Structural and evolutionary relationships of “AT-less” type I polyketide synthase ketosynthases
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. 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 partialmore »
- Authors:
-
- The Scripps Research Inst., Jupiter, FL (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Rice Univ., Houston, TX (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
- OSTI Identifier:
- 1248045
- Grant/Contract Number:
- AC02-06CH11357; GM094585; GM098248; CA106150
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 112; Journal Issue: 41; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; biosynthesis; iso-migrastatin; leinamycin; oxazolomycin; secondary metabolism
Citation Formats
Lohman, Jeremy R., Ma, Ming, Osipiuk, Jerzy, Nocek, Boguslaw, Kim, Youngchang, Chang, Changsoo, Cuff, Marianne E., Mack, Jamey, Bigelow, Lance, Li, Hui, Endres, Michael, Babnigg, Gyorgy, Joachimiak, Andrzej, Phillips, Jr., George N., and Shen, Ben G. Structural and evolutionary relationships of “AT-less” type I polyketide synthase ketosynthases. United States: N. p., 2015.
Web. doi:10.1073/pnas.1515460112.
Lohman, Jeremy R., Ma, Ming, Osipiuk, Jerzy, Nocek, Boguslaw, Kim, Youngchang, Chang, Changsoo, Cuff, Marianne E., Mack, Jamey, Bigelow, Lance, Li, Hui, Endres, Michael, Babnigg, Gyorgy, Joachimiak, Andrzej, Phillips, Jr., George N., & Shen, Ben G. Structural and evolutionary relationships of “AT-less” type I polyketide synthase ketosynthases. United States. https://doi.org/10.1073/pnas.1515460112
Lohman, Jeremy R., Ma, Ming, Osipiuk, Jerzy, Nocek, Boguslaw, Kim, Youngchang, Chang, Changsoo, Cuff, Marianne E., Mack, Jamey, Bigelow, Lance, Li, Hui, Endres, Michael, Babnigg, Gyorgy, Joachimiak, Andrzej, Phillips, Jr., George N., and Shen, Ben G. Tue .
"Structural and evolutionary relationships of “AT-less” type I polyketide synthase ketosynthases". United States. https://doi.org/10.1073/pnas.1515460112. https://www.osti.gov/servlets/purl/1248045.
@article{osti_1248045,
title = {Structural and evolutionary relationships of “AT-less” type I polyketide synthase ketosynthases},
author = {Lohman, Jeremy R. and Ma, Ming and Osipiuk, Jerzy and Nocek, Boguslaw and Kim, Youngchang and Chang, Changsoo and Cuff, Marianne E. and Mack, Jamey and Bigelow, Lance and Li, Hui and Endres, Michael and Babnigg, Gyorgy and Joachimiak, Andrzej and Phillips, Jr., George N. and Shen, Ben G.},
abstractNote = {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.},
doi = {10.1073/pnas.1515460112},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 41,
volume = 112,
place = {United States},
year = {Tue Sep 29 00:00:00 EDT 2015},
month = {Tue Sep 29 00:00:00 EDT 2015}
}
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