An Enzymatic Domain for the Formation of Cyclic Ethers in Complex Polyketides

Pöplau, Petra; Frank, Sarah; Morinaka, Brandon I.; Piel, Jörn

doi:10.1002/anie.201307406

Cited by 83 publications

(77 citation statements)

References 41 publications

(15 reference statements)

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“…They may also mediate the interconversion of α/β- trans , γ/δ- cis and α/β- cis , γ/δ- trans dienes as appears to be the role of the DH-like enzyme at the C-terminal end of type C dehydrating bimodules. Other reactions catalyzed by DH-like enzymes within trans -AT PKSs include double bond-shifting, either in the same site that catalyzes dehydration or in an active site devoted to isomerization, as in the case of enoyl-isomerases (Moldenhauer et al, 2010; Gay et al, 2014b), as well as pyran and furan formation (Pöplau et al, 2013). The diverse chemistries catalyzed by these highly-related enzymes warrant mechanistic attention.…”

Section: Resultsmentioning

confidence: 99%

Structural and Functional Trends in Dehydrating Bimodules from trans-Acyltransferase Polyketide Synthases

et al. 2017

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SUMMARY In an effort to uncover the structural motifs and biosynthetic logic of the relatively uncharacterized trans-acyltransferase polyketide synthases, we have begun the dissection of the enigmatic dehydrating bimodules common in these enzymatic assembly lines. We report the 1.98 Å-resolution structure of a ketoreductase (KR) from the first half of a type A dehydrating bimodule and the 2.22 Å-resolution structure of a dehydratase (DH) from the second half of a type B dehydrating bimodule. The KR, from the third module of the bacillaene synthase, and the DH, from the tenth module of the difficidin synthase, possess features not observed in structurally-characterized homologs. The DH architecture provides clues for how it catalyzes a unique double dehydration. Correlations between the chemistries proposed for dehydrating bimodules and bioinformatic analysis indicate that type A dehydrating bimodules generally produce an α/β-cis alkene moiety while type B dehydrating bimodules generally produce an α/β-trans, γ/δ-cis diene moiety.

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Section: Resultsmentioning

confidence: 99%

Structural and Functional Trends in Dehydrating Bimodules from trans-Acyltransferase Polyketide Synthases

et al. 2017

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“…Architecturally, it closely follows the trans-AT colinearity rules 22 , with the exception of an apparently skipped last module and the as-yet unknown formation of the tail-associated tetrahydropyran (THP) ring. Biosynthesis of this THP unit is still unclear; unlike in the dihydropyran system in the macrolide portion, the corresponding PKS module lacks a PS domain 39 . The module harbors an aberrant DH domain that might be involved in cyclization 42 .…”

Section: Discussionmentioning

confidence: 99%

Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms

et al. 2015

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Actin-targeting macrolides comprise a large, structurally diverse group of cytotoxins isolated from remarkably dissimilar micro- and macroorganisms. In spite of their disparate origins and structures, many of these compounds bind actin at the same site and exhibit structural relationships reminiscent of modular, combinatorial drug libraries. Here we investigate biosynthesis and evolution of three compound groups: misakinolides, scytophycin-type compounds and luminaolides. For misakinolides from the sponge Theonella swinhoei WA, our data suggest production by an uncultivated 'Entotheonella' symbiont, further supporting the relevance of these bacteria as sources of bioactive polyketides and peptides in sponges. Insights into misakinolide biosynthesis permitted targeted genome mining for other members, providing a cyanobacterial luminaolide producer as the first cultivated source for this dimeric compound family. The data indicate that this polyketide family is bacteria-derived and that the unusual macrolide diversity is the result of combinatorial pathway modularity for some compounds and of convergent evolution for others.

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“…S1B) (8). Two other modifications found within AT-less type I PKSs are pyran/furan formation by pyran synthase domains (9) and migration of α/β alkenes to β/γ alkenes by enoyl-isomerases (SI Appendix, Fig. S1 A and C) (10).…”

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confidence: 99%

Structural and evolutionary relationships of “AT-less” type I polyketide synthase ketosynthases

Lohman

Osipiuk

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Acyltransferase (AT)-less type I polyketide synthases (PKSs) break the type I PKS paradigm. They lack the integrated AT domains within their modules and instead use a discrete AT that acts in trans, whereas a type I PKS module minimally contains AT, acyl carrier protein (ACP), and ketosynthase (KS) domains. Structures of canonical type I PKS KS-AT didomains reveal structured linkers that connect the two domains. AT-less type I PKS KSs have remnants of these linkers, which have been hypothesized to be AT docking domains. Natural products produced by AT-less type I PKSs are very complex because of an increased representation of unique modifying domains. AT-less type I PKS KSs possess substrate specificity and fall into phylogenetic clades that correlate with their substrates, whereas canonical type I PKS KSs are monophyletic. We have solved crystal structures of seven AT-less type I PKS KS domains that represent various sequence clusters, revealing insight into the large structural and subtle amino acid residue differences that lead to unique active site topologies and substrate specificities. One set of structures represents a larger group of KS domains from both canonical and AT-less type I PKSs that accept amino acid-containing substrates. One structure has a partial AT-domain, revealing the structural consequences of a type I PKS KS evolving into an AT-less type I PKS KS. These structures highlight the structural diversity within the AT-less type I PKS KS family, and most important, provide a unique opportunity to study the molecular evolution of substrate specificity within the type I PKSs.biosynthesis | secondary metabolism | iso-migrastatin | leinamycin | oxazolomycin

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An Enzymatic Domain for the Formation of Cyclic Ethers in Complex Polyketides

Abstract: We thank Roy Meoded for technical assistance with protein expression. We are grateful for financial support from the EU (BlueGenics to J.P.), the DFG (SFB 642 and PI 430/8-1 to J.P.), and the Alexander von Humboldt Foundation (to B.M.).

Cited by 83 publications

References 41 publications

Structural and Functional Trends in Dehydrating Bimodules from trans-Acyltransferase Polyketide Synthases

Structural and Functional Trends in Dehydrating Bimodules from trans-Acyltransferase Polyketide Synthases

Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms

Structural and evolutionary relationships of “AT-less” type I polyketide synthase ketosynthases

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