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Evolutionary Implications of Bacterial Polyketide Synthases

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Evolutionary Implications of Bacterial Polyketide Synthases Evolutionary Implications of Bacterial Polyketide Synthases Holger Jenke-Kodama,* Axel Sandmann, Rolf Mu¨ller, and Elke Dittmann* *Humboldt University, Institute of Biology, Chausseestrasse, Berlin, Germany; and Pharmaceutical Biotechnology, Saarland University, Saarbru¨cken, Germany Polyketide synthases (PKS) perform a stepwise biosynthesis of diverse carbon skeletons from simple activated carboxylic acid units. The products of the complex pathways possess a wide range of pharmaceutical properties, including antibiotic, antitumor, antifungal, and immunosuppressive activities. We have performed a comprehensive phylogenetic analysis of multimodular and iterative PKS of bacteria and fungi and of the distinct types of fatty acid synthases (FAS) from different groups of organisms based on the highly conserved ketoacyl synthase (KS) domains. Apart from enzymes that meet the classification standards we have included enzymes involved in the biosynthesis of mycolic acids, polyunsaturated fatty acids (PUFA), and glycolipids in bacteria. This study has revealed that PKS and FAS have passed through a long joint evolution process, in which modular PKS have a central position. They appear to have derived from bacterial FAS and primary iterative PKS and, in addition, share a common ancestor with animal FAS and secondary iterative PKS. Further- Downloaded from https://academic.oup.com/mbe/article/22/10/2027/1138202 by guest on 24 September 2021 more, we have carried out a phylogenomic analysis of all modular PKS that are encoded by the complete eubacterial genomes currently available in the database. The phylogenetic distribution of acyltransferase and KS domain sequences revealed that multiple gene duplications, gene losses, as well as horizontal gene transfer (HGT) have contributed to the evolution of PKS I in bacteria. The impact of these factors seems to vary considerably between the bacterial groups. Whereas in actinobacteria and cyanobacteria the majority of PKS I genes may have evolved from a common ancestor, several lines of evidence indicate that HGT has strongly contributed to the evolution of PKS I in proteobacteria. Discovery of new evolutionary links between PKS and FAS and between the different PKS pathways in bacteria may help us in understanding the selective advantage that has led to the evolution of multiple secondary metabolite biosyntheses within individual bacteria. Introduction The polyketide class of natural products shows a re- that comprise iteratively acting modules, e.g., the biosyn- markable functional and structural diversity. Apart from be- thesis of aureothin (He and Hertweck 2003). ing toxic for microorganisms or higher eukaryotes, some of Modular PKS I are predominantly found in actinobac- the compounds play a role in metal transport (Crosa and teria, myxobacteria, pseudomonades, and cyanobacteria Walsh 2002), others are closely linked to microbial differ- (Bode and Mu¨ller 2005). A minimal module is composed entiation (Black and Wolk 1994; Ohnishi et al. 1999). Poly- of a ketoacyl synthase (KS) domain, an acyltransferase ketides are classified according to the architecture of their (AT) domain, and an acyl carrier protein (ACP) domain. Fre- biosynthesis enzymes. Each of the classes of polyketide quently ketoreductase (KR), dehydratase (DH), and enoyl synthases (PKS) resembles one of the classes of fatty acid reductase (ER) domains are also embedded in the multifunc- synthases (FAS): the type I PKS possess a multidomain tional megasynthases (fig. 1). Genetics and biochemistry of architecture similar to the type I FAS of fungi and animals bacterial type I polyketide biosynthesis has been well inves- and type II PKS carry each catalytic site on a separate tigated for the biosynthesis of the aglycone of erythromycin protein, characteristic of FAS II found in bacteria and in Saccharopolyspora erythrea (Donadio et al. 1991). These plants (fig. 1). Whereas fungi usually contain monomodular findings have subsequently led to the elucidation of many iterative PKS I, the majority of bacterial PKS I consists of PKS I pathways, in particular those involved in the forma- multiple sets of domains, or modules, that normally corre- tion of promising drug leads (for review, see Staunton and spond to the number of acyl units in the product (Staunton Weissman 2001). In bacteria, the type I PKS pathway is fre- and Weissman 2001, fig. 1). Apart from the clearly defined quently co-occurring with a second type of natural product PKS and FAS types an increasing number of biosynthe- pathway, the nonribosomal peptide synthetases (NRPS, sis pathways are described in the literature that show Shen et al. 2001). Both types of enzymes can form hybrid hitherto unknown organization forms (Moss, Martin, and biosynthesis complexes, and modules of both enzyme clas- Wilkinson 2004). Enzymes involved in the biosynthesis ses can even form hybrid synthetases (Duitman et al. 1999; of x-3-polyunsaturated fatty acids (PUFA) in Shewanella Paitan et al. 1999; Silakowski et al. 1999). are authentic bacterial iterative PKS I (Metz et al. 2001, As striking as the number of PKS gene clusters in fig. 1) as well as enzymes involved in avilamycin (Gaitatzis some bacteria is the irregular distribution of metabolites et al. 2001), neocarzinostatin (Liu et al. 2005), and myxo- and the corresponding genes in single strains and genera chromide (Wenzel et al. 2005) biosynthesis in strepto- in all producing families of bacteria. This has raised the hy- mycetes and myxobacteria. Furthermore, a number of pothesis of a horizontal gene transfer (HGT) between bac- multimodular PKS I pathways are described in the literature terial strains. Recent phylogenetic studies of PKS I were based on the highly conserved KS domains. Kroken et al. (2003) have found evidence that fungal KS domains Key words: secondary metabolites, polyketides, multimodular enzymes, fatty acid synthases, Bayesian analysis. cluster according to the reduced or unreduced character of the polyketide products. Furthermore, KS domains from E-mail: [email protected]. hybrid PKS/NRPS complexes form a distinct branch in Mol. Biol. Evol. 22(10):2027–2039. 2005 doi:10.1093/molbev/msi193 phylogenetic trees (Shen et al. 2001). Piel et al. have shown Advance Access publication June 15, 2005 that KS domains fall into a separate group when distinct Ó The Author 2005. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: [email protected] 2028 Jenke-Kodama et al. Downloaded from https://academic.oup.com/mbe/article/22/10/2027/1138202 by guest on 24 September 2021 FIG. 1.—Schematic representation of fatty acid and polyketide biosynthesis. (A) Organization types of FAS and PKS. Distinct proteins are indicated as squares and domains integrated within proteins as circles, respectively. Optional domains of PKS I are designated. Enzymes additionally required for the synthesis of the respective end products are not shown. Example structures are provided next to each scheme. The roman numbers in brackets recur in the phylogenetic tree shown in figure 2. (B) Sequence of reactions performed by FAS and PKS. (C) Possibilities that follow each condensation step to give keto, hydroxyl, enoyl, or alkyl functionality, depending on the enyzmatic activities used by a PKS module. Abbreviations: KS, ketosynthase; AT, acyltransferase; DH, dehydratase; ER, enoyl reductase; KR, ketoreductase; ACP, acyl carrier protein; AcT, acetyltransferase; PPT, phosphopantetheinyl transferase. acyltransferases (so-called trans-ATs, fig. 1) are associated on the diversity and genealogy of all available fungal PKS with PKS I systems that lack internal ATs (Piel et al. 2004). sequences. The authors have concluded that the discontin- Whereas most of the studies were based on a limited set of uous distributions of orthologous PKS among fungal spe- data, Kroken et al. (2003) have presented a systematic study cies can be explained by gene duplication, divergence, and Evolution of Secondary Metabolites in Bacteria 2029 gene loss and that HGT among fungi was not necessarily with known substrate specificities from biochemically char- involved in the evolution process. acterized pathways, (2) AT domains with substrate specif- A systematic study on the evolution of bacterial PKS is icities predicted by the SEARCHPKS program, (3) AT still missing. A high number of genomes of eubacteria has domains manually assigned to a substrate by analysis of been completely sequenced within the last few years (http:// amino acid residues assumed to be involved in substrate rec- www.ncbi.nlm.nih.gov/sutils/genom_table.cgi). Bioinfor- ognition, and (4) AT domains with unclear specificity. RNA matic approaches are now being developed for annotation sequences of the small ribosomal subunits (SSU RNA) were and specific analyses of the genomes. Yadav, Gokhale, and retrieved from the European ribosomal RNA database Mohanty (2003) have developed a platform for the analysis (http://www.psb.ugent.be/rRNA/ssu). of PKS megasynthases that includes almost all current The amino acid sequences of FabH and FabF homolo- knowledge about these types of enzymes and that can be gues and annotated FAS and PKS were retrieved from Gen- applied to dissect the arrangement of domains within these Bank(http://www.ncbi.nlm.nih.gov/sutils/genom_table.cgi). enzymes and to assign hypothetical substrate specificities of Downloaded from https://academic.oup.com/mbe/article/22/10/2027/1138202 by
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