! ! ! RuvABC plus a hypothetical ! Spore Coat ! Rubrerythrin ! ! ! ! ! ! SpeBrRNA−SpeF modification extended Bacteria regulon ! !! ! !! rRNA modification ArchaeaSortase ! ! Soluble cytochromes and Rrf2functionally family transcriptional related electron regulators carriers ! ! ! RNA processing and degradation,Signal peptidase bacterial ! ! ! !! ! SigmaB stressRNA polymerase responce regulation bacterial ! ! !! ! ! Siderophore Pyoverdine ! !!!!!! Ribosome SSU bacterial ! ! ! ! ! ! ! ! ! ! !!!! ! Siderophore Enterobactin ! !! !! ! Ribosome LSU bacterial ! ! !!!!! ! ! ! ! ! ! RibosomeSiderophore biogenesis Aerobactin bacterial ! ! ! ! ! ! ! RibosomeSialic activity Acid Metabolismmodulation ! ! ! ! ! ! ! ! Sex pheromones in Enterococcus faecalis and other Firmicutes ! ! ! ! Ribosomal protein S5p acylation !

! Serotype determining CapsularRibosomal polysaccharide protein S12pbiosynthesis Asp methylthiotransferase in Staphylococcus ! !! ! ! ! ! ! !! ! Serine−glyoxylate cycle ! ! ! ! Ribonucleotide reduction ! ! ! ! ! ! SerineRibonuclease Biosynthesis H ! ! Riboflavin,Selenocysteine FMN and FAD metabolism ! ! ScaffoldRibitol, proteins Xylitol, for [4FeArabitol,−4S] Mannitol cluster assembly and Sorbitol (MRP utilization family) !

! ! ! ! RhamnoseSalicylate containing ester degradation glycans ! ! ! ! ! SalicylateRestriction and− gentisateModification catabolism System ! ! ! ! RuvABC plus a hypothetical ! ! Respiratory dehydrogenases 1 ! ! ! ! ! !! ! Rubrerythrin ! ! Respiratory Complex I !!! ! !! ! ! ! ! rRNAResistance modification to Vancomycin Bacteria ! !! ! !! !! ! ResistancerRNA modification to fluoroquinolones Archaea ! ! Regulatory IntramembraneRrf2 family transcriptional Proteolysis regulatorsPathways ! ! ! RNA processing and degradation, bacterial ! !! ! Redox−dependent regulation of nucleus processes ! !! ! Quorum Sensing:RNA Autoinducer polymerase−2 Synthesis bacterial ! ! !! ! ! ! !!!!!! QuinolinicRibosome acid and SSUits derivatives bacterial ! ! ! ! ! ! ! ! ! ! !!!! ! ! !! !! ! RibosomeQuinate LSU degradation bacterial ! ! !!!!! ! ! ! ! ! ! !! ! ! ! Ribosome biogenesis bacterial ! ! ! ! Queuosine−Archaeosine Biosynthesis ! ! ! Pyruvate:ferredoxinRibosome activity oxidoreductase modulation ! ! Ribosomal protein S5p acylation !! Pyruvate metabolism II: acetyl−CoA, acetogenesis from pyruvate ! ! ! ! Ribosomal protein S12p Asp methylthiotransferase ! ! ! ! !! Pyruvate metabolism I: anaplerotic reactions, PEP ! ! ! ! ! ! ! ! Ribonucleotide reduction ! ! ! ! ! Pyruvate Alanine Serine Interconversions ! ! ! Pyrroloquinoline QuinoneRibonuclease biosynthesis H ! Riboflavin, FMN andPyrimidine FAD metabolism utilization ! ! Ribitol, Xylitol, Arabitol, Mannitol and Sorbitol utilization ! ! ! Pyridoxin (Vitamin B6) Biosynthesis ! ! ! ! ! ! ! ! ! ! ! pVirRhamnose Plasmid containing of Campylobacter glycans ! PutativeRestriction sulfate−Modification assimilation System cluster ! ! ! Putative sugarRespiratory ABC transporter dehydrogenases (ytf cluster) 1 ! ! ! ! !! ! PutativeRespiratory hemin transporter Complex I !!! ! !! Putative diaminopropionateResistance ammonia to− lyaseVancomycin cluster ! ! Resistance to Purinefluoroquinolones Utilization ! ! ! ! ! Regulatory Intramembrane Proteolysis Pathways ! ! ! ! ! ! Purine conversions ! ! ! ! ! !! Redox−dependent regulation ofPterin nucleus metabolism processes 3 ! Quorum Sensing: AutoinducerPterin− 2metabolism Synthesis ! PterinQuinolinic carbinolamine acid and its dehydratase derivatives QuinatePterin biosynthesisdegradation ! ! ! ! Queuosine−ArchaeosinePseudouridine Biosynthesis catabolism ! ! ! Protocatechuate branchPyruvate:ferredoxin of beta−ketoadipate oxidoreductase pathway ! ! ! ! ! Pyruvate metabolism II: acetyl−CoA, acetogenesis from pyruvate ! ! Proteolysis in bacteria, ATP−dependent ! ! ! ! ! ! ! ! PyruvateProtein metabolism YjgK cluster I: anaplerotic linked to biofilm reactions, formation PEP ! ! ! ! ! ! Pyruvate Alanine Serine Interconversions ! ! Protein degradation ! ! ! ! Pyrroloquinoline Quinone biosynthesis !! ! Protein chaperones ! ! ! ! Pyrimidine utilization ! Proteasome bacterial ! ! ! ! ! Pyridoxin (Vitamin B6) Biosynthesis ! !! ! ! PROSC !! ! PropionylpVir−CoA Plasmid to Succinyl of Campylobacter−CoA Module ! ! PropionatePutative −sulfateCoA to assimilation Succinate Module cluster Putative sugar ABC transporterPropanediol (ytf utilization cluster) ! Proline, 4−hydroxyprolinePutative uptake hemin and transporter utilization ! ! Putative diaminopropionate ammoniaProline−lyase Synthesis cluster ! ProgrammedPurine frameshiftUtilization ! ! ! ! ! ! ! ! ! ! Predicted carbohydratePurine conversions hydrolases ! ! ! ! ! !! Pterin metabolism 3 ! Potassium homeostasis ! Pterin metabolism Polysaccharide deacetylases ! Pterin carbinolaminepolyprenyl dehydratase synthesis ! ! ! Polyprenyl DiphosphatePterin Biosynthesisbiosynthesis ! ! PolyhydroxybutyratePseudouridine metabolism catabolism ! ! !! ! !! ! Protocatechuate branch of betaPolyamine−ketoadipate Metabolism pathway ! ! ! ! ! ! ! Proteolysis in bacteria,Polyadenylation ATP−dependent bacterial ! ! ! Protein YjgK cluster linked to biofilm formation Poly−gamma−glutamate biosynthesis ! ! Protein degradation ! !! ! PnuC−like transporters ! ! ! !! ! ProteinPlasmid chaperones replication ! ! ! ! ! ! PhotorespirationProteasome (oxidative C2 bacterial cycle) ! ! ! !! Phosphorylcholine incorporationPROSC in LPS !! ! ! ! ! ! ! ! ! Propionyl−CoA toPhosphate Succinyl−CoA metabolism Module ! ! ! ! PhenylpropanoidPropionate−CoA compound to Succinate degradation Module Phenylalanine and Tyrosine BranchesPropanediol from Chorismate utilization ! ! ! Proline, 4−hydroxyprolinePhage shock uptake protein and (psp) utilization operon ! PhageProline capsid Synthesis proteins ! ! ! PeriplasmicProgrammed disulfide interchange frameshift ! ! ! PeripheralPredicted Glucose carbohydrate Catabolism hydrolases Pathways !! ! ! Potassium homeostasis ! Peptidyl−prolyl cis−trans isomerase ! ! ! ! !! ! ! Polysaccharide deacetylases ! ! ! ! !!!! ! !! ! Peptidoglycan Biosynthesis ! ! ! ! Peptide methioninepolyprenyl sulfoxide reductasesynthesis ! ! ! ! Polyprenyl Diphosphate Biosynthesis ! ! ! Pentose phosphate pathway ! ! ! ! pPolyhydroxybutyrate−Hydroxybenzoate degradationmetabolism ! !! ! !! ! p−AminobenzoylPolyamine−Glutamate Metabolism Utilization ! ! ! ! ! !! ! Polyadenylation bacterial ! ! Oxidative stress ! Poly−gammaOrphan−glutamate regulatory biosynthesis proteins ! ! ! ! One−carbon metabolismPnuC by tetrahydropterines−like transporters ! ! ! ! ! PlasmidOmega replication−amidase ! ! ! ! ! ! Photorespiration (oxidativeNusA−TFII C2 Cluster cycle) !! Nudix proteinsPhosphorylcholine (nucleoside triphosphate incorporation hydrolases) in LPS ! ! ! ! ! ! ! ! ! Nucleoside triphosphate pyrophosphohydrolasePhosphate metabolism MazG ! ! ! ! Phenylpropanoid compound degradation Nitrosative stress ! Phenylalanine and Tyrosine Branches fromNitrogen Chorismate fixation Phage shock Nitricprotein oxide (psp) synthase operon ! Nitrate andPhage nitrite capsidammonification proteins ! ! ! PeriplasmicNiFe hydrogenase disulfide interchange maturation ! ! NiacinPeripheral−Choline Glucose transport Catabolism and metabolism Pathways ! ! NeotrehalosadiaminePeptidyl (NTD)−prolyl Biosynthesis cis−trans isomerase Operon ! ! ! ! !! ! ! ! ! ! !!!! !!! ! Peptidoglycan Biosynthesis ! ! ! ! ! NAD regulation ! !! ! Peptide methionine sulfoxide reductase ! ! ! ! ! NAD and NADP cofactor biosynthesis global ! ! ! ! ! ! ! ! ! Na+ translocating decarboxylases and relatedPentose biotin−dependent phosphate enzymes pathway ! ! ! ! ! ! ! ! Na(+)−translocating NADH−quinone oxidoreductase and rnf−like groupp of−Hydroxybenzoate electron transport degradation complexes ! p−Aminobenzoyln−Phenylalkanoic−Glutamate acid degradation Utilization ! ! ! ! ! ! ! Oxidative stress ! ! N−linked Glycosylation in Bacteria ! ! N−Acetyl−Galactosamine andOrphan Galactosamine regulatory Utilization proteins ! ! ! ! ! ! One−carbon metabolism by tetrahydropterines ! mycolic acid synthesis ! ! Omega−amidase Murein hydrolase regulation and cell death ! ! ! ! NusA−TFII Cluster ! !! ! ! Multidrug Resistance Efflux Pumps ! ! ! Multidrug effluxNudix pump proteins in Campylobacter (nucleoside triphosphatejejuni (CmeABC hydrolases) operon) ! Nucleoside triphosphateMukBEF pyrophosphohydrolase Chromosome Condensation MazG ! Muconate lactonizingNitrosative enzyme stressfamily ! Molybdenum cofactorNitrogen biosynthesis fixation

Nitric oxide synthase ! ! mnm5U34 biosynthesis bacteria ! ! ! ! ! Nitrate and nitrite ammonificationMLST ! NiFeMethylglyoxal hydrogenase Metabolism maturation Niacin−Choline transportMethylcitrate and metabolism cycle ! Neotrehalosadiamine (NTD) BiosynthesisMethionine SalvageOperon ! ! ! ! ! MethionineNAD Degradation regulation ! !! ! ! ! ! ! ! NAD and NADP cofactor biosynthesis global ! !! ! ! ! Methionine Biosynthesis ! ! ! ! ! ! ! Na+ translocating decarboxylases and related biotin−dependent enzymes ! ! Methicillin resistance in Staphylococci ! ! !! ! ! ! Na(+)−translocating NADH−quinone oxidoreductase and rnf−like group of electronMethanopterin transport biosynthesis2 complexes ! n−PhenylalkanoicMercury resistance acid degradation operon ! ! ! ! N−linked GlycosylationMercuric in reductase Bacteria ! ! N−Acetyl−GalactosamineMenaquinone and Biosynthesis Galactosamine via FutalosineUtilization ! ! ! ! Menaquinone and Phylloquinonemycolic acid Biosynthesis synthesis ! ! ! ! MureinMembrane hydrolase−bound regulation Ni, Fe −andhydrogenase cell death ! ! ! ! ! Multidrug ResistanceMelibiose Efflux Utilization Pumps ! ! Multidrug efflux pump in Campylobactermcm5s2U jejuni biosynthesis (CmeABC operon)in tRNA ! MazEF toxin−antitoxingMukBEF (programmed Chromosome cell death)Condensation system Muconate lactonizing enzyme family ! ! Mannose Metabolism ! Molybdenum cofactorMannitol biosynthesis Utilization ! ! ! ! ! ! ! ! mnm5U34 biosynthesis bacteria ! ! ! ! ! Maltose and Maltodextrin Utilization ! ! ! ! ! MLST ! Macromolecular synthesis operon !! ! ! !! MethylglyoxalLysine degradationMetabolism

Methylcitrate cycle ! ! ! ! Lysine Biosynthesis DAP Pathway ! ! MethionineLuciferases Salvage ! ! ! Methionine Degradation ! LOS core oligosaccharide biosynthesis ! ! !! Methionine Biosynthesis !! ! ! ! LMPTP YwlE cluster !! ! ! ! ! ! Methicillin resistance in Staphylococci ! ! !! LMPTP YfkJ cluster ! Listeria surfaceMethanopterin proteins: biosynthesis2 LPXTG motif Mercury resistance operon Listeria surface proteins: Internalin−like proteins ! Listeria phi−A118Mercuric−like prophages reductase ListeriaMenaquinone Pathogenicity Biosynthesis Island LIPI via− 1Futalosine extended ! ! Menaquinone and Phylloquinone Biosynthesis ! ! ! Lipopolysaccharide−related cluster in Alphaproteobacteria ! ! ! Membrane−bound Ni, Fe−hydrogenase ! ! ! Lipopolysaccharide assembly ! LipoicMelibiose acid metabolism Utilization !

! ! Lipid A−Ara4N mcm5s2Upathway (Polymyxin biosynthesis resistance) in tRNA ! MazEF toxin−antitoxing (programmed cell death) system Lipid A modifications ! ! ! Mannose Metabolism ! linker unit−arabinogalactan synthesis ! ! ! ! ! ! ! Leucine Degradation and HMGMannitol−CoA Metabolism Utilization !! ! ! ! ! ! ! ! Maltose and MaltodextrinLeucine Biosynthesis Utilization ! ! !

Macromolecular synthesis operon !! ! ! !! Legionaminic Acid Biosynthesis ! LysineLactose degradation utilization ! ! ! ! Lactose andLysine Galactose Biosynthesis Uptake andDAP Utilization Pathway !! ! ! Lacto−N−Biose I and Galacto−N−Biose MetabolicLuciferases Pathway ! ! ! LOS core oligosaccharide biosynthesis ! ! ! ! Lactate utilization ! ! ! ! L−LMPTPrhamnose YwlE utilization cluster ! !! ! ! ! ! L−fucoseLMPTP utilization YfkJ cluster temp ! ! Listeria surface proteins:L−fucose LPXTG utilization motif !

Listeria surface proteins: Internalin−like proteins ! ! L−Cystine Uptake and Metabolism ! L−ascorbate utilizationListeria (and phi− relatedA118− likegene prophages clusters) ! Listeria Pathogenicity IslandL−Arabinose LIPI−1 utilizationextended ! ! ! ! Lipopolysaccharide−relatedKetoisovalerate cluster in Alphaproteobacteria oxidoreductase ! ! ! ! ! ! Lipopolysaccharide assembly ! ! !!! ! KDO2−Lipid A biosynthesis ! ! ! ! ! ! ! ! ! Lipoic acid metabolism ! ! ! ! Isoprenoid Biosynthesis ! ! ! ! ! ! ! ! Lipid A−Ara4N pathway Isoleucine(Polymyxin degradation resistance) ! Isobutyryl−CoA to PropionylLipid A −modificationsCoA Module ! ! ! ! ! !! ! linker unit−arabinogalactan synthesis !! ! ! ! ! Iron−sulfur cluster assembly ! ! ! ! ! ! Leucine Degradation andIron HMG acquisition−CoA Metabolism in Vibrio ! ! ! ! Iron acquisitionLeucine in Streptococcus Biosynthesis ! ! !! ! ! ! Legionaminic Acid Biosynthesis !! ! ! ! ! Iojap ! ! ! ! ! Lactose utilizationInteins ! Lactose and Galactose UptakeInositol and catabolism Utilization ! ! Lacto−N−Biose I and Galacto−InorganicN−Biose MetabolicSulfur Assimilation Pathway ! ! ! ! LactateHydrogenases utilization ! ! LHydantoin−rhamnose metabolism utilization ! ! ! L−fucose utilization temp ! HPr kinase and hprK operon in Gram−positive organisms ! ! Homogentisate pathway of aromatic compoundL−fucose degradation utilization ! ! L−Cystine UptakeHMG and CoA Metabolism Synthesis ! L−ascorbate utilization (and relatedHistidine gene Degradation clusters) ! ! LHistidine−Arabinose Biosynthesis utilization ! ! ! ! ! High affinity phosphate transporterKetoisovalerate and control ofoxidoreductase PHO regulon ! ! ! !!! ! KDO2−Lipid A biosynthesisHfl operon ! ! ! ! ! ! ! ! ! ! ! ! ! ! Hexose PhosphateIsoprenoid Uptake Biosynthesis System ! ! ! ! ! Heterocyst formationIsoleucine in cyanobacteria degradation ! ! Isobutyryl−CoA to Propionyl−CoA Module ! Hemin transport system ! ! ! ! ! ! Iron−sulfur cluster assembly ! ! !! Heme, hemin uptake and utilization systems in GramPositives ! ! ! Heme, hemin uptake and utilization systemsIron acquisition in GramNegatives in Vibrio ! ! ! !! ! ! ! ! Iron acquisitionHeme biosynthesis in Streptococcus orphans ! !! ! ! ! !! ! ! ! Iojap ! ! ! ! ! ! Heme and Siroheme Biosynthesis ! ! ! ! Inteins ! ! ! ! ! Heat shock dnaK gene cluster extended ! Group II intron−Inositolassociated catabolism genes Inorganic SulfurGroEL Assimilation GroES ! GlyoxylateHydrogenases bypass Hydantoin metabolism ! ! ! ! ! ! ! Glycolysis and Gluconeogenesis, including Archaeal enzymes ! ! ! ! ! HPr kinase and hprK operon in Gram−positive organisms !! !! ! ! ! ! Glycolysis and Gluconeogenesis ! !! ! ! Homogentisate pathwayGlycolate, of aromatic glyoxylate compound interconversions degradation !

GlycogenHMG CoA metabolism Synthesis ! ! ! ! Glycine reductase, sarcosine reductase andHistidine betaine Degradation reductase ! GlycineHistidine cleavage Biosynthesis system ! ! ! ! ! ! High affinity phosphate transporter and controlGlycine of PHOBiosynthesis regulon ! ! ! ! ! Hfl operon ! ! Glycine and Serine Utilization ! ! ! ! Hexose Phosphate Uptake System !! ! ! ! ! ! ! Glycerolipid and Glycerophospholipid Metabolism in Bacteria ! !! ! GlycerolHeterocyst fermenation formation to in1,3 cyanobacteria−propanediol ! ! ! ! ! Hemin transport system ! ! ! ! Glycerol and Glycerol−3−phosphate Uptake and Utilization ! Heme, hemin uptakeGlutathionylspermidine and utilization systems and in GramPositivesTrypanothione ! ! ! Heme, hemin uptake and utilization systemsGlutathione: in GramNegatives Redox cycle ! ! ! ! Glutathione:Heme biosynthesisNon−redox reactions orphans ! Glutathione: BiosynthesisHeme and Sirohemegamma−glutamyl Biosynthesis cycle ! ! ! ! ! ! ! ! ! Glutathione−regulated potassiumHeat−efflux shock system dnaK and gene associated cluster extendedfunctions ! Group II intron−associatedGlutaredoxins genes ! ! ! ! GroEL GroES ! ! Glutamine, Glutamate, Aspartate and Asparagine Biosynthesis ! ! ! ! ! Glyoxylate bypass ! Glutamine synthetases ! ! ! ! ! ! ! ! ! ! Glycolysis and Gluconeogenesis, includingGlutamate Archaeal dehydrogenases enzymes ! ! ! ! ! ! ! ! ! ! ! Glutamate andGlycolysis Aspartate and uptakeGluconeogenesis in Bacteria ! !! ! ! ! ! Glycolate, glyoxylateGentisare interconversions degradation

! ! ! ! Galactosylceramide andGlycogen Sulfatide metabolism ! ! ! ! GlycineG3E familyreductase, of P− sarcosineloop GTPases reductase (metallocenter and betaine biosynthesis) reductase ! ! ! GlycineFructose cleavage utilization system ! ! ! ! Fructose and MannoseGlycine Inducible Biosynthesis PTS ! ! ! ! ! ! ! ! ! ! ! ! ! Glycine and Serine Utilization ! ! ! Fructooligosaccharides(FOS) and Raffinose Utilization ! !! ! ! ! ! ! ! Glycerolipid and Glycerophospholipid MetabolismFormate hydrogenase in Bacteria ! !! ! ! Formaldehyde assimilation:Glycerol Ribulose fermenation monophosphate to 1,3−propanediol pathway ! ! ! ! ! ! ! ! ! Glycerol and Glycerol−3−phosphate UptakeFolate and Biosynthesis Utilization !

Glutathionylspermidine and TrypanothioneFlavodoxin ! ! ! FlagellumGlutathione: in Campylobacter Redox cycle ! ! Glutathione: Non−redox Flagellumreactions ! ! Glutathione: Biosynthesis and gammaFlagellar−glutamyl motility cycle ! Glutathione−regulated Ferrouspotassium iron−efflux transporter system EfeUOB, and associated low−pH −functionsinduced ! Glutaredoxins ! Fermentations: Mixed acid ! ! ! ! ! ! ! ! ! ! !! ! ! ! ! ! Glutamine, Glutamate, Aspartate and AsparagineFermentations: Biosynthesis Lactate ! ! ! ! Glutamine synthetases ! ! ! ! Fatty Acid Biosynthesis FASII ! ! ! ! ! ! ! GlutamateF0F1−type dehydrogenases ATP synthase !!! ! ! ! Extracellular PolysaccharideGlutamate and AspartateBiosynthesis uptake of Streptococci in Bacteria ! ! Gentisare degradation Experimental−yggC ! GalactosylceramideExperimental−Ubiquinone and Sulfatide BiosynthesisVDC metabolism ! ! ! ! G3E family of P−loop GTPases (metallocenter biosynthesis) ! ! Experimental−PTPS ! ! Fructose utilization ! ! Experimental − Histidine Degradation ! ! ! FructoseExopolysaccharide and Mannose Inducible Biosynthesis PTS ! ! ! ! ! ! ! ! ! Fructooligosaccharides(FOS) and Raffinose Utilization ! ! Ethanolamine utilization ! ESAT−6 proteins secretionFormate system hydrogenasein Firmicutes ! ! Formaldehyde assimilation: Ribulose monophosphate pathway ! ! ! Entner−Doudoroff Pathway ! ! ! ! ! ! ! Encapsulating protein for DyP−type peroxidase and ferritin−likeFolate protein Biosynthesis oligomers Ectoine biosynthesis andFlavodoxin regulation ! ! ! ! ! Flagellum in Campylobacter ! EcsAB transporter affecting expression and secretion of secretory preproteins ! ! Flagellum !!! ! ! ! ECF class transporters ! ! ! dTDP−rhamnoseFlagellar synthesis motility ! ! ! ! Ferrous iron transporter EfeUOB, lowDOE−pH COG3533−induced ! ! Fermentations:DOE Mixed COG2016 acid ! ! ! ! ! ! ! ! ! ! ! !! !! !! ! Fermentations: Lactate !!! ! DNA−replication ! ! ! ! ! ! ! ! Fatty Acid Biosynthesis FASII ! ! ! ! ! ! DNA−binding regulatory proteins, strays ! ! ! !!!!! F0F1−type ATP synthase ! DNA topoisomerases, Type II, ATP−dependent ! ! ! ExtracellularDNA Polysaccharide topoisomerases, Biosynthesis Type I, ATP of− Streptococciindependent ! ! ! ! ! ! DNA structuralExperimental proteins, bacterial−yggC ! ! ! Experimental−UbiquinoneDNA replication, BiosynthesisVDC archaeal ! ! Experimental−PTPS !! ! DNA repair, UvrABC system ! ! DNA repair,Experimental bacterial UvrD − Histidineand related Degradation helicases ! ! ! ! Exopolysaccharide Biosynthesis ! DNA repair, bacterial RecFOR pathway ! !! ! ! ! Ethanolamine utilization !! DNA repair, bacterial MutL−MutS system ! ! ESAT−6DNA proteins repair, secretion bacterial system DinG inand Firmicutes relatives ! ! ! ! !!! !! ! !! Entner−Doudoroff Pathway ! ! ! !! ! DNA repair, bacterial ! ! ! ! ! Encapsulating protein for DyP−type peroxidase and ferritin−like protein oligomers ! ! ! ! DNA Repair Base Excision ! ! Ectoine biosynthesisDMT and transporter regulation ! ! ! ! EcsAB transporter affecting expression and secretion of secretory preproteins ! Dissimilatory nitrite reductase ! !!! ! DimethylarginineECF class transporters metabolism ! ! dTDPDihydroxyacetone−rhamnose synthesis kinases ! ! ! ! ! DOE COG3533 ! ! ! Deoxyribose and Deoxynucleoside Catabolism ! ! ! DOEDenitrification COG2016 ! ! ! !! !! !! ! ! !!! ! ! DNA−replication ! ! !! ! ! ! ! De Novo Pyrimidine Synthesis ! ! ! ! ! ! ! ! ! DNA−bindingDe regulatoryNovo Purine proteins, Biosynthesis strays ! ! ! ! ! DNA topoisomerases,D−tyrosyl Type−tRNA(Tyr) II, ATP− dependentdeacylase ! ! ! DNA topoisomerases,D−Tagatose Type and I,Galactitol ATP−independent Utilization ! ! ! ! ! ! D−Sorbitol(D−Glucitol)DNA structural and L−Sorbose proteins, Utilization bacterial ! ! ! DNA replication, archaeal ! ! ! D−ribose utilization ! ! !! D−gluconate andDNA ketogluconates repair, UvrABC metabolism system ! ! ! DNAD−Galacturonate repair, bacterial and UvrD D−Glucuronate and related Utilizationhelicases ! ! ! ! DNA repair, bacterialD−galactonate RecFOR catabolism pathway ! !! ! ! ! ! D−galactarate, DNAD−glucarate repair, bacterial and D−glycerate MutL−MutS catabolism system ! ! DNA repair, bacterial DDinG−allose and utilization relatives !! ! ! !! ! !! ! DNA repair, bacterial ! ! ! ! ! D−Alanyl Lipoteichoic Acid Biosynthesis !! ! ! ! ! ! ! DNA RepairCytR Base regulation Excision ! ! Cytolysin and LipaseDMT operon transporter in Vibrio ! DissimilatoryCysteine nitrite Biosynthesis reductase ! ! DimethylarginineCyanophycin metabolismMetabolism ! CyanobacterialDihydroxyacetone Circadian kinases Clock ! ! ! Deoxyribose and DeoxynucleosideCyanate Catabolism hydrolysis ! ! ! ! Denitrification ! ! ! CRISPRs !! ! ! ! ! ! CreatineDe and Novo Creatinine Pyrimidine Degradation Synthesis ! ! ! ! ! ! Copper homeostasis:De Novo Purine copper Biosynthesis tolerance ! ! ! ! D−tyrosyl−tRNA(Tyr)Copper homeostasis deacylase ! ! ! ! D−Tagatose and Galactitol Utilization ! ! Control of cell elongation − division cycle in Bacilli ! ! ! ! ! ! ! Conserved geneD−Sorbitol(D cluster possibly−Glucitol) involved and L− inSorbose RNA metabolism Utilization ! ! ! ! ! ! D−ribose utilization ! ! ! ! ! Conserved gene cluster associated with Met−tRNA formyltransferase ! ! ! Conserved cluster aroundD−gluconate acetyltransferase and ketogluconates YpeA in Enterobacteria metabolism ! ! ! ! D−GalacturonateConjugative and transposon,D−Glucuronate Bacteroidales Utilization !

D−galactonateConjugative catabolism transfer ! ! ! D−galactarate, D−glucarate and D−glycerate catabolism ! Competence or DNA damage−inducible protein CinA and related protein families !

D−allose utilization !! ! Common Pathway For Synthesis of Aromatic Compounds (DAHP synthase to chorismate) ! !! ! ! ! D−Alanyl Lipoteichoic Acid Biosynthesis !! ! Colanic acid biosynthesis ! ! CytR COG4319regulation Cytolysin and Lipase operonCOG3760 in Vibrio ! ! ! ! ! Cysteine Biosynthesis ! ! COG3533 ! ! ! CyanophycinCOG3380 Metabolism COG2907 CyanobacterialCOG3146 Circadian experimental Clock Cyanate hydrolysis ! COG2509 !! ! ! ! ! ! ! ! COG2363CRISPRs ! ! ! !! ! ! ! ! Creatine and Creatinine DegradationCOG2302 ! ! ! ! ! Copper homeostasis: copperCOG2078 tolerance ! ! ! Copper homeostasisCOG1836 ! ! ! ! Control of cell elongation − division cycleCOG1565 in Bacilli ! ! ! ! ! ! !!! ! ! Conserved gene cluster possibly involved in RNA metabolism ! ! COG1399 ! ! ! ! ! ! ! ! ! ! Conserved gene cluster associated with Met−tRNA formyltransferase ! ! ! ! COG0523 ! !! ! Conserved cluster around acetyltransferase YpeA in EnterobacteriaCOG0451 ! ! ! Conjugative transposon, BacteroidalesCOG0398 ! Conjugative transfer ! ! COG0277 ! ! Competence or DNA damage−inducible protein CinA andCoenzyme related proteinF420 synthesis families ! ! !! ! ! ! ! Common Pathway For Synthesis of Aromatic Compounds (DAHPCoenzyme synthase B12 to biosynthesischorismate) ! ! ! ! ! ! Colanic acid biosynthesis ! ! ! Coenzyme A Biosynthesis ! ! ! ! COG4319 ! Cobalt−zinc−cadmium resistance ! ! CobalaminCOG3760 synthesis ! ! ! ! ! CO2 uptake, carboxysomeCOG3533 ! ! ! CMP−N−acetylneuraminateCOG3380 Biosynthesis COG2907 ! Cluster−based Subsystem Grouping Hypotheticals − perhapsCOG3146 Proteosome experimental Related ! ! Cluster Ytf and putative sugar transporterCOG2509 !! ! ! ! ! ! ! Citrate Metabolism, Transport, and RegulationCOG2363 ! ! ! ! COG2302 ! ! ! ! Cinnamic Acid Degradation ! Chorismate: Intermediate for synthesis of Tryptophan, PAPA antibiotics, PABA, 3−hydroxyanthranilate COG2078and more. ! ! ! ! ! COG1836 !! Chorismate Synthesis ! !! CholineCOG1565 Transport ! !!! ! ! ! COG1399 !! ! ! ! Choline and Betaine Uptake and Betaine Biosynthesis ! ! ! ! ! ! ! Chlorophyll BiosynthesisCOG0523 ! !! ! ! ! Chloroaromatic degradationCOG0451 pathway !

Chitin and N−acetylglucosamineCOG0398 utilization ! ! ! ! Central meta−cleavage pathway of aromatic compound degradationCOG0277 ! ! ! ! Coenzyme F420 synthesis ! ! Cellulosome ! ! ! ! ! ! Cell envelope−associated LytR−CpsA−PsrCoenzyme transcriptional B12 biosynthesis attenuators ! ! ! ! CBSSCoenzyme−342610.3.peg.1536 A Biosynthesis ! !! ! ! ! ! Cobalt−CBSSzinc−cadmium−262719.3.peg.410 resistance !! ! CBSSCobalamin−196620.1.peg.2477 synthesis ! ! ! ! CBSSCO2 uptake,−176280.1.peg.1561 carboxysome ! ! ! CMP−N−acetylneuraminate Biosynthesis ! Catechol branch of beta−ketoadipate pathway ! ! Cluster−based Subsystem Grouping Hypotheticals − perhaps ProteosomeCarotenoids Related ! !

Cluster Ytf and putative sugarCarboxysome transporter ! Citrate Metabolism,carbazol Transport, degradation and Regulation cluster Capsular surfaceCinnamic virulence Acid Degradation antigen loci ! ! ! Chorismate: Intermediate for synthesis of Tryptophan, PAPACapsular antibiotics, Polysaccharides PABA, 3−hydroxyanthranilate Biosynthesis and andAssembly more. ! ! ! ! !! ! Capsular Polysaccharide (CPS)Chorismate of Campylobacter Synthesis ! !! ! ! Capsular heptoseCholine biosynthesis Transport ! ! ! ! Choline and Betaine Uptake and Betaine Biosynthesis ! ! ! ! ! ! ! ! Campylobacter Iron Metabolism ! cAMPChlorophyll signaling Biosynthesis in bacteria ! !

! ! ! ! ! ! Chloroaromatic degradation pathway ! Calvin−Benson cycle ! ! Chitin and N−acetylglucosamineButanol Biosynthesis utilization ! ! ! ! ! Central meta−cleavage pathwayBranched of −aromaticChain Amino compound Acid Biosynthesis degradation ! ! ! ! Biphenyl CellulosomeDegradation ! ! !

! Cell envelope−associated LytR−CpsABiotin−Psr biosynthesistranscriptional Experimental attenuators !

CBSS−342610.3.peg.1536 ! !! Biotin biosynthesis ! ! ! ! BiogenesisCBSS of c−−262719.3.peg.410type cytochromes ! ! ! ! Biofilm formationCBSS−196620.1.peg.2477 in Staphylococcus ! ! ! ! Beta−lactamaseCBSS cluster−176280.1.peg.1561 in Streptococcus ! ! ! ! ! !! Catechol branch of beta−ketoadipate pathway ! ! Beta−lactamase ! ! ! ! ! Beta−GlucosideCarotenoids Metabolism ! ! Carboxysome ! ! Benzoate transport and degradation cluster ! carbazolBenzoate degradation degradation cluster Capsular surfaceBacteriocin virulence−like peptides antigen lociBlp Capsular Polysaccharides Biosynthesis and Assembly ! ! ! ! Bacterial signal recognition particle (SRP) ! ! ! ! Capsular Polysaccharide (CPS) of Campylobacter ! ! Bacterial RNA−metabolizing Zn−dependent hydrolases ! ! ! CapsularBacterial heptose hemoglobinsbiosynthesis ! ! ! ! ! ! ! ! ! ! Campylobacter Iron Metabolism ! ! ! ! ! Bacterial Cytoskeleton ! !!!! Bacterial cyanide production andcAMP tolerance signaling mechanisms in bacteria ! ! ! ! ! ! ! BacterialCalvin−Benson Chemotaxis cycle ! ! ! ! ! !!! ! Butanol Biosynthesis ! ! ! ! ! Bacterial Cell Division ! ! !! ! ! ! Bacillus biofilm matrixBranched protein− componentChain Amino TasA Acid and Biosynthesis homologs BiphenylAuxin biosynthesisDegradation ! Autoinducer 2 (AI−2) transport and processingBiotin biosynthesis (lsrACDBFGE Experimental operon) ! Biotin biosynthesis !! ! ATP−dependent RNA helicases, bacterial ! ! ! ! ! BiogenesisATP of− dependentc−type cytochromes Nuclease ! ! ! ! ! Biofilm formation in StaphylococcusAt5g63420 ! ! ! ! ! Beta−lactamase cluster in Streptococcus ! At5g48545 and At3g56490 At1g31160 ! ! ! ! ! ! ! Beta−At5g38900lactamase ! ! ! ! ! ! ! ! Beta−Glucoside MetabolismAt5g37530 ! ! ! Benzoate transport and degradation cluster ! At5g11840 At5g67370 ! ! At5g04520Benzoate degradationAT1G06240 ! ! Bacteriocin−like peptides Blp ! ! At4g38090 ! ! ! ! ! ! Bacterial signal recognition particle (SRP) ! ! ! ! At4g10620 At3g57180 At3g47450 ! ! ! ! Bacterial RNA−metabolizing Zn−dependent hydrolasesAt3g50560 ! ! ! Bacterial hemoglobins ! At3g21300 ! ! ! ! ! Bacterial Cytoskeleton ! ! !!!! ! ! At2g33980 At1g28960 ! ! Bacterial cyanide production and tolerance mechanisms ! ! At2g23840 ! At1g69340Bacterial Chemotaxis At2g40600 ! ! ! !!! ! ! ! ! ! ! Bacterial CellAt1g54520 Division ! ! !! ! ! ! Bacillus biofilm matrix protein component TasA andAt1g48360 homologs At1g26220Auxin biosynthesis At1g32070 ! ! Autoinducer 2 (AI−2) transport and processing (lsrACDBFGE operon) At1g21350 ! ! ! ATP−dependent RNA helicases, bacterial ! At1g14345 !! ATP−dependent Nuclease ! ! ! Arsenic resistance ! ! ! Aromatic amino acid interconversions withAt5g63420 aryl acids ! ! ! ! At5g48545Aromatic and amino At3g56490 acid degradation At1g31160 ! ! ! ! Aromatic Amin CatabolismAt5g38900 ! ! ! Arginine DeiminaseAt5g37530 Pathway ! ! ! Arginine At5g11840Biosynthesis At5g67370 extended ! ! At5g04520 AT1G06240 ! ! ! ! Arginine and Ornithine Degradation ! ! ! ! ! At4g38090 ! ! ! ! Archaeal lipids ! ! ! ! ! ! ! ! ! At4g10620 At3g57180 At3g47450 ! ! Anaerobic respiratory reductases ! ! At3g50560 ! ! Ammonia assimilation ! ! ! Aminoglycoside adenylyltransferasesAt3g21300 ! ! AlphaAt2g33980−acetolactate At1g28960 operon ! ! ! !! AllantoinAt2g23840 Utilization ! AlkylphosphonateAt1g69340 At2g40600 utilization ! ! AlkanesulfonatesAt1g54520 Utilization Alkanesulfonate assimilationAt1g48360 ! At1g26220Alginate metabolismAt1g32070 ! ! ! Alanine biosynthesisAt1g21350 ! ! ! ! Agrobacterium opineAt1g14345 transport !! ! Arsenic resistance ! ! ! ! Aerotolerance operon in Bacteroides and potentially orthologous operons in other organisms ! ! Aromatic amino acid interconversionsAdhesion of Campylobacter with aryl acids ! AromaticAdhesins amino in acid Staphylococcus degradation ! AromaticAdenosyl Amin nucleosidases Catabolism ! ArginineAcid resistance Deiminase mechanisms Pathway ! Arginine Biosynthesis extended ! Acetyl−CoA fermentation to Butyrate ! ! ! ! ! ! ArginineAcetoin, and butanediolOrnithine Degradation metabolism ! ! ! ! ! ! ABC transporter peptide Archaeal(TC 3.A.1.5.5) lipids ! ! ! ! ! ABC transporterAnaerobic oligopeptide respiratory (TC reductases 3.A.1.5.1) ! !! ! ! ! ! ABC transporter dipeptideAmmonia (TC assimilation 3.A.1.5.2) ! ABC transporter branchedAminoglycoside−chain amino adenylyltransferases acid (TC 3.A.1.4.1) ! ABC transporter alkylphosphonateAlpha−acetolactate (TC 3.A.1.9.1) operon ! ! ! Allantoin Utilization ! !! ! ! 5−FCL−like protein ! ! 4−HydroxyphenylaceticAlkylphosphonate acid catabolic utilization pathway 2Alkanesulfonates−phosphoglycolate Utilization salvage ! ! Alkanesulfonate2−Ketogluconate assimilation Utilization !

! ! ! Alginate metabolism ! 16S rRNA modification within P site of ribosome ! ! ! Alanine biosynthesis ! ! Agrobacterium opine transport

! ! Aerotolerance operon in Bacteroides and potentially orthologous operons in other organisms ! ! ! Adhesion of Campylobacter ! Adhesins in Staphylococcus ! Adenosyl nucleosidases

Acid resistance mechanisms ! ! Acetyl−CoA fermentation to Butyrate ! ! !

Acetoin, butanediol metabolism ! ! ABC transporter peptide (TC 3.A.1.5.5) ! ABC transporter oligopeptide (TC 3.A.1.5.1) ! !! ABC transporter dipeptide (TC 3.A.1.5.2) ABC transporter branched−chain amino acid (TC 3.A.1.4.1) ABC transporter alkylphosphonate (TC 3.A.1.9.1) ! ! ! !! ! ! 5−FCL−like protein ! ! 4−Hydroxyphenylacetic acid catabolic pathway 2−phosphoglycolate salvage ! ! 2−Ketogluconate Utilization !

! ! 16S rRNA modification within P site of ribosome ! ! !

−10 −5 0 5 10 Median Absolute Log2 Difference

−10 −5 0 5 10 Median Absolute Log2 Difference Color Key − Value 2 2

Unknown Iron acquisition and metabolism Sulfur Metabolism Nitrogen Metabolism Motility and Chemotaxis Secondary Metabolism Dormancy and Sporulation Fatty Acids, Lipids, and Isoprenoids Phosphorus Metabolism Miscellaneous Amino Acids and Derivatives Potassium metabolism Phages, Prophages, Transposable elements, Plasmids Metabolism of Aromatic Compounds Respiration Cofactors, Vitamins, Prosthetic Groups, Pigments Stress Response Cell Wall and Capsule Virulence, Disease and Defense Membrane Transport Carbohydrates Regulation and Cell signaling Protein Metabolism Cell Division and Cell Cycle Nucleosides and Nucleotides RNA Metabolism DNA Metabolism Clustering−based subsystems B31_avg B27_avg N30_avg N4_avg − 5 Color Key Value 0 5

Siderophores Protein secretion system, Type V Histidine Metabolism Protein secretion system, Type II Proteolytic pathway Sodium Ion−Coupled Energetics Organic sulfur assimilation Plant Hormones Branched−chain amino acids Aromatic amino acids and derivatives Tetrapyrroles Glycoside hydrolases Inorganic sulfur assimilation Acid stress Biologically active compounds in metazoan cell defence and differentiation Polysaccharides proteosome related Gram−Negative cell wall components Electron donating reactions Invasion and intracellular resistance Osmotic stress Unknown Metabolism of central aromatic intermediates Adhesion Phages, Prophages Transposable elements Flagellar motility in Prokaryota Quinone cofactors Protein and nucleoprotein secretion system, Type IV Biotin Protein processing and modification Lipoic acid Organic acids Arginine; urea cycle, polyamines Proline and 4−hydroxyproline Sugar alcohols Carbohydrates Monosaccharides Selenoproteins CRISPs Aminosugars Peripheral pathways for catabolism of aromatic compounds Toxins and superantigens Fermentation Oxidative stress Alanine, serine, and glycine Capsular and extracellular polysacchrides Folate and pterines One−carbon Metabolism Glutamine, glutamate, aspartate, asparagine; ammonia assimilation Programmed Cell Death and Toxin−antitoxin Systems Coenzyme F420 Sugar Phosphotransferase Systems, PTS Bacteriocins, ribosomally synthesized antibacterial peptides Triacylglycerols Protein biosynthesis DNA replication Detection DNA recombination Pyrimidines Cell wall of Mycobacteria Riboflavin, FMN, FAD Transcription ATP synthases Purines Pyridoxine Heat shock Fatty acid metabolic cluster Regulation of virulence NAD and NADP Coenzyme A Fatty acids Protein folding Isoprenoids Protein degradation Phospholipids DNA polymerase III epsilon cluster Quorum sensing and biofilm formation Resistance to antibiotics and toxic compounds Lysine, threonine, methionine, and cysteine Central carbohydrate metabolism Electron accepting reactions Di− and oligosaccharides Pathogenicity islands Detoxification Gram−Positive cell wall components Clustering−based subsystems DNA repair ABC transporters CO2 fixation Protein translocation across cytoplasmic membrane Plant−Prokaryote DOE project RNA processing and modification B31_avg B27_avg N30_avg N4_avg − 5 0 Color Key Value 5 10

Mercury resistance operon Inositol catabolism COG2078 Siderophore Pyoverdine Taurine Utilization Ycd cluster (putative 2−hydroxyacid dehydrogenase) Widespread colonization island p−Aminobenzoyl−Glutamate Utilization Orphan regulatory proteins Hydrogenases Urea decomposition Transport of Nickel and Cobalt Transport of Molybdenum Agrobacterium opine transport Glutathione: Biosynthesis and gamma−glutamyl cycle Histidine Biosynthesis Cluster Ytf and putative sugar transporter Listeria phi−A118−like prophages Lysine degradation Two partner secretion pathway (TPS) Aminoglycoside adenylyltransferases Streptococcus pyogenes recombinatorial zone At1g48360 Protein YjgK cluster linked to biofilm formation Choline Transport Cytolysin and Lipase operon in Vibrio At3g50560 Muconate lactonizing enzyme family Ferrous iron transporter EfeUOB, low−pH−induced Terminal cytochrome C oxidases Regulatory Intramembrane Proteolysis Pathways Siderophore Aerobactin Nitric oxide synthase HMG CoA Synthesis Spore Coat D−galactonate catabolism Formate hydrogenase Glutathionylspermidine and Trypanothione Unknown sugar utilization (cluster yphABCDEFG) At5g38900 Hydantoin metabolism Listeria surface proteins: LPXTG motif Capsular surface virulence antigen loci D−allose utilization Mercuric reductase COG0398 Aromatic amino acid interconversions with aryl acids Cyanobacterial Circadian Clock Membrane−bound Ni, Fe−hydrogenase Chlorophyll Biosynthesis Luciferases Putative diaminopropionate ammonia−lyase cluster NiFe hydrogenase maturation 4−Hydroxyphenylacetic acid catabolic pathway Aromatic amino acid degradation Threonine degradation ESAT−6 proteins secretion system in Firmicutes Utilization of glutathione as a sulphur source Nitrate and nitrite ammonification Type IV pilus Na+ translocating decarboxylases and related biotin−dependent enzymes Hemin transport system Pseudouridine catabolism p−Hydroxybenzoate degradation Phenylpropanoid compound degradation Heme, hemin uptake and utilization systems in GramNegatives Twin−arginine translocation system Chorismate: Intermediate for synthesis of Tryptophan, PAPA antibiotics, PABA, 3−hydroxyanthranilate and more. Conjugative transfer Trehalose Biosynthesis Sporulation gene orphans Cobalamin synthesis Branched−Chain Amino Acid Biosynthesis G3E family of P−loop GTPases (metallocenter biosynthesis) Methylcitrate cycle Leucine Biosynthesis Nitrosative stress Propanediol utilization Auxin biosynthesis Ethanolamine utilization Soluble cytochromes and functionally related electron carriers Methylglyoxal Metabolism Coenzyme B12 biosynthesis Allantoin Utilization Tryptophan synthesis Alkanesulfonates Utilization Omega−amidase Streptococcus pneumoniae Vancomycin Tolerance Locus Putative sulfate assimilation cluster Nitrogen fixation Methionine Salvage Phosphorylcholine incorporation in LPS Molybdenum cofactor biosynthesis Glutathione: Non−redox reactions Acetyl−CoA fermentation to Butyrate Transcription initiation, bacterial sigma factors Phenylalanine and Tyrosine Branches from Chorismate Pterin biosynthesis Homogentisate pathway of aromatic compound degradation SigmaB stress responce regulation Toxin−antitoxin replicon stabilization systems Bacillus biofilm matrix protein component TasA and homologs Experimental−Ubiquinone BiosynthesisVDC Sulfur oxidation Periplasmic disulfide interchange Multidrug efflux pump in Campylobacter jejuni (CmeABC operon) Siderophore Enterobactin Glycine cleavage system Unknown carbohydrate utilization (cluster Yeg) Propionyl−CoA to Succinyl−CoA Module ABC transporter branched−chain amino acid (TC 3.A.1.4.1) Niacin−Choline transport and metabolism Polyhydroxybutyrate metabolism Flagellum D−galactarate, D−glucarate and D−glycerate catabolism Unknown D−Galacturonate and D−Glucuronate Utilization Poly−gamma−glutamate biosynthesis Choline and Betaine Uptake and Betaine Biosynthesis Bacterial hemoglobins Histidine Degradation Denitrification CytR regulation L−Arabinose utilization Encapsulating protein for DyP−type peroxidase and ferritin−like protein oligomers COG3533 Cysteine Biosynthesis Aromatic Amin Catabolism V−Type ATP synthase Catechol branch of beta−ketoadipate pathway Selenocysteine metabolism L−fucose utilization L−fucose utilization temp Tetrathionate respiration Steroid sulfates At1g21350 Conserved cluster around acetyltransferase YpeA in Enterobacteria Putative sugar ABC transporter (ytf cluster) Alkylphosphonate utilization Alpha−acetolactate operon MukBEF Chromosome Condensation L−Cystine Uptake and Metabolism Acetoin, butanediol metabolism Neotrehalosadiamine (NTD) Biosynthesis Operon Ubiquinone Biosynthesis carbazol degradation cluster L−rhamnose utilization Tn552 Creatine and Creatinine Degradation Dimethylarginine metabolism Lactose utilization Fructose and Mannose Inducible PTS Formaldehyde assimilation: Ribulose monophosphate pathway Predicted carbohydrate hydrolases Capsular Polysaccharides Biosynthesis and Assembly Inorganic Sulfur Assimilation Isobutyryl−CoA to Propionyl−CoA Module Alkanesulfonate assimilation Acid resistance mechanisms Zinc resistance Experimental−yggC Campylobacter Iron Metabolism Iron acquisition in Streptococcus Biogenesis of c−type cytochromes Hexose Phosphate Uptake System Listeria Pathogenicity Island LIPI−1 extended Cellulosome Xyloglucan Utilization Aerotolerance operon in Bacteroides and potentially orthologous operons in other organisms Colanic acid biosynthesis Xanthosine utilization (xap region) Capsular Polysaccharide (CPS) of Campylobacter Inteins Rubrerythrin dTDP−rhamnose synthesis Lipid A−Ara4N pathway (Polymyxin resistance) Pyrroloquinoline Quinone biosynthesis Cluster−based Subsystem Grouping Hypotheticals − perhaps Proteosome Related Capsular heptose biosynthesis Lipopolysaccharide assembly Benzoate transport and degradation cluster Iron acquisition in Vibrio Glycogen metabolism Valine degradation Chorismate Synthesis Flagellar motility Gentisare degradation Butanol Biosynthesis Heme and Siroheme Biosynthesis Common Pathway For Synthesis of Aromatic Compounds (DAHP synthase to chorismate) ABC transporter dipeptide (TC 3.A.1.5.2) Na(+)−translocating NADH−quinone oxidoreductase and rnf−like group of electron transport complexes Transport of Iron Copper homeostasis: copper tolerance Polysaccharide deacetylases KDO2−Lipid A biosynthesis LOS core oligosaccharide biosynthesis Cell envelope−associated LytR−CpsA−Psr transcriptional attenuators Cyanate hydrolysis Staphylococcal accessory gene regulator system TCA Cycle Rrf2 family transcriptional regulators Flagellum in Campylobacter DNA−binding regulatory proteins, strays Arsenic resistance Bacterial Chemotaxis Biotin biosynthesis Experimental YhgI, YhgH Conjugative transposon, Bacteroidales Multidrug Resistance Efflux Pumps Salicylate and gentisate catabolism Potassium homeostasis Teichuronic acid biosynthesis Arginine Biosynthesis extended Lipoic acid metabolism COG3380 COG2907 Quinate degradation Listeria surface proteins: Internalin−like proteins Experimental − Histidine Degradation Arginine and Ornithine Degradation Propionate−CoA to Succinate Module Biotin biosynthesis Proline Synthesis Isoleucine degradation Rhamnose containing glycans Ribonuclease H Respiratory dehydrogenases 1 Thiamin biosynthesis Alginate metabolism Ammonia assimilation Oxidative stress Glutathione: Redox cycle Peptidyl−prolyl cis−trans isomerase Glutaredoxins CRISPRs N−linked Glycosylation in Bacteria Lacto−N−Biose I and Galacto−N−Biose Metabolic Pathway N−Acetyl−Galactosamine and Galactosamine Utilization Beta−lactamase Translation elongation factor G family YcfH Streptococcus pyogenes Virulome ATP−dependent RNA helicases, bacterial At5g04520 AT1G06240 Hfl operon Glycine and Serine Utilization Pyruvate metabolism I: anaplerotic reactions, PEP Legionaminic Acid Biosynthesis D−gluconate and ketogluconates metabolism Peptide methionine sulfoxide reductase D−Sorbitol(D−Glucitol) and L−Sorbose Utilization Uncharacterized sugar kinase cluster (ygc) Extracellular Polysaccharide Biosynthesis of Streptococci Resistance to Vancomycin DNA repair, bacterial UvrD and related helicases Proline, 4−hydroxyproline uptake and utilization Salicylate ester degradation Xylose utilization Adhesins in Staphylococcus Chloroaromatic degradation pathway Galactosylceramide and Sulfatide metabolism Exopolysaccharide Biosynthesis Central meta−cleavage pathway of aromatic compound degradation Autoinducer 2 (AI−2) transport and processing (lsrACDBFGE operon) Heterocyst formation in cyanobacteria Glycine reductase, sarcosine reductase and betaine reductase Protocatechuate branch of beta−ketoadipate pathway Heme, hemin uptake and utilization systems in GramPositives DNA repair, bacterial DinG and relatives MazEF toxin−antitoxing (programmed cell death) system Photorespiration (oxidative C2 cycle) Chitin and N−acetylglucosamine utilization DOE COG3533 cAMP signaling in bacteria Sortase ECF class transporters Staphylococcal phi−Mu50B−like prophages Streptolysin S Biosynthesis and Transport Biphenyl Degradation Unknown carbohydrate utilization (cluster Ydj) Beta−Glucoside Metabolism Alanine biosynthesis COG3760 Leucine Degradation and HMG−CoA Metabolism ZZ gjo need homes 2−phosphoglycolate salvage CBSS−196620.1.peg.2477 CBSS−176280.1.peg.1561 Glutamate and Aspartate uptake in Bacteria Unknown carbohydrate utilization containing Fructose−bisphosphate aldolase Serotype determining Capsular polysaccharide biosynthesis in Staphylococcus Putative hemin transporter Ectoine biosynthesis and regulation Coenzyme F420 synthesis 2−Ketogluconate Utilization Phage shock protein (psp) operon Bacteriocin−like peptides Blp Melibiose Utilization Sucrose utilization Copper homeostasis Phage capsid proteins Sucrose utilization Shewanella Teichoic and lipoteichoic acids biosynthesis HPr kinase and hprK operon in Gram−positive organisms Fructooligosaccharides(FOS) and Raffinose Utilization Sex pheromones in Enterococcus faecalis and other Firmicutes At4g38090 Synechocystis experimental Ketoisovalerate oxidoreductase Lactose and Galactose Uptake and Utilization D−Tagatose and Galactitol Utilization Trehalose Uptake and Utilization Staphylococcal pathogenicity islands SaPI Pyruvate metabolism II: acetyl−CoA, acetogenesis from pyruvate At1g69340 At2g40600 Unspecified monosaccharide transport cluster Transport of Manganese Cobalt−zinc−cadmium resistance Glycolate, glyoxylate interconversions Anaerobic respiratory reductases Nudix proteins (nucleoside triphosphate hydrolases) DNA repair, bacterial MutL−MutS system Biofilm formation in Staphylococcus Ribosome biogenesis bacterial Iron−sulfur cluster assembly Sugar utilization in Thermotogales At2g33980 At1g28960 Methionine Biosynthesis D−ribose utilization Mannose Metabolism Deoxyribose and Deoxynucleoside Catabolism Methionine Degradation Beta−lactamase cluster in Streptococcus Pyruvate:ferredoxin oxidoreductase Heme biosynthesis orphans Yfa cluster Respiratory Complex I Nucleoside triphosphate pyrophosphohydrolase MazG Lipid A modifications Dissimilatory nitrite reductase Quinolinic acid and its derivatives Glutamate dehydrogenases Ton and Tol transport systems Pterin carbinolamine dehydratase polyprenyl synthesis At1g54520 SpeB−SpeF extended regulon Glutamine synthetases linker unit−arabinogalactan synthesis Peripheral Glucose Catabolism Pathways COG0451 COG0277 DNA structural proteins, bacterial Succinate dehydrogenase tRNA aminoacylation, Glu and Gln mycolic acid synthesis Protein chaperones Pyridoxin (Vitamin B6) Biosynthesis Pentose phosphate pathway Adenosyl nucleosidases Pterin metabolism YjeE COG4319 DMT transporter Terminal cytochrome oxidases Terminal cytochrome d ubiquinol oxidases Threonine anaerobic catabolism gene cluster Proteasome bacterial Iojap Bacterial Cytoskeleton At2g23840 YebC Heat shock dnaK gene cluster extended Calvin−Benson cycle Glycolysis and Gluconeogenesis tRNA processing tRNAmodification position 34 COG1399 Phosphate metabolism Pyruvate Alanine Serine Interconversions tRNA modification Archaea Scaffold proteins for [4Fe−4S] cluster assembly (MRP family) Conserved gene cluster possibly involved in RNA metabolism Murein hydrolase regulation and cell death YggW Coenzyme A Biosynthesis Fatty Acid Biosynthesis FASII Queuosine−Archaeosine Biosynthesis Menaquinone and Phylloquinone Biosynthesis Streptococcal Mga Regulon Serine Biosynthesis Glycine Biosynthesis YgfZ−Iron Adhesion of Campylobacter Purine Utilization Polyadenylation bacterial YbbK Lactate utilization RNA processing and degradation, bacterial NAD regulation Carotenoids YgfZ Serine−glyoxylate cycle 5−FCL−like protein NAD and NADP cofactor biosynthesis global Polyamine Metabolism n−Phenylalkanoic acid degradation Glyoxylate bypass Carboxysome Flavodoxin COG3146 experimental Methanopterin biosynthesis2 Pterin metabolism 3 COG1565 Lipopolysaccharide−related cluster in Alphaproteobacteria Ribosomal protein S12p Asp methylthiotransferase Menaquinone Biosynthesis via Futalosine COG1836 Stringent Response, (p)ppGpp metabolism PnuC−like transporters Protein degradation Glycerol fermenation to 1,3−propanediol Folate Biosynthesis DNA topoisomerases, Type I, ATP−independent Polyprenyl Diphosphate Biosynthesis Entner−Doudoroff Pathway Isoprenoid Biosynthesis Cinnamic Acid Degradation One−carbon metabolism by tetrahydropterines DNA repair, bacterial tRNA modification Bacteria Thioredoxin−disulfide reductase Two−component regulatory systems in Campylobacter Ribosome activity modulation Transport of Zinc Experimental−PTPS Competence or DNA damage−inducible protein CinA and related protein families COG2363 Restriction−Modification System De Novo Purine Biosynthesis YeiH Proteolysis in bacteria, ATP−dependent mcm5s2U biosynthesis in tRNA Glutamine, Glutamate, Aspartate and Asparagine Biosynthesis Glycerol and Glycerol−3−phosphate Uptake and Utilization Glycerolipid and Glycerophospholipid Metabolism in Bacteria CBSS−342610.3.peg.1536 Group II intron−associated genes Ribosome LSU bacterial Ribosome SSU bacterial GroEL GroES F0F1−type ATP synthase Ribosomal protein S5p acylation Plasmid replication Redox−dependent regulation of nucleus processes Translation initiation factors eukaryotic and archaeal Transcription factors cyanobacterial RpoD−like sigma factors D−Alanyl Lipoteichoic Acid Biosynthesis Fermentations: Lactate YgjD and YeaZ RNA polymerase bacterial Translation elongation factors eukaryotic and archaeal Universal stress protein family At3g21300 Macromolecular synthesis operon ABC transporter oligopeptide (TC 3.A.1.5.1) tRNA aminoacylation, Asp and Asn pVir Plasmid of Campylobacter UDP−N−acetylmuramate from Fructose−6−phosphate Biosynthesis tRNA nucleotidyltransferase Cyanophycin Metabolism At5g11840 At5g67370 Pyrimidine utilization Quorum Sensing: Autoinducer−2 Synthesis DOE COG2016 Trans−translation by stalled ribosomes At1g14345 Programmed frameshift Signal peptidase Bacterial signal recognition particle (SRP) Fermentations: Mixed acid Wyeosine−MimG Biosynthesis DNA topoisomerases, Type II, ATP−dependent tRNA modification yeast mitochondrial rRNA modification Archaea Universal GTPases Two cell division clusters relating to chromosome partitioning COG2302 CO2 uptake, carboxysome ABC transporter alkylphosphonate (TC 3.A.1.9.1) L−ascorbate utilization (and related gene clusters) Citrate Metabolism, Transport, and Regulation At1g26220 At1g32070 CMP−N−acetylneuraminate Biosynthesis Triacylglycerol metabolism Arginine Deiminase Pathway Riboflavin, FMN and FAD metabolism Bacterial cyanide production and tolerance mechanisms DNA repair, UvrABC system At5g37530 Archaeal lipids PROSC Fructose utilization rRNA modification Bacteria Sialic Acid Metabolism ATP−dependent Nuclease Methicillin resistance in Staphylococci Lysine Biosynthesis DAP Pathway YrdC−YciO−Sua5 protein family mnm5U34 biosynthesis bacteria Ribitol, Xylitol, Arabitol, Mannitol and Sorbitol utilization DNA−replication At4g10620 At3g57180 At3g47450 Dihydroxyacetone kinases Benzoate degradation Glutathione−regulated potassium−efflux system and associated functions At5g48545 and At3g56490 At1g31160 Maltose and Maltodextrin Utilization tRNA modification yeast cytoplasmic Peptidoglycan Biosynthesis Bacterial RNA−metabolizing Zn−dependent hydrolases LMPTP YwlE cluster COG0523 DNA replication, archaeal Bacterial Cell Division COG2509 16S rRNA modification within P site of ribosome DNA repair, bacterial RecFOR pathway RuvABC plus a hypothetical Transcription factors bacterial De Novo Pyrimidine Synthesis Glycolysis and Gluconeogenesis, including Archaeal enzymes ABC transporter peptide (TC 3.A.1.5.5) CBSS−262719.3.peg.410 YaaA Threonine and Homoserine Biosynthesis Ubiquinone Menaquinone−cytochrome c reductase complexes EcsAB transporter affecting expression and secretion of secretory preproteins Mannitol Utilization DNA Repair Base Excision Control of cell elongation − division cycle in Bacilli High affinity phosphate transporter and control of PHO regulon LMPTP YfkJ cluster D−tyrosyl−tRNA(Tyr) deacylase Conserved gene cluster associated with Met−tRNA formyltransferase At5g63420 NusA−TFII Cluster Ribonucleotide reduction Xanthine Metabolism in Bacteria Purine conversions Resistance to fluoroquinolones MLST B31_avg B27_avg N30_avg N4_avg 16S rRNA modification within P site of ribosome

2−Ketogluconate Utilization

2−phosphoglycolate salvage

5−FCL−like protein

ABC transporter alkylphosphonate (TC 3.A.1.9.1)

ABC transporter oligopeptide (TC 3.A.1.5.1)

ATP−dependent Nuclease

ATP−dependent RNA helicases, bacterial

Acetoin, butanediol metabolism

Adhesins in Staphylococcus

Adhesion of Campylobacter

Alanine biosynthesis

Allantoin Utilization

Alpha−acetolactate operon

Ammonia assimilation

Anaerobic respiratory reductases

Archaeal lipids

Arginine Deiminase Pathway

Arginine and Ornithine Degradation

Arsenic resistance

At1g69340 At2g40600

At2g23840

At2g33980 At1g28960

At4g10620 At3g57180 At3g47450

At5g04520 AT1G06240

At5g37530

At5g63420

Bacterial Cell Division

Bacterial Cytoskeleton

Bacterial RNA−metabolizing Zn−dependent hydrolases

Bacterial signal recognition particle (SRP)

Beta−Glucoside Metabolism

Beta−lactamase

Beta−lactamase cluster in Streptococcus

Biofilm formation in Staphylococcus

Biotin biosynthesis

Biphenyl Degradation

CBSS−176280.1.peg.1561

CBSS−196620.1.peg.2477

CBSS−262719.3.peg.410

CBSS−342610.3.peg.1536

CMP−N−acetylneuraminate Biosynthesis

COG0523

COG1399

COG1565

COG2302

COG2363

COG3533

Calvin−Benson cycle

Campylobacter Iron Metabolism

Capsular Polysaccharides Biosynthesis and Assembly

Carboxysome

Carotenoids

Catechol branch of beta−ketoadipate pathway

Central meta−cleavage pathway of aromatic compound degradation

Chitin and N−acetylglucosamine utilization

Chloroaromatic degradation pathway

Choline and Betaine Uptake and Betaine Biosynthesis

Cinnamic Acid Degradation

Cobalt−zinc−cadmium resistance

Coenzyme A Biosynthesis

Coenzyme B12 biosynthesis

Coenzyme F420 synthesis

Competence or DNA damage−inducible protein CinA and related protein families

Conserved gene cluster associated with Met−tRNA formyltransferase

Control of cell elongation − division cycle in Bacilli

Copper homeostasis

Cyanophycin Metabolism

Cysteine Biosynthesis

D−Alanyl Lipoteichoic Acid Biosynthesis

D−Galacturonate and D−Glucuronate Utilization

D−Sorbitol(D−Glucitol) and L−Sorbose Utilization

D−Tagatose and Galactitol Utilization

D−galactarate, D−glucarate and D−glycerate catabolism

D−gluconate and ketogluconates metabolism

D−ribose utilization

D−tyrosyl−tRNA(Tyr) deacylase

DNA Repair Base Excision

DNA repair, UvrABC system

DNA repair, bacterial

DNA repair, bacterial DinG and relatives

DNA repair, bacterial MutL−MutS system

DNA repair, bacterial RecFOR pathway

DNA repair, bacterial UvrD and related helicases

DNA structural proteins, bacterial

DNA topoisomerases, Type I, ATP−independent

DNA topoisomerases, Type II, ATP−dependent

DNA−binding regulatory proteins, strays

DNA−replication

De Novo Purine Biosynthesis

De Novo Pyrimidine Synthesis

Deoxyribose and Deoxynucleoside Catabolism

ECF class transporters

Ectoine biosynthesis and regulation

Entner−Doudoroff Pathway

Ethanolamine utilization

Exopolysaccharide Biosynthesis

Extracellular Polysaccharide Biosynthesis of Streptococci

F0F1−type ATP synthase

Fatty Acid Biosynthesis FASII

Fermentations: Lactate

Fermentations: Mixed acid

Flagellum

Flagellum in Campylobacter

Folate Biosynthesis

Fructooligosaccharides(FOS) and Raffinose Utilization

Fructose and Mannose Inducible PTS

Fructose utilization

Galactosylceramide and Sulfatide metabolism

Glutamate and Aspartate uptake in Bacteria

Glutamine synthetases

Glutamine, Glutamate, Aspartate and Asparagine Biosynthesis

Glutathione: Redox cycle

Glycerol and Glycerol−3−phosphate Uptake and Utilization

Glycerolipid and Glycerophospholipid Metabolism in Bacteria

Glycine and Serine Utilization

Glycine reductase, sarcosine reductase and betaine reductase

Glycolate, glyoxylate interconversions

Glycolysis and Gluconeogenesis

Glycolysis and Gluconeogenesis, including Archaeal enzymes

HPr kinase and hprK operon in Gram−positive organisms

Heat shock dnaK gene cluster extended

Heme and Siroheme Biosynthesis

Heme, hemin uptake and utilization systems in GramPositives

High affinity phosphate transporter and control of PHO regulon

Iojap

Iron−sulfur cluster assembly

Isoleucine degradation

Isoprenoid Biosynthesis

KDO2−Lipid A biosynthesis

Ketoisovalerate oxidoreductase

L−Cystine Uptake and Metabolism

L−rhamnose utilization

LMPTP YfkJ cluster

LMPTP YwlE cluster

LOS core oligosaccharide biosynthesis

Lactate utilization

Lacto−N−Biose I and Galacto−N−Biose Metabolic Pathway

Lactose and Galactose Uptake and Utilization

Legionaminic Acid Biosynthesis

Leucine Degradation and HMG−CoA Metabolism

Lipopolysaccharide−related cluster in Alphaproteobacteria

Lysine Biosynthesis DAP Pathway

MLST

Macromolecular synthesis operon

Maltose and Maltodextrin Utilization

Mannitol Utilization

Mannose Metabolism

Menaquinone and Phylloquinone Biosynthesis

Methicillin resistance in Staphylococci

Methionine Biosynthesis

Methionine Degradation

Multidrug Resistance Efflux Pumps

Murein hydrolase regulation and cell death

N−Acetyl−Galactosamine and Galactosamine Utilization

N−linked Glycosylation in Bacteria

NAD and NADP cofactor biosynthesis global

NAD regulation

Na+ translocating decarboxylases and related biotin−dependent enzymes

Nudix proteins (nucleoside triphosphate hydrolases)

NusA−TFII Cluster

One−carbon metabolism by tetrahydropterines

Oxidative stress

Pentose phosphate pathway

Peptide methionine sulfoxide reductase

Peptidoglycan Biosynthesis

Phage capsid proteins

Phosphate metabolism

Photorespiration (oxidative C2 cycle)

Plasmid replication

PnuC−like transporters

Poly−gamma−glutamate biosynthesis

Polyadenylation bacterial

Polyamine Metabolism

Polyhydroxybutyrate metabolism

Polyprenyl Diphosphate Biosynthesis

Potassium homeostasis

Proline, 4−hydroxyproline uptake and utilization

Propanediol utilization

Proteasome bacterial

Protein chaperones

Protein degradation

Proteolysis in bacteria, ATP−dependent

Protocatechuate branch of beta−ketoadipate pathway

Purine Utilization

Purine conversions

Pyridoxin (Vitamin B6) Biosynthesis

Pyrimidine utilization

Pyruvate Alanine Serine Interconversions

Pyruvate metabolism I: anaplerotic reactions, PEP

Pyruvate metabolism II: acetyl−CoA, acetogenesis from pyruvate

Queuosine−Archaeosine Biosynthesis

RNA polymerase bacterial

RNA processing and degradation, bacterial

Redox−dependent regulation of nucleus processes

Resistance to Vancomycin

Resistance to fluoroquinolones

Respiratory dehydrogenases 1

Restriction−Modification System

Rhamnose containing glycans

Ribonuclease H

Ribonucleotide reduction

Ribosomal protein S12p Asp methylthiotransferase

Ribosomal protein S5p acylation

Ribosome LSU bacterial

Ribosome SSU bacterial

Ribosome biogenesis bacterial

Rrf2 family transcriptional regulators

RuvABC plus a hypothetical

Salicylate and gentisate catabolism

Salicylate ester degradation

Serine−glyoxylate cycle

Sex pheromones in Enterococcus faecalis and other Firmicutes

Sialic Acid Metabolism

Sortase

Staphylococcal accessory gene regulator system

Staphylococcal pathogenicity islands SaPI

Staphylococcal phi−Mu50B−like prophages

Streptococcus pyogenes Virulome

Stringent Response, (p)ppGpp metabolism

Succinate dehydrogenase

Sucrose utilization

Sucrose utilization Shewanella

Sugar utilization in Thermotogales

Teichoic and lipoteichoic acids biosynthesis

Thiamin biosynthesis

Thioredoxin−disulfide reductase

Threonine anaerobic catabolism gene cluster

Threonine and Homoserine Biosynthesis

Transcription factors bacterial

Transcription factors cyanobacterial RpoD−like sigma factors

Transcription initiation, bacterial sigma factors

Translation elongation factor G family

Translation elongation factors eukaryotic and archaeal

Translation initiation factors eukaryotic and archaeal

Transport of Manganese

Trehalose Uptake and Utilization

Triacylglycerol metabolism

Two cell division clusters relating to chromosome partitioning

UDP−N−acetylmuramate from Fructose−6−phosphate Biosynthesis

Ubiquinone Menaquinone−cytochrome c reductase complexes

Uncharacterized sugar kinase cluster (ygc)

Universal GTPases

Universal stress protein family

Unknown carbohydrate utilization (cluster Ydj)

Unspecified monosaccharide transport cluster

Wyeosine−MimG Biosynthesis

Xanthine Metabolism in Bacteria

Xylose utilization

YbbK

YcfH

YebC

YgfZ

YgfZ−Iron

YgjD and YeaZ

YjeE

YrdC−YciO−Sua5 protein family

ZZ gjo need homes

cAMP signaling in bacteria

linker unit−arabinogalactan synthesis

mcm5s2U biosynthesis in tRNA

mnm5U34 biosynthesis bacteria

n−Phenylalkanoic acid degradation

pVir Plasmid of Campylobacter

rRNA modification Archaea

rRNA modification Bacteria

tRNA aminoacylation, Asp and Asn

tRNA aminoacylation, Glu and Gln

tRNA modification Archaea

tRNA modification Bacteria

tRNA modification yeast cytoplasmic

tRNA modification yeast mitochondrial

tRNA nucleotidyltransferase

tRNA processing

tRNAmodification position 34 16S rRNA modification within P site of ribosome

5−FCL−like protein

ATP−dependent RNA helicases, bacterial

Acetyl−CoA fermentation to Butyrate

Acid resistance mechanisms

Aerotolerance operon in Bacteroides and potentially orthologous operons in other organisms

Alginate metabolism

Alkanesulfonate assimilation

Ammonia assimilation

Anaerobic respiratory reductases

Arginine and Ornithine Degradation

Arsenic resistance

At4g10620 At3g57180 At3g47450

At5g48545 and At3g56490 At1g31160

At5g63420

Bacterial Cell Division

Bacterial Cytoskeleton

Bacterial RNA−metabolizing Zn−dependent hydrolases

Benzoate transport and degradation cluster

Beta−Glucoside Metabolism

Beta−lactamase

Biogenesis of c−type cytochromes

Butanol Biosynthesis

CBSS−176280.1.peg.1561

CBSS−342610.3.peg.1536

COG0523

COG1399

COG2363

COG3533

CRISPRs

Calvin−Benson cycle

Campylobacter Iron Metabolism

Capsular Polysaccharide (CPS) of Campylobacter

Capsular Polysaccharides Biosynthesis and Assembly

Capsular heptose biosynthesis

Carotenoids

Catechol branch of beta−ketoadipate pathway

Cellulosome

Chitin and N−acetylglucosamine utilization

Chorismate Synthesis

Chorismate: Intermediate for synthesis of Tryptophan, PAPA antibiotics, PABA, 3−hydroxyanthranilate and more.

Cluster−based Subsystem Grouping Hypotheticals − perhaps Proteosome Related

Cobalamin synthesis

Cobalt−zinc−cadmium resistance

Coenzyme A Biosynthesis

Coenzyme B12 biosynthesis

Colanic acid biosynthesis

Common Pathway For Synthesis of Aromatic Compounds (DAHP synthase to chorismate)

Conjugative transfer

Conjugative transposon, Bacteroidales

Conserved gene cluster associated with Met−tRNA formyltransferase

Copper homeostasis: copper tolerance

D−Galacturonate and D−Glucuronate Utilization

D−ribose utilization

DNA repair, UvrABC system

DNA repair, bacterial

DNA repair, bacterial MutL−MutS system

DNA repair, bacterial RecFOR pathway

DNA structural proteins, bacterial

DNA−replication

DOE COG3533

De Novo Purine Biosynthesis

De Novo Pyrimidine Synthesis

Deoxyribose and Deoxynucleoside Catabolism

Dissimilatory nitrite reductase

Entner−Doudoroff Pathway

Experimental−PTPS

Experimental−yggC

Extracellular Polysaccharide Biosynthesis of Streptococci

Fatty Acid Biosynthesis FASII

Flagellar motility

Flagellum

Flavodoxin

Formate hydrogenase

Fructooligosaccharides(FOS) and Raffinose Utilization

Fructose utilization

G3E family of P−loop GTPases (metallocenter biosynthesis)

Glutamate dehydrogenases

Glutamine synthetases

Glutamine, Glutamate, Aspartate and Asparagine Biosynthesis

Glutaredoxins

Glutathione: Redox cycle

Glycerol and Glycerol−3−phosphate Uptake and Utilization

Glycerolipid and Glycerophospholipid Metabolism in Bacteria

Glycine Biosynthesis

Glycine and Serine Utilization

Glycogen metabolism

Glycolysis and Gluconeogenesis

Glycolysis and Gluconeogenesis, including Archaeal enzymes

Group II intron−associated genes

Heme and Siroheme Biosynthesis

Heme, hemin uptake and utilization systems in GramNegatives

Hemin transport system

Hexose Phosphate Uptake System

Inorganic Sulfur Assimilation

Iojap

Iron acquisition in Streptococcus

Iron acquisition in Vibrio

Isobutyryl−CoA to Propionyl−CoA Module

Isoleucine degradation

Isoprenoid Biosynthesis

KDO2−Lipid A biosynthesis

L−fucose utilization

L−fucose utilization temp

L−rhamnose utilization

LMPTP YwlE cluster

Lactate utilization

Lipid A modifications

Lipid A−Ara4N pathway (Polymyxin resistance)

Lipopolysaccharide assembly

Listeria Pathogenicity Island LIPI−1 extended

Listeria surface proteins: Internalin−like proteins

Lysine Biosynthesis DAP Pathway

Maltose and Maltodextrin Utilization

Mannose Metabolism

Menaquinone and Phylloquinone Biosynthesis

Methionine Biosynthesis

Methionine Degradation

Methylglyoxal Metabolism

Multidrug Resistance Efflux Pumps

Multidrug efflux pump in Campylobacter jejuni (CmeABC operon)

N−Acetyl−Galactosamine and Galactosamine Utilization

N−linked Glycosylation in Bacteria

NAD and NADP cofactor biosynthesis global

NAD regulation

Na(+)−translocating NADH−quinone oxidoreductase and rnf−like group of electron transport complexes

Na+ translocating decarboxylases and related biotin−dependent enzymes

Nitrate and nitrite ammonification

Nitrosative stress

One−carbon metabolism by tetrahydropterines

Oxidative stress

Pentose phosphate pathway

Peptidoglycan Biosynthesis

Peptidyl−prolyl cis−trans isomerase

Peripheral Glucose Catabolism Pathways

Periplasmic disulfide interchange

Phage capsid proteins

Phosphate metabolism

PnuC−like transporters

Polyadenylation bacterial

Polyamine Metabolism

Polysaccharide deacetylases

Potassium homeostasis

Predicted carbohydrate hydrolases

Proline, 4−hydroxyproline uptake and utilization

Propionyl−CoA to Succinyl−CoA Module

Proteasome bacterial

Protein chaperones

Protein degradation

Proteolysis in bacteria, ATP−dependent

Purine Utilization

Purine conversions

Pyridoxin (Vitamin B6) Biosynthesis

Pyrroloquinoline Quinone biosynthesis

Pyruvate Alanine Serine Interconversions

Pyruvate metabolism I: anaplerotic reactions, PEP

Pyruvate:ferredoxin oxidoreductase

Queuosine−Archaeosine Biosynthesis

Quinolinic acid and its derivatives

RNA processing and degradation, bacterial

Respiratory Complex I

Respiratory dehydrogenases 1

Restriction−Modification System

Rhamnose containing glycans

Ribonuclease H

Ribonucleotide reduction

Ribosomal protein S12p Asp methylthiotransferase

Ribosome activity modulation

Ribosome biogenesis bacterial

Rubrerythrin

Serine Biosynthesis

Serine−glyoxylate cycle

Siderophore Enterobactin

Sortase

Streptococcus pyogenes Virulome

Stringent Response, (p)ppGpp metabolism

Succinate dehydrogenase

Sugar utilization in Thermotogales

TCA Cycle

Teichuronic acid biosynthesis

Thiamin biosynthesis

Thioredoxin−disulfide reductase

Threonine degradation

Tn552

Ton and Tol transport systems

Transcription factors bacterial

Translation elongation factor G family

Transport of Iron

Transport of Zinc

Trehalose Biosynthesis

Twin−arginine translocation system

Type IV pilus

Unknown carbohydrate utilization (cluster Yeg)

Urea decomposition

Valine degradation

Xanthosine utilization (xap region)

Xyloglucan Utilization

Xylose utilization

YgfZ

YjeE

ZZ gjo need homes

Zinc resistance

dTDP−rhamnose synthesis

linker unit−arabinogalactan synthesis

mycolic acid synthesis

polyprenyl synthesis

rRNA modification Bacteria

tRNA aminoacylation, Glu and Gln

tRNA modification Archaea

tRNA modification Bacteria

tRNA modification yeast cytoplasmic

tRNA processing

tRNAmodification position 34 00030 Pentose phosphate pathway [PATH:ko00030]

00040 Pentose and glucuronate interconversions [PATH:ko00040]

00051 Fructose and mannose metabolism [PATH:ko00051]

00052 Galactose metabolism [PATH:ko00052]

00061 Fatty acid biosynthesis [PATH:ko00061]

00071 Fatty acid metabolism [PATH:ko00071]

00072 Synthesis and degradation of ketone bodies [PATH:ko00072]

00130 Ubiquinone and other terpenoid−quinone biosynthesis [PATH:ko00130]

00190 Oxidative phosphorylation [PATH:ko00190]

00194 Photosynthesis proteins [BR:ko00194]

00195 Photosynthesis [PATH:ko00195]

00230 Purine metabolism [PATH:ko00230]

00240 Pyrimidine metabolism [PATH:ko00240]

00250 Alanine, aspartate and glutamate metabolism [PATH:ko00250]

00260 Glycine, serine and threonine metabolism [PATH:ko00260]

00270 Cysteine and methionine metabolism [PATH:ko00270]

00280 Valine, leucine and isoleucine degradation [PATH:ko00280]

00290 Valine, leucine and isoleucine biosynthesis [PATH:ko00290]

00300 Lysine biosynthesis [PATH:ko00300]

00310 Lysine degradation [PATH:ko00310]

00311 Penicillin and cephalosporin biosynthesis [PATH:ko00311]

00330 Arginine and proline metabolism [PATH:ko00330]

00340 Histidine metabolism [PATH:ko00340]

00350 Tyrosine metabolism [PATH:ko00350]

00361 gamma−Hexachlorocyclohexane degradation [PATH:ko00361]

00362 Benzoate degradation via hydroxylation [PATH:ko00362]

00380 Tryptophan metabolism [PATH:ko00380]

00400 Phenylalanine, tyrosine and tryptophan biosynthesis [PATH:ko00400]

00430 Taurine and hypotaurine metabolism [PATH:ko00430]

00450 Selenoamino acid metabolism [PATH:ko00450]

00460 Cyanoamino acid metabolism [PATH:ko00460]

00471 D−Glutamine and D−glutamate metabolism [PATH:ko00471]

00473 D−Alanine metabolism [PATH:ko00473]

00480 Glutathione metabolism [PATH:ko00480]

00500 Starch and sucrose metabolism [PATH:ko00500]

00510 N−Glycan biosynthesis [PATH:ko00510]

00511 Other glycan degradation [PATH:ko00511]

00520 Amino sugar and nucleotide sugar metabolism [PATH:ko00520]

00540 Lipopolysaccharide biosynthesis [PATH:ko00540]

00550 Peptidoglycan biosynthesis [PATH:ko00550]

00561 Glycerolipid metabolism [PATH:ko00561]

00562 Inositol phosphate metabolism [PATH:ko00562]

00564 Glycerophospholipid metabolism [PATH:ko00564]

00600 Sphingolipid metabolism [PATH:ko00600]

00601 Glycosphingolipid biosynthesis − lacto and neolacto series [PATH:ko00601]

00603 Glycosphingolipid biosynthesis − globo series [PATH:ko00603]

00620 Pyruvate metabolism [PATH:ko00620]

00624 1− and 2−Methylnaphthalene degradation [PATH:ko00624]

00626 Naphthalene and anthracene degradation [PATH:ko00626]

00628 Fluorene degradation [PATH:ko00628]

00630 Glyoxylate and dicarboxylate metabolism [PATH:ko00630]

00632 Benzoate degradation via CoA ligation [PATH:ko00632]

00640 Propanoate metabolism [PATH:ko00640]

00641 3−Chloroacrylic acid degradation [PATH:ko00641]

00642 Ethylbenzene degradation [PATH:ko00642]

00650 Butanoate metabolism [PATH:ko00650]

00660 C5−Branched dibasic acid metabolism [PATH:ko00660]

00670 One carbon pool by folate [PATH:ko00670]

00680 Methane metabolism [PATH:ko00680]

00710 Carbon fixation in photosynthetic organisms [PATH:ko00710]

00720 Reductive carboxylate cycle (CO2 fixation) [PATH:ko00720]

00730 Thiamine metabolism [PATH:ko00730]

00740 Riboflavin metabolism [PATH:ko00740]

00750 Vitamin B6 metabolism [PATH:ko00750]

00760 Nicotinate and nicotinamide metabolism [PATH:ko00760]

00770 Pantothenate and CoA biosynthesis [PATH:ko00770]

00790 Folate biosynthesis [PATH:ko00790]

00830 Retinol metabolism [PATH:ko00830]

00860 Porphyrin and chlorophyll metabolism [PATH:ko00860]

00900 Terpenoid backbone biosynthesis [PATH:ko00900]

00903 Limonene and pinene degradation [PATH:ko00903]

00908 Zeatin biosynthesis [PATH:ko00908]

00910 Nitrogen metabolism [PATH:ko00910]

00970 Aminoacyl−tRNA biosynthesis [PATH:ko00970]

00980 Metabolism of xenobiotics by cytochrome P450 [PATH:ko00980]

00982 Drug metabolism − cytochrome P450 [PATH:ko00982]

00983 Drug metabolism − other enzymes [PATH:ko00983]

01001 Protein kinases [BR:ko01001]

01002 Peptidases [BR:ko01002]

01003 Glycosyltransferases [BR:ko01003]

01004 Lipid biosynthesis proteins [BR:ko01004]

01005 Lipopolysaccharide biosynthesis proteins [BR:ko01005]

02000 Transporters [BR:ko02000]

02010 ABC transporters [PATH:ko02010]

02020 Two−component system [PATH:ko02020]

02022 Two−component system [BR:ko02022]

02042 Bacterial toxins [BR:ko02042]

02044 Secretion system [BR:ko02044]

02060 Phosphotransferase system (PTS) [PATH:ko02060]

03000 Transcription factors [BR:ko03000]

03010 Ribosome [PATH:ko03010]

03011 Ribosome [BR:ko03011]

03012 Translation factors [BR:ko03012]

03018 RNA degradation [PATH:ko03018]

03020 RNA polymerase [PATH:ko03020]

03030 DNA replication [PATH:ko03030]

03032 DNA replication proteins [BR:ko03032]

03036 Chromosome [BR:ko03036]

03060 Protein export [PATH:ko03060]

03070 Bacterial secretion system [PATH:ko03070]

03110 Chaperones and folding catalysts [BR:ko03110]

03400 DNA repair and recombination proteins [BR:ko03400]

03410 Base excision repair [PATH:ko03410]

03420 Nucleotide excision repair [PATH:ko03420]

03430 Mismatch repair [PATH:ko03430]

03440 Homologous recombination [PATH:ko03440]

04070 Phosphatidylinositol signaling system [PATH:ko04070]

04112 Cell cycle − Caulobacter [PATH:ko04112]

04146 Peroxisome [PATH:ko04146]

04626 Plant−pathogen interaction [PATH:ko04626]

04812 Cytoskeleton proteins [BR:ko04812]

04930 Type II diabetes mellitus [PATH:ko04930]

05010 Alzheimer's disease [PATH:ko05010]

05111 Vibrio cholerae pathogenic cycle [PATH:ko05111]

05340 Primary immunodeficiency [PATH:ko05340]

Glycolysis / Gluconeogenesis [PATH:ko00010] 00030 Pentose phosphate pathway [PATH:ko00030]

00040 Pentose and glucuronate interconversions [PATH:ko00040]

00051 Fructose and mannose metabolism [PATH:ko00051]

00052 Galactose metabolism [PATH:ko00052]

00053 Ascorbate and aldarate metabolism [PATH:ko00053]

00061 Fatty acid biosynthesis [PATH:ko00061]

00071 Fatty acid metabolism [PATH:ko00071]

00130 Ubiquinone and other terpenoid−quinone biosynthesis [PATH:ko00130]

00190 Oxidative phosphorylation [PATH:ko00190]

00230 Purine metabolism [PATH:ko00230]

00240 Pyrimidine metabolism [PATH:ko00240]

00250 Alanine, aspartate and glutamate metabolism [PATH:ko00250]

00253 Tetracycline biosynthesis [PATH:ko00253]

00260 Glycine, serine and threonine metabolism [PATH:ko00260]

00270 Cysteine and methionine metabolism [PATH:ko00270]

00280 Valine, leucine and isoleucine degradation [PATH:ko00280]

00281 Geraniol degradation [PATH:ko00281]

00300 Lysine biosynthesis [PATH:ko00300]

00310 Lysine degradation [PATH:ko00310]

00330 Arginine and proline metabolism [PATH:ko00330]

00340 Histidine metabolism [PATH:ko00340]

00350 Tyrosine metabolism [PATH:ko00350]

00360 Phenylalanine metabolism [PATH:ko00360]

00380 Tryptophan metabolism [PATH:ko00380]

00400 Phenylalanine, tyrosine and tryptophan biosynthesis [PATH:ko00400]

00401 Novobiocin biosynthesis [PATH:ko00401]

00410 beta−Alanine metabolism [PATH:ko00410]

00430 Taurine and hypotaurine metabolism [PATH:ko00430]

00480 Glutathione metabolism [PATH:ko00480]

00500 Starch and sucrose metabolism [PATH:ko00500]

00510 N−Glycan biosynthesis [PATH:ko00510]

00511 Other glycan degradation [PATH:ko00511]

00520 Amino sugar and nucleotide sugar metabolism [PATH:ko00520]

00521 Streptomycin biosynthesis [PATH:ko00521]

00523 Polyketide sugar unit biosynthesis [PATH:ko00523]

00524 Butirosin and neomycin biosynthesis [PATH:ko00524]

00531 Glycosaminoglycan degradation [PATH:ko00531]

00540 Lipopolysaccharide biosynthesis [PATH:ko00540]

00550 Peptidoglycan biosynthesis [PATH:ko00550]

00561 Glycerolipid metabolism [PATH:ko00561]

00562 Inositol phosphate metabolism [PATH:ko00562]

00564 Glycerophospholipid metabolism [PATH:ko00564]

00590 Arachidonic acid metabolism [PATH:ko00590]

00600 Sphingolipid metabolism [PATH:ko00600]

00603 Glycosphingolipid biosynthesis − globo series [PATH:ko00603]

00604 Glycosphingolipid biosynthesis − ganglio series [PATH:ko00604]

00620 Pyruvate metabolism [PATH:ko00620]

00624 1− and 2−Methylnaphthalene degradation [PATH:ko00624]

00630 Glyoxylate and dicarboxylate metabolism [PATH:ko00630]

00631 1,2−Dichloroethane degradation [PATH:ko00631]

00632 Benzoate degradation via CoA ligation [PATH:ko00632]

00640 Propanoate metabolism [PATH:ko00640]

00641 3−Chloroacrylic acid degradation [PATH:ko00641]

00650 Butanoate metabolism [PATH:ko00650]

00660 C5−Branched dibasic acid metabolism [PATH:ko00660]

00670 One carbon pool by folate [PATH:ko00670]

00680 Methane metabolism [PATH:ko00680]

00710 Carbon fixation in photosynthetic organisms [PATH:ko00710]

00720 Reductive carboxylate cycle (CO2 fixation) [PATH:ko00720]

00730 Thiamine metabolism [PATH:ko00730]

00750 Vitamin B6 metabolism [PATH:ko00750]

00760 Nicotinate and nicotinamide metabolism [PATH:ko00760]

00770 Pantothenate and CoA biosynthesis [PATH:ko00770]

00830 Retinol metabolism [PATH:ko00830]

00860 Porphyrin and chlorophyll metabolism [PATH:ko00860]

00900 Terpenoid backbone biosynthesis [PATH:ko00900]

00903 Limonene and pinene degradation [PATH:ko00903]

00910 Nitrogen metabolism [PATH:ko00910]

00920 Sulfur metabolism [PATH:ko00920]

00950 Isoquinoline alkaloid biosynthesis [PATH:ko00950]

00960 Tropane, piperidine and pyridine alkaloid biosynthesis [PATH:ko00960]

00970 Aminoacyl−tRNA biosynthesis [PATH:ko00970]

00980 Metabolism of xenobiotics by cytochrome P450 [PATH:ko00980]

01002 Peptidases [BR:ko01002]

01003 Glycosyltransferases [BR:ko01003]

01004 Lipid biosynthesis proteins [BR:ko01004]

01005 Lipopolysaccharide biosynthesis proteins [BR:ko01005]

01051 Biosynthesis of ansamycins [PATH:ko01051]

01053 Biosynthesis of siderophore group nonribosomal peptides [PATH:ko01053]

01055 Biosynthesis of vancomycin group antibiotics [PATH:ko01055]

02000 Transporters [BR:ko02000]

02010 ABC transporters [PATH:ko02010]

02020 Two−component system [PATH:ko02020]

02022 Two−component system [BR:ko02022]

02030 Bacterial chemotaxis [PATH:ko02030]

02035 Bacterial motility proteins [BR:ko02035]

02040 Flagellar assembly [PATH:ko02040]

02042 Bacterial toxins [BR:ko02042]

02044 Secretion system [BR:ko02044]

03000 Transcription factors [BR:ko03000]

03010 Ribosome [PATH:ko03010]

03011 Ribosome [BR:ko03011]

03018 RNA degradation [PATH:ko03018]

03020 RNA polymerase [PATH:ko03020]

03036 Chromosome [BR:ko03036]

03041 Spliceosome [BR:ko03041]

03051 Proteasome [BR:ko03051]

03060 Protein export [PATH:ko03060]

03070 Bacterial secretion system [PATH:ko03070]

03110 Chaperones and folding catalysts [BR:ko03110]

03320 PPAR signaling pathway [PATH:ko03320]

03400 DNA repair and recombination proteins [BR:ko03400]

03440 Homologous recombination [PATH:ko03440]

04000 Receptors and channels [BR:ko04000]

04090 Cellular antigens [BR:ko04090]

04112 Cell cycle − Caulobacter [PATH:ko04112]

04120 Ubiquitin mediated proteolysis [PATH:ko04120]

04121 Ubiquitin system [BR:ko04121]

04142 Lysosome [PATH:ko04142]

04146 Peroxisome [PATH:ko04146]

04612 Antigen processing and presentation [PATH:ko04612]

04621 NOD−like receptor signaling pathway [PATH:ko04621]

04626 Plant−pathogen interaction [PATH:ko04626]

04910 Insulin signaling pathway [PATH:ko04910]

04914 Progesterone−mediated oocyte maturation [PATH:ko04914]

04920 Adipocytokine signaling pathway [PATH:ko04920]

04962 Vasopressin−regulated water reabsorption [PATH:ko04962]

05120 Epithelial cell signaling in Helicobacter pylori infection [PATH:ko05120]

05200 Pathways in cancer [PATH:ko05200]

05215 Prostate cancer [PATH:ko05215]

Citrate cycle (TCA cycle) [PATH:ko00020]

Glycolysis / Gluconeogenesis [PATH:ko00010] Sample: B1 B2 N1 N2 1) Read counts per function Count: 2 6 47 60 in each sample

2) Convert to proportional distributions Within-condition Between-condition difference difference 3) Calculate within and & between condition distributions

11 6 26 Between 4) Divide between-group Max[Within] difference by the largest within-group difference 2.4 1 2

3

4 5 6

A B

E

D C Table S1. Nugent scoring results

Sample ID Field No. Lactobacillus Score Gardnerella Score Mobiluncus Score Total Score pH

1 >30 0 0 2 >30 4 0 N4 3 >30 2 0 2 <= 4.5 4 >30 4 0 Average >30 0 2.5 2 0 0 1 >30 1 0 2 >30 6 0 N30 3 >30 0 0 2 <= 4.5 4 >30 2 0 Average >30 0 2.25 2 0 0 1 0 >30 >30 2 0 >30 >30 B27 3 0 >30 >30 10 5.5 4 0 >30 >30 Average 0 4 >30 4 >30 2 1 16 >30 >30 2 12 >30 >30 B31 3 12 >30 >30 7 5.0 4 3 >30 >30 Average 10.75 1 >30 4 >30 2 Table S2. Sequence and mapping data.

N4 N30 B27 B31 Total

Raw reads 47,634,967 46,943,184 48,832,687 53,655,422 197,066,260

Reads mapped to human 2,649,739 4,525,289 1,385,096 300,792 8,860,916 genome (excluded) 5.56% 9.64% 2.84% 0.56% 4.50%

Reads mapped to Total mapped 20,556,493 14,690,153 11,981,948 12,556,674 59,785,268 bacterial library Unique 12,178,729 10,260,422 9,321,042 8,349,061 40,109,254 Non-unique 8,377,764 4,429,731 2,660,906 4,207,613 19,676,014

Unique mapped to CDS* 10,635,713 8,809,565 7,469,729 5,487,128 32,402,135

No. of unique refseqs 10,770 11,745 20,162 22,860 33,412† mapped

No. refseqs assigned to 18507 (55.4%) 2056 unique KOs KEGG No. refseqs assigned to 22735 (68.0%) 2772 unique subsys4 SEED subsys4 No.refseqs assigned to 25951 (77.7%) 2300 unique COGs COG

*These are reads mapping uniquely to coding sequences (CDS). These reads were used for differential expression analysis. †This is the total number of unique reference sequence CDS (refseqs) mapped across all samples Table S3. Read counts after mapping to curtated, non-redundant cpn60 database

Taxon 4N 30N 27B 31B Lactobacillus_iners 1060 6910 2759 5284 Lactobacillus_crispatus 14261 7010 0 707 Gardnerella_vaginalis 0 0 408 308 Megasphaera_sp 0 0 3202 0 Prevotella_amnii 15 12 34186 3113 Prevotella_disiens 0 0 0 918 Prevotella_timonensis 0 0 220 688 Lactobacillus_jensenii 222 194 0 17 Lactobacillus_johnsonii 22 0 0 0 Lactobacillus_kefironofacieus 190 0 0 0 Lactobacillus_rhamnosus 17 13 18 20 Lactobacillus_acidophilus 14 12 0 0 Lactobacillus_ruminis 0 0 46 0 Alloscardovia_omnicolens 0 0 15 0 Atopobium_vaginae 0 0 50 12 Clostridium_genomosp_BVAB3 0 0 33 27 Fusobacterium_sp 0 0 23 0 Peptoniphilus_lacrimalis 0 0 0 48 Porphyromonas_uenonis 0 0 37 0 Prevotella_bivia 0 0 21 0 Prevotella_buccalis 0 0 42 14 Prevotella_melaninogenica 0 0 0 30 Streptococcus_thermophilus 145 102 81 94 Vagococcus_fluvialis 49 0 30 54 total_reads 15995 14253 41171 11334 Table S4. List of organisms used to build reference mapping library

Organism name GenBank or Refseq accession No. of CDS Actinomyces coleocanis DSM 15436 ACFG00000000 1546 Actinomyces urogenitalis DSM 15434 ACFH00000000 2403 Aerococcus viridans ATCC 11563 ADNT00000000 1929 Anaerococcus lactolyticus ATCC 51172 ABYO00000000 2253 Anaerococcus tetradius ATCC 35098 ACGC00000000 2079 Atopobium vaginae DSM 15829 ACGK00000000 1271 Atopobium vaginae PB189-T1-4 AEDQ00000000 1217 Bifidobacterium dentium ATCC 27679 AEEQ00000000 2336 Bifidobacterium dentium JCVIHMP022 AEHJ00000000 2278 Brevibacterium mcbrellneri ATCC 49030 ADNU00000000 2432 Chryseobacterium gleum F93, ATCC 35910 ACKQ00000000 5289 Clostridiales genomosp. BVAB3 UPII9-5 CP001850 1526 Corynebacterium aurimucosum ATCC 700975 ACLH00000000 2614 Corynebacterium genitalium ATCC 33030 ACLJ00000000 2226 Corynebacterium glucuronalyticum ATCC 51867 ABYP00000000 2645 Corynebacterium glucuronolyticum ATCC 51866 ACHF00000000 2733 Corynebacterium jeikeium ATCC 43734 ACYW00000000 2224 Corynebacterium lipophiloflavum DSM 44291 ACHJ00000000 2371 Corynebacterium pseudogenitalium ATCC 33035 ABYQ00000000 2607 Corynebacterium striatum ATCC 6940 ACGE00000000 2677 Dialister microaerophilus UPII-345-E AENT00000000 1310 Enterococcus faecalis ATCC 29200 ACHK00000000 2955 Enterococcus faecalis HH22 ACIX00000000 3227 Enterococcus faecalis TX 0312 AECB00000000 2789 Enterococcus faecalis TX 0635 AEBZ00000000 3263 Enterococcus faecalis TX0855 AEBV00000000 3032 Eremococcus coleocola ACS-139-V-Col8 AENN00000000 1720 Escherichia coli 83972 ACGN00000000 5255 Finegoldia magna ACS-171-V-Col3 AECM00000000 1740 Finegoldia magna ATCC 29328 NC_010371 182 Finegoldia magna ATCC 29328 NC_010376 1631 Finegoldia magna ATCC 53516 ACHM00000000 1838 Finegoldia magna BVS033A4 AEDP00000000 1904 Fusobacterium nucleatum nucleatum ATCC 23726 ADVK00000000 2126 Gardnerella vaginalis ATCC 14019 NC_014644 1365 Gardnerella vaginalis 409-05 NC_013721 1261 Gardnerella vaginalis AMD ADAM00000000 1313 Lactobacillus acidophilus NCFM NC_006814 1864 Lactobacillus crispatus 214-1 ADGR00000000 2163 Lactobacillus crispatus JV-V01 ACKR00000000 2209 Lactobacillus crispatus MV-3A-US ACQC00000000 2330 Lactobacillus crispatus ST1 NC_014106 2024 Lactobacillus delbrueckii bulgaricus PB2003/044-T3-4 AEAT00000000 1909 Lactobacillus fermentum IFO NC_010610 1843 Lactobacillus gasseri 202-4 ACOZ00000000 1773 Lactobacillus gasseri 224-1 ADFT00000000 2252 Lactobacillus gasseri JV-V03 ACGO00000000 1977 Lactobacillus gasseri MV-22 ABWH00000000 1917 Lactobacillus iners AB-1 ADHG00000000 1190 Lactobacillus iners ATCC 55195 AEPX00000000 1144 Lactobacillus iners DSM 13335 ACLN00000000 1214 Lactobacillus iners LactinV 01V1-a AEHQ00000000 1527 Lactobacillus iners LactinV 03V1-b AEHP00000000 1459 Lactobacillus iners LactinV 09V1-c AEHO00000000 1361 Lactobacillus iners LactinV 11V1-d AEHN00000000 1338 Organism name GenBank or Refseq accession No. of CDS Lactobacillus iners LEAF 2052A-d AEKI00000000 1256 Lactobacillus iners LEAF 2053A-b AEKH00000000 1277 Lactobacillus iners LEAF 2062A-h1 AEKJ00000000 1265 Lactobacillus iners LEAF 3008A-a AEKK00000000 1210 Lactobacillus iners SPIN 2503V10-D AEHR00000000 1273 Lactobacillus jensenii 1153 ABWG00000000 1395 Lactobacillus jensenii 208-1 ADEX00000000 3182 Lactobacillus jensenii 269-3 ACOY00000000 1575 Lactobacillus jensenii JV-V16 ACGQ00000000 1450 Lactobacillus johnsonii ATCC 33200 ACGR00000000 1838 Lactobacillus johnsonii FI9785 NC_012552 2 Lactobacillus johnsonii FI9785 NC_013504 1710 Lactobacillus johnsonii FI9785 NC_013505 23 Lactobacillus johnsonii FI9785 NC_005362 1821 Lactobacillus oris PB013-T2-3 AEKL00000000 2038 Lactobacillus reuteri_JCM 1112 NC_010609 1820 Lactobacillus rhamnosus_Lc 705 NC_013199 2878 Lactobacillus rhamnosus_Lc 705 NC_013200 79 Lactobacillus salivarius ACS-116-V-Col5a AEBA00000000 2121 Lactobacillus vaginalis ATCC 49540 ACGV00000000 1870 Leptotrichia buccalis C 1013 NC_013192 2220 Megasphaera genomosp. type_1 28L ADGP00000000 1610 Mobiluncus curtisii ATCC 43063 NC_014246 1909 Mobiluncus curtisii ATCC 51333 AEPY00000000 1855 Mobiluncus curtisii curtisii ATCC 35241 AEEE00000000 1894 Mobiluncus curtisii holmesii ATCC 35242 AEPZ00000000 1829 Mobiluncus mulieris 28-1 ADBR00000000 2321 Mobiluncus mulieris ATCC 35239 AEET00000000 2380 Mobiluncus mulieris ATCC 35243 ACKW00000000 2300 Mobiluncus mulieris FB024-16 AEGV00000000 2113 Mycobacterium parascrofulaceum ATCC BAA-614 ADNV00000000 6456 Peptoniphilus duerdenii ATCC BAA-1640 AEEH00000000 1988 Peptoniphilus lacrimalis 315-B ADDO00000000 1589 Porphyromonas asaccharolytica PR426713P-I AENO00000000 1655 Porphyromonas uenonis 60-3 ACLR00000000 1977 Prevotella amnii CRIS 21A-A ADFQ00000000 2025 Prevotella bivia JCVIHMP010 ADFO00000000 2041 Prevotella buccalis ATCC 35310 ADEG00000000 2456 Prevotella disiens FB035-09AN AEDO00000000 2621 Prevotella melaninogenica ATCC 25845 NC_014370 1338 Prevotella melaninogenica ATCC 25845 NC_014371 958 Prevotella oralis ATCC 33269 AEPE00000000 2488 Prevotella timonensis CRIS 5C-B1 ADEF00000000 2202 Proteus mirabilis ATCC 29906 ACLE00000000 3812 Roseomonas cervicalis ATCC 49957 ADVL00000000 4778 Sphingobacterium spiritivorum ATCC 33300 ACHB00000000 4925 Sphingobacterium spiritivorum ATCC 33861 ACHA00000000 4471 Staphylococcus aureus aureus MN8 ACJA00000000 2833 Staphylococcus aureus COL NC_002951 2612 Staphylococcus aureus COL NC_006629 3 Streptococcus agalactiae 2603V NC_004116 2124 Streptococcus bovis ATCC 700338 AEEL00000000 2088 Streptococcus pseudoporcinus SPIN 20026 AENS00000000 2030 Treponema phagedenis F0421 AEFH00000000 3146 Veillonella atypica ACS-049-V-Sch6 AEDR00000000 1840 Total 230031 Table S5S4. Read coverage of Lactobacillus iners coding sequences (CDS)

Average number of CDS* 1293 Average CDS length (nt) 970 Product 1254210

N4 N30 N27 N31 Total mapped reads to 122332 617960 1928856 2931047 L. iners' CDS x 50 bp per read 6116600 30898000 96442800 146552350

Approx. CDS coverage 4.88 24.64 76.90 116.85

*See Table S4S3 Table S6. Summary of reads mapped to CRISPR spacer sequences

N4 N30 B27 B31 CRISPR spacer sequence ID % of total % of total % of total % of total No. reads No. reads No. reads No. reads mapped reads mapped reads mapped reads mapped reads lcl|1713|ref|NC_007716| Aster yellows witches'-broom phytoplasma AYWB 277436-277525 0 0.00 0 0.00 0 0.00 1 0.00 lcl|1714|ref|NC_007716| Aster yellows witches'-broom phytoplasma AYWB 277342-277417 58 0.03 109 0.07 15 0.07 55 0.06 lcl|1716|ref|NC_007716| Aster yellows witches'-broom phytoplasma AYWB 277167-277226 0 0.00 0 0.00 1 0.00 0 0.00 lcl|2498|ref|NC_011891| Anaeromyxobacter dehalogenans 2CP-1 3151161-3151315 0 0.00 1 0.00 0 0.00 0 0.00 lcl|3269|ref|NC_009674| Bacillus cereus subsp. cytotoxis NVH 391-98 3571402-3571478 8 0.00 18 0.01 3 0.01 7 0.01 lcl|3270|ref|NC_009674| Bacillus cereus subsp. cytotoxis NVH 391-98 3571303-3571377 10 0.00 95 0.06 228 1.06 779 0.81 lcl|3272|ref|NC_009674| Bacillus cereus subsp. cytotoxis NVH 391-98 3571141-3571198 21 0.01 250 0.16 95 0.44 356 0.37 lcl|10652|ref|NC_008593| Clostridium novyi NT 1866066-1866100 2 0.00 0 0.00 0 0.00 0 0.00 lcl|13253|ref|NC_012785| Kosmotoga olearia TBF 19.5.1 723753-723786 0 0.00 0 0.00 0 0.00 1 0.00 lcl|13330|ref|NC_010080| Lactobacillus helveticus DPC 4571 1587946-1587980 15 0.01 17 0.01 0 0.00 0 0.00 lcl|13337|ref|NC_010080| Lactobacillus helveticus DPC 4571 1695949-1696043 101829 45.21 63058 41.28 14304 66.60 56128 58.03 lcl|13338|ref|NC_010080| Lactobacillus helveticus DPC 4571 1695809-1695937 90804 40.31 63592 41.63 6194 28.84 31881 32.96 lcl|13339|ref|NC_010080| Lactobacillus helveticus DPC 4571 1695675-1695797 27975 12.42 24092 15.77 15 0.07 5400 5.58 lcl|13340|ref|NC_010080| Lactobacillus helveticus DPC 4571 1695542-1695663 2698 1.20 1254 0.82 441 2.05 1408 1.46 lcl|15149|ref|NC_006360| Mycoplasma hyopneumoniae 232 338057-338117 0 0.00 0 0.00 45 0.21 33 0.03 lcl|15151|ref|NC_006360| Mycoplasma hyopneumoniae 232 337855-337962 1 0.00 1 0.00 22 0.10 178 0.18 lcl|16408|ref|NC_013316| Clostridium difficile R20291 chromosome 1292772-1292809 1 0.00 8 0.01 0 0.00 0 0.00 lcl|16502|ref|NC_010376| Finegoldia magna ATCC 29328 chromosome 197417-197654 0 0.00 0 0.00 0 0.00 3 0.00 lcl|16505|ref|NC_010376| Finegoldia magna ATCC 29328 chromosome 196644-196855 0 0.00 0 0.00 0 0.00 4 0.00 lcl|17873|ref|NC_009454| Pelotomaculum thermopropionicum SI chromosome 1998702-1998738 0 0.00 0 0.00 1 0.00 0 0.00 lcl|18404|ref|NC_006814| Lactobacillus acidophilus NCFM chromosome 1541067-1541098 13 0.01 0 0.00 0 0.00 0 0.00 lcl|18406|ref|NC_006814| Lactobacillus acidophilus NCFM chromosome 1542898-1542929 37 0.02 30 0.02 33 0.15 122 0.13 lcl|20031|ref|NC_012032| Chloroflexus sp. Y-400-fl chromosome 4548942-4548978 0 0.00 0 0.00 8 0.04 17 0.02 lcl|20808|ref|NC_013511| Mycoplasma hominis 259090-259162 0 0.00 0 0.00 0 0.00 1 0.00 lcl|25524|ref|NC_009523| Roseiflexus sp. RS-1 chromosome 3157153-3157189 0 0.00 3 0.00 0 0.00 1 0.00 lcl|25767|ref|NC_014752| Neisseria lactamica ST-640 1672927-1672964 1770 0.79 229 0.15 66 0.31 310 0.32 lcl|26144|ref|NC_014484| Spirochaeta thermophila DSM 6192 chromosome 461133-461170 0 0.00 0 0.00 1 0.00 0 0.00 lcl|31970|ref|NC_000919| Treponema pallidum subsp. pallidum str. Nichols chromosome 77273-77566 0 0.00 0 0.00 0 0.00 15 0.02 lcl|32709|ref|NC_010175| Chloroflexus aurantiacus J-10-fl chromosome 4538893-4538930 0 0.00 0 0.00 5 0.02 17 0.02 lcl|33777|ref|NC_010741| Treponema pallidum subsp. pallidum SS14 77270-77563 0 0.00 0 0.00 0 0.00 10 0.01 lcl|39861|ref|NC_015499| Thermodesulfobium narugense DSM 14796 chromosome 1770147-1770185 0 0.00 0 0.00 0 0.00 1 0.00 lcl|35999|ref|NC_013715| Rothia mucilaginosa DY-18 chromosome 1380875-1381203 0 0.00 1 0.00 0 0.00 0 0.00 lcl|40601|ref|NC_009437| Caldicellulosiruptor saccharolyticus DSM 8903 chromosome 357323-357358 0 0.00 0 0.00 0 0.00 2 0.00 Total reads mapped 225242 152758 21477 96730