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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
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  1. The Scripps Research Inst., Jupiter, FL (United States)
  2. Argonne National Lab. (ANL), Argonne, IL (United States)
  3. Rice Univ., Houston, TX (United States)
+ Show Author Affiliations

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. Here, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357; GM094585; GM098248; CA106150
OSTI ID:
1248045
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, Issue 41; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 40 works
Citation information provided by
Web of Science

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Cited By (15)

A prominent glycyl radical enzyme in human gut microbiomes metabolizes trans -4-hydroxy-l-proline journal February 2017
Diversity of Gene Clusters for Polyketide and Nonribosomal Peptide Biosynthesis Revealed by Metagenomic Analysis of the Yellow Sea Sediment journal February 2018
Evolutionary dynamics of natural product biosynthesis in bacteria journal January 2020
Unraveling the iterative type I polyketide synthases hidden in Streptomyces journal March 2020
Protein–protein interactions in polyketide synthase–nonribosomal peptide synthetase hybrid assembly lines journal January 2018
Discovery of the leinamycin family of natural products by mining actinobacterial genomes journal December 2017
Acquisition and loss of secondary metabolite clusters shaped the evolutionary path of three recently emerged phytopathogens of wheat posted_content March 2018
Antibiotics from Gram-negative bacteria: a comprehensive overview and selected biosynthetic highlights journal January 2017
Protein–protein interactions in trans -AT polyketide synthases journal January 2018
A 3‐hydroxy‐3‐methylglutaryl‐CoA synthase‐based probe for the discovery of the acyltransferase‐less type I polyketide synthases journal September 2019
A 3-hydroxy-3-methylglutaryl-CoA synthase-based probe for the discovery of the acyltransferase-less type I polyketide synthases posted_content January 2019
Characterization of the Ketosynthase and Acyl Carrier Protein Domains at the LnmI Nonribosomal Peptide Synthetase–Polyketide Synthase Interface for Leinamycin Biosynthesis journal August 2016
The modules of trans -acyltransferase assembly lines redefined with a central acyl carrier protein journal March 2018
Acyltransferases as Tools for Polyketide Synthase Engineering journal July 2018
Acquisition and Loss of Secondary Metabolites Shaped the Evolutionary Path of Three Emerging Phytopathogens of Wheat journal February 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
biosynthesis
iso-migrastatin
leinamycin
oxazolomycin
secondary metabolism