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Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):12693-8. doi: 10.1073/pnas.1515460112. Epub 2015 Sep 29.

Structural and evolutionary relationships of "AT-less" type I polyketide synthase ketosynthases.

Author information

1
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
2
Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, IL 60439;
3
BioSciences at Rice, Rice University, Houston, TX 77251; Department of Chemistry, Rice University, Houston, TX 77251;
4
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458; Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL 33458 shenb@scripps.edu.

Abstract

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.

KEYWORDS:

biosynthesis; iso-migrastatin; leinamycin; oxazolomycin; secondary metabolism

PMID:
26420866
PMCID:
PMC4611616
DOI:
10.1073/pnas.1515460112
[Indexed for MEDLINE]
Free PMC Article

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