Supporting Information © Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2007 © Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2007 Supporting Information for Identification of Protein Fold Topology Shared between Different Folds Inhibited by Natural Products Bernadette M. McArdle, Ronald J. Quinn* Table S-1 Result of data-mining for natural product inhibitors of the Zincin-like fold [a] NP/derivative NP type/ mode Inhibits Potency PDB Fold Doesn’t Inhibit Fold [41, [41] [44] [44] [45] actinonin peptide deformylase Ki = 0.28 nM 1q1y 1ix1 Peptide ACE Zincin-like 42] [41] [45] IC50 = 0.8 nM 1g2a deformylase (IC50 > 100 µM) [42] [46] Ki = 0.3 nM 1lqw [46] Ki = 0.012 -0.025 1lqy µM[43] 1lru[46] aminopeptidase P Creatinase/ 1lry[46] (3.4.11.9)[101] aminopeptidase Kis = 0.135 µM[94] no pdb glutamyl ?homology with meprin A Kii = 1.57 µM[94] ?Zincin-like aminopeptidase TET (homology with (3.4.11.7)[96] astacin) Kis = 130 µM[94] aminopeptidase W ?no pdb astacin Kii = 9500 µM[94] Zincin-like (3.4.11.16)[96] no sequence [95] IC50 = 25 nM no pdb aminopeptidase A ? [96] alanyl aminopeptidase IC50 = 2 µM ?Zincin-like (?EC) [87-91] [97] [97] (N/M) (3.4.11.2) IC50 = 0.4 µg/mL (homology with IC50 >100µg/mL LTA4H) [98] Ki = 1.4 mM arginine [99] human neutrophil IC50 = 0.3 µM Zincin-like aminopeptidase (B) ?Zincin-like [97] collagenase (MMP-8) (3.4.11.6) IC 50 > (homology with [99] IC50 = 0.19 µM 100 µg/mL LTA4H) [45] collagenase IC50 = 1 µM Zincin-like (MMP-1) [99] IC50 = 0.33 µM gelatinase B Zincin-like (MMP-9) [99] IC50 = 1.7 µM [45] stromelysin IC50 = 6 µM Zincin-like (MMP-3) [45] IC50 = 3 µM gelatinase A Zincin-like (MMP-2) [45] IC50 = 7 µM neprilysin Zincin-like strongly [92] cytosol alanyl Phosphorylase / aminopeptidase hydrolase like (3.4.11.14)[92, 93] [97] IC50 = 1 µg/mL leucine Phosphorylase / aminopeptidase hydrolase like [51] [100] (3.4.11.1) IC50 = 0.40 µg/mL no pdb glutamyl ?homology with aminopeptidase TET (3.4.11.7) [48] [48] aclacinomycin A anthracycyline bacterial IC50 = 9.9 µM CUB-like elastase ?(depends on collogenase[102] type) independent of (3.4.24.3) chelate effect ?[102] trypsin [48] Trypsin-like aclacinomycin 1q0z [47] Alpha/beta serine methylesterase hydrolase proteases (RdmC) (biosynthetic enzyme)[47] [103] [48] adriamycin anthracycyline gelatinase A Ki = 49 µM Zincin-like elastase ?(depends on (doxorubicin) (MMP-2) type) [104] [48] chelation prolidase (3.4.13.9) IC50 = 10 µM Creatinase/ trypsin Trypsin-like aminopeptidase serine proteases [48] independent of bacterial IC50 = 1.1 µM CUB-like chelate effect ?[102] collogenase[102] (3.4.24.3) bontoxilysin[49] 1i1e[49] Zincin-like [63] amastatin leucine ?IC50 = 1 µM Phosphorylase/ LTA4H Zincin-like [3] aminopeptidase hydrolase like (IC50 > 10 mM) IV(3.4.11.22) aminopeptidase P Creatinase/ [52] [52] [101, 112, 113] slow and tight leucine Ki = 30 nM Phosphorylase/ (3.4.11.9) aminopeptidase [53] [54] aminopeptidase Ki = 200 nM 1bll hydrolase like (3.4.11.1)[50, 51] arginine ?Zincin-like aminopeptidase (B) (homology with tetrahedral ?Phosphorylase/ (3.4.11.6)[114] LTA4H) [55] aminopeptidase (TET) 1y0y (no hydrolase like SCOP) (homology with picornain 2A Tryspin-like leucine (3.4.22.29) (IC50 > serine protease [ [115] aminopeptidase 0.1 mM) 55] ) cystinyl Phosphorylase/ [53] alanyl aminopeptidase Ki = 190 µM no pdb ?Zincin-like aminopeptidase hydrolase like [53, 91, [96] [106] (N/M) (3.4.11.2) IC50 = 1.5 – 2 µM (homology with (3.4.11.3) 105-107] [52] Ki = 52 nM LTA4H) [53] [116] Ki = 20 nM meprin A ?Zincin-like slow and tight[52] cystinyl (homology with aminopeptidase Phosphorylase/ astacin) [50] (3.4.11.3) hydrolase like [96] glutamyl IC50 = 1.5 – 2 µM no pdb ?homology with glutamate ?Phosphorylas/ aminopeptidase TET carboxypeptidase II hydrolase like [96, 106] [117] (3.4.11.7) (3.4.17.21) (200 (homology with µM, 88 % activity) 1cx8) [96] aminopeptidase W IC50 = 1.5 – 2 µM ?no pdb [96] (3.4.11.16) no sequence [92] cytosol alanyl strongly aminopeptidase Phosphorylase/ [92, 93] (3.4.11.14) hydrolase like aminopeptidase Y 0.02 mM, 10% no pdb ?Zincin-like [108] [108] (3.4.11.15) activity (homology with LTA4H) [52] [52] slow and tight bacterial leucyl Ki = 0.26 nM Phosphorylase/ aminopeptidase hydrolase like (3.4.11.10) [111] pyroglutamyl IC50 = 1 µg/ml Phosphorylase/ aminopeptidase hydrolase like (3.4.19.3) mitochondrial No pdb ?Zincin-like intermediate peptidase (homology with (3.4.24.59)[109] neurolysin) X-his dipeptidase No pdb ?Phosphorylase (3.4.13.3)[110] /hydrolase like (homology with peptidase T) [118] ancovenin ACE IC50 = 0.87 µM Zincin-like [119] [119] [119] antibiotic A 58365A competitive ACE IC50 = 0.0018 µM Zincin-like [119] [119] [119] antibiotic A 58365B competitive ACE IC50 = 0.004 µM Zincin-like [119] [120] [119] antibiotic I5B1/K4 non-competitive ACE Ki = 0.18 µM Zincin-like Trypsin Trypsin-like serine protease carboxypeptidase A Weak 2,3%[119] Phosphorylase/ hydroalse Carboxypeptidase Phosphorylase/ B[119] hydrolase [119] [119, 121] antibiotic I5B2 competitive ACE IC50 = 0.091 µM Zincin-like [119] [122] [122] antibiotic K 13 non-competitive ACE Ki = 0.349 µM Zincin-like trypsin Trypsin-like serine protease leucine 6 % inhibition[122] Phosphorylase/ aminopeptidase hydrolase like carboxypeptidase Phosphorylase/ A [122] hydrolase aminopeptidas B 5,3 % inhibition[122] ?Zincin-like or phosphorylase/ hydrolase like [119] [119] [119] antibiotic K 26 non-competitive ACE Ki = 0.03 µM Zincin-like trypsin Trypsin-like [123] IC50 = 6.7 ng/ml serine protease papain[119] carboxypeptidase A 13,7 % inhibition[123] Phosphorylase/ Cysteine hydrolase like proteinase carboxypeptidase B[119] Phosphorylase/ hydrolase leucine aminopeptidase[119] Phosphorylase/ hydrolase thermolysin[119] Zincin-like chymostrypsin[119] ?Zincin-like or phosphorylase/ hydrolase antipain MEP (3.4.24.20) weak[165] Zincin-like serralysin[124] Zincin-like cytosol alanyl 0.1 mM, 39 % Phosphorylase/ aminopeptidase inhibition[93] hydrolase like (3.4.11.14) aminopeptidase Y 0.05 mg/ml, 19 % no pdb ?Zincin-like (3.4.11.15)[125] inhibition[125] (homology with LTA4H) alanyl aminopeptidase 0.1 mM, 47 % no pdb ?Zincin-like (N/M) (3.4.11.2)[107] inhibition[107] (homology with LTA4H) aminopeptidase P Creatinase/ (3.4.11.9)[126] aminopeptidase arginine no pdb ?Zincin-like aminopeptidase (B) (homology with (3.4.11.6)[127] LTA4H) tissue kallkrein No pdb/no (3.4.21.B47)[128] sequence renal tissue kallikrein Trypsin-like (3.4.21.35)[128] serine protease plasma kallikrein Trypsin-like (3.4.21.34)[129, 130] serine protease chymase partial[166] Trypsin-like (3.4.21.39)[131] serine protease 0.01 mM, 94 % Trypsin-like tryptase (3.4.21.59)[131, inhibition[167] serine protease 132] slight[168] Trypsin-like lysyl endopeptidase serine protease (3.4.21.50) [169] IC50 = 43 nM Trypsin-like u-plasminogenactivator serine protease (3.4.21.73) Trypsin-like granzyme B serine protease (3.4.21.79)[133] Trypsin-like enteropeptidase serine protease (3.4.21.9)[134] [115] IC50 = 0.065 mM Trypsin-like picornain 2A serine protease (3.4.22.29)[135] Cysteine dipeptidyl proteinase aminopeptidase (3.4.14.1)[136, 137] 1 µM, 93 % Cysteine cathepsin B inhibition[170] proteinase (3.4.22.1)[138-148] strongly [149] Cysteine cathepsin L proteinase (3.4.22.15)[149-151] 0.1 mM, 91 % Cysteine cathepsin H inhibition[152] proteinase (3.4.22.16)[152] 0.01 mM, 53 % inhibition[171] Cysteine proteinase papain (3.4.22.2)[153] 0.05 µM, complete ?Cysteine V-cath endopeptidase inhibition[154] proteinase (3.4.22.50)[154] (homology with cathepsin F) 0.01 mM, 80 – 90 % No pdb Cysteine calpain-1 inhibition[155] proteinase (3.4.22.52)[155] 0.01 mM, 80 - 90 % Cysteine calpain-2 inhibition[155] proteinase (3.4.22.53)[156, 157] 0.02 mM, 82 – 87 % [172] loss of activity 0.05 mM, complete [173] inhibition [174] Ki = 2.06 µM Subtilisin-like subtilisin (3.4.21.62)[158] Subtilisin-like thermitase (3.4.21.66)[159] moderately [160] Subtilisin-like furin (3.4.21.75) [160, 161] 1 mM, 35.9 - 45.7 % activity[175] 1bcr[56] Alpha/beta carboxypeptidase D hydrolase (3.4.16.6)[56] no pdb ?Phosphorylase tripeptidase /hydrolase like aminopeptidase (homology with (3.4.11.4)[162] Peptidase T) no pdb ?Alpha/beta oligopeptidase B hydrolase (3.4.21.83)[163, 164] (homology with prolyloligopeptid ase) [48] [48] aranciamycin anthracycline bacterial collagenase IC50 = 0.37 µM CUB-like elastase ?(depends on (3.4.24.3) type) trypsin[48] Trypsin-like serine proteases [178] arphamenine A arginine IC50 = 0.007 µg/mL No pdb ?Zincin-like leucine ? [178] aminopeptidase (B) IC50 = 0.005 µg/mL (homology with aminopeptidase [176] [179] (3.4.11.6) Ki = 2.5 nM LTA4H) (EC.?) carboxypeptidase A [177] Phosphorylase/ aminopeptidase A ? (inhibited by hydrolase like (EC. ?) derivatives) alanyl aminopeptidase 0.5 mM, 42 % no pdb ?Zincin-like (N/M) (3.4.11.2)[91] inhibition[91] (homology with LTA4H) cystinyl Phosphorylase/ aminopeptidase hydrolase like (3.4.11.3)[50] leucine Phosphorylase/ aminopeptidase hydrolase like (3.4.11.1)[50] dipeptidyl No pdb aminopeptidase No sequence (3.4.14.4)[176] match ACE[176] Zincin-like carboxypeptidase No pdb ?Zincin-like (3.4.17.19)[176] (homology search) cytosol alanyl 0.1 mM, 80 % Phosphorylase/ aminopeptidase inhibition[93] hydrolase like (3.4.11.14) [179] arphamenine B arginine Ki = 0.84 nM No pdb ?Zincin-like leucine ? aminopeptidase (B) (homology with aminopeptidase (3.4.11.6)[87] LTA4H) (EC.?) ? carboxypeptidase A [177] Phosphorylase/ aminopeptidase A (inhibited by hydrolase like (EC.