Structural Basis of Polyketide Synthase O-Methylation

Skiba, Meredith A.; Bivins, Marissa M.; Schultz, John R.; Bernard, Steffen M.; Fiers, William D.; Dan, Qingyun; Kulkarni, Sarang; Wipf, Peter; Gerwick, William H.; Sherman, David H.; Aldrich, Courtney C.; Smith, Janet L.

doi:10.1021/acschembio.8b00687

Title: Structural Basis of Polyketide Synthase O-Methylation

Journal Article · Thu Nov 29 00:00:00 EST 2018 · ACS Chemical Biology

DOI:https://doi.org/10.1021/acschembio.8b00687· OSTI ID:1502222

^[1]; Bivins, Marissa M. ^[2]; Schultz, John R. ^[3]; Bernard, Steffen M. ^[4]; Fiers, William D. ^[5];

^[6]; Kulkarni, Sarang ^[7];

^[7];

^[8];

^[6];

^[3];

^[6]

Univ. of Michigan, Ann Arbor, MI (United States); Harvard Medical School, Boston, MA (United States)
Univ. of Michigan, Ann Arbor, MI (United States); Univ. of North Carolina, Chapel Hill, NC (United States)
Univ. of Minnesota, Minneapolis, MN (United States)
Univ. of Michigan, Ann Arbor, MI (United States); The Scripps Research Inst., La Jolla, CA (United States)
Univ. of Minnesota, Minneapolis, MN (United States); Weill Cornell Medicine, New York, NY (United States)
Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Pittsburgh, PA (United States)
Univ. of California, San Diego, La Jolla, CA (United States)

Modular type I polyketide synthases (PKSs) produce some of the most chemically complex metabolites in nature through a series of multienzyme modules. Each module contains a variety of catalytic domains to selectively tailor the growing molecule. PKS O-methyltransferases (O-MTs) are predicted to methylate β-hydroxyl or β-keto groups, but their activity and structure have not been reported. We determined the domain boundaries and characterized the catalytic activity and structure of the StiD and StiE O-MTs, which methylate opposite β-hydroxyl stereocenters in the myxobacterial stigmatellin biosynthetic pathway. Substrate stereospecificity was demonstrated for the StiD O-MT. Key catalytic residues were identified in the crystal structures and investigated in StiE O-MT via site-directed mutagenesis and further validated with the cyanobacterial CurL O-MT from the curacin biosynthetic pathway. Here the initial structural and biochemical analysis of PKS O-MTs supplies a new chemoenzymatic tool, with the unique ability to selectively modify hydroxyl groups during polyketide biosynthesis.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: DK042303; CA108874; GM008353

OSTI ID:: 1502222

Journal Information:: ACS Chemical Biology, Vol. 13, Issue 12; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 5 works

Citation information provided by
Web of Science

References (41)

An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea Cortes, Jesus; Haydock, Stephen F.; Roberts, Gareth A. Nature, Vol. 348, Issue 6297 https://doi.org/10.1038/348176a0	journal	November 1990
Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis Ikeda, H.; Nonomiya, T.; Usami, M. Proceedings of the National Academy of Sciences, Vol. 96, Issue 17 https://doi.org/10.1073/pnas.96.17.9509	journal	August 1999
The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Schwecke, T.; Aparicio, J. F.; Molnar, I. Proceedings of the National Academy of Sciences, Vol. 92, Issue 17 https://doi.org/10.1073/pnas.92.17.7839	journal	August 1995
Characterization of the Streptomyces peucetius ATCC 29050 genes encoding doxorubicin polyketide synthase Grimm, Ann; Madduri, Krishnamurthy; Ali, Arif Gene, Vol. 151, Issue 1-2 https://doi.org/10.1016/0378-1119(94)90625-4	journal	December 1994
Modular organization of genes required for complex polyketide biosynthesis Donadio, S.; Staver, M.; McAlpine, J. Science, Vol. 252, Issue 5006 https://doi.org/10.1126/science.2024119	journal	May 1991
Stereocontrol within polyketide assembly lines Keatinge-Clay, Adrian T. Natural Product Reports, Vol. 33, Issue 2 https://doi.org/10.1039/C5NP00092K	journal	January 2016
Elucidation of the Stereospecificity of C -Methyltransferases from trans -AT Polyketide Synthases Xie, Xinqiang; Khosla, Chaitan; Cane, David E. Journal of the American Chemical Society, Vol. 139, Issue 17 https://doi.org/10.1021/jacs.7b02911	journal	April 2017
The status of type I polyketide synthase ketoreductases Zheng, Jianting; Keatinge-Clay, Adrian T. Med. Chem. Commun., Vol. 4, Issue 1 https://doi.org/10.1039/C2MD20191G	journal	January 2013
Conserved Amino Acid Residues Correlating With Ketoreductase Stereospecificity in Modular Polyketide Synthases Caffrey, Patrick ChemBioChem, Vol. 4, Issue 7 https://doi.org/10.1002/cbic.200300581	journal	June 2003
Stereospecificity of the Dehydratase Domain of the Erythromycin Polyketide Synthase Valenzano, Chiara R.; You, Young-Ok; Garg, Ashish Journal of the American Chemical Society, Vol. 132, Issue 42 https://doi.org/10.1021/ja107344h	journal	October 2010
Structure and Stereospecificity of the Dehydratase Domain from the Terminal Module of the Rifamycin Polyketide Synthase Gay, Darren; You, Young-Ok; Keatinge-Clay, Adrian Biochemistry, Vol. 52, Issue 49 https://doi.org/10.1021/bi400988t	journal	November 2013
Vinylogous Dehydration by a Polyketide Dehydratase Domain in Curacin Biosynthesis Fiers, William D.; Dodge, Greg J.; Sherman, David H. Journal of the American Chemical Society, Vol. 138, Issue 49 https://doi.org/10.1021/jacs.6b09748	journal	November 2016
Stereospecific Formation of Z -Trisubstituted Double Bonds by the Successive Action of Ketoreductase and Dehydratase Domains from trans -AT Polyketide Synthases Xie, Xinqiang; Cane, David E. Biochemistry, Vol. 57, Issue 22 https://doi.org/10.1021/acs.biochem.7b01253	journal	January 2018
Stereospecificity of Enoylreductase Domains from Modular Polyketide Synthases Zhang, Luyun; Ji, Junjie; Yuan, Meijuan ACS Chemical Biology, Vol. 13, Issue 4 https://doi.org/10.1021/acschembio.7b00982	journal	February 2018
Prediction and Manipulation of the Stereochemistry of Enoylreduction in Modular Polyketide Synthases Kwan, David H.; Sun, Yuhui; Schulz, Frank Chemistry & Biology, Vol. 15, Issue 11 https://doi.org/10.1016/j.chembiol.2008.09.012	journal	November 2008
Engineering strategies for rational polyketide synthase design Klaus, Maja; Grininger, Martin Natural Product Reports, Vol. 35, Issue 10 https://doi.org/10.1039/C8NP00030A	journal	January 2018
New Lessons for Combinatorial Biosynthesis from Myxobacteria: THE MYXOTHIAZOL BIOSYNTHETIC GENE CLUSTER OF Silakowski, Barbara; Schairer, Hans Ulrich; Ehret, Heidi Journal of Biological Chemistry, Vol. 274, Issue 52 https://doi.org/10.1074/jbc.274.52.37391	journal	December 1999
The Biosynthesis of the Aromatic Myxobacterial Electron Transport Inhibitor Stigmatellin Is Directed by a Novel Type of Modular Polyketide Synthase Gaitatzis, Nikolaos; Silakowski, Barbara; Kunze, Brigitte Journal of Biological Chemistry, Vol. 277, Issue 15 https://doi.org/10.1074/jbc.M111738200	journal	April 2002
Melithiazol Biosynthesis Weinig, Stefan; Hecht, Hans-Jürgen; Mahmud, Taifo Chemistry & Biology, Vol. 10, Issue 10 https://doi.org/10.1016/j.chembiol.2003.09.012	journal	October 2003
Biosynthetic Pathway and Gene Cluster Analysis of Curacin A, an Antitubulin Natural Product from the Tropical Marine Cyanobacterium Lyngbya majuscula Chang, Zunxue; Sitachitta, Namthip; Rossi, James V. Journal of Natural Products, Vol. 67, Issue 8, p. 1356-1367 https://doi.org/10.1021/np0499261	journal	August 2004
Structure and Biosynthesis of the Jamaicamides, New Mixed Polyketide-Peptide Neurotoxins from the Marine Cyanobacterium Lyngbya majuscula Edwards, Daniel J.; Marquez, Brian L.; Nogle, Lisa M. Chemistry & Biology, Vol. 11, Issue 6 https://doi.org/10.1016/j.chembiol.2004.03.030	journal	June 2004
Construction of a Bacterial Artificial Chromosome Library for a Myxobacterium of the Genus Cystobacter and Characterization of an Antibiotic Biosynthetic Gene Cluster Feng, Zhiyang; Qi, Jianhua; Tsuge, Takashi Bioscience, Biotechnology, and Biochemistry, Vol. 69, Issue 7 https://doi.org/10.1271/bbb.69.1372	journal	January 2005
An Unusual Thioesterase Promotes Isochromanone Ring Formation in Ajudazol Biosynthesis Buntin, Kathrin; Weissman, Kira J.; Müller, Rolf ChemBioChem, Vol. 11, Issue 8 https://doi.org/10.1002/cbic.200900712	journal	April 2010
Genome streamlining and chemical defense in a coral reef symbiosis Kwan, J. C.; Donia, M. S.; Han, A. W. Proceedings of the National Academy of Sciences, Vol. 109, Issue 50 https://doi.org/10.1073/pnas.1213820109	journal	November 2012
Calyculin biogenesis from a pyrophosphate protoxin produced by a sponge symbiont Wakimoto, Toshiyuki; Egami, Yoko; Nakashima, Yu Nature Chemical Biology, Vol. 10, Issue 8 https://doi.org/10.1038/nchembio.1573	journal	June 2014
Biosynthesis of Crocacin Involves an Unusual Hydrolytic Release Domain Showing Similarity to Condensation Domains Müller, Stefan; Rachid, Shwan; Hoffmann, Thomas Chemistry & Biology, Vol. 21, Issue 7 https://doi.org/10.1016/j.chembiol.2014.05.012	journal	July 2014
Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties Krastel, Philipp; Roggo, Silvio; Schirle, Markus Angewandte Chemie International Edition, Vol. 54, Issue 35 https://doi.org/10.1002/anie.201505069	journal	July 2015
Isolation, Structure Elucidation, and (Bio)Synthesis of Haprolid, a Cell-Type-Specific Myxobacterial Cytotoxin Steinmetz, Heinrich; Li, Jun; Fu, Chengzhang Angewandte Chemie International Edition, Vol. 55, Issue 34 https://doi.org/10.1002/anie.201603288	journal	July 2016
Domain Organization and Active Site Architecture of a Polyketide Synthase C -methyltransferase Skiba, Meredith A.; Sikkema, Andrew P.; Fiers, William D. ACS Chemical Biology, Vol. 11, Issue 12 https://doi.org/10.1021/acschembio.6b00759	journal	October 2016
Functional and Structural Analysis of Programmed C-Methylation in the Biosynthesis of the Fungal Polyketide Citrinin Storm, Philip A.; Herbst, Dominik A.; Maier, Timm Cell Chemical Biology, Vol. 24, Issue 3 https://doi.org/10.1016/j.chembiol.2017.01.008	journal	March 2017
Cyanobacterial Polyketide Synthase Docking Domains: A Tool for Engineering Natural Product Biosynthesis Whicher, Jonathan R.; Smaga, Sarah S.; Hansen, Douglas A. Chemistry & Biology, Vol. 20, Issue 11 https://doi.org/10.1016/j.chembiol.2013.09.015	journal	November 2013
The Missing Linker: A Dimerization Motif Located within Polyketide Synthase Modules Zheng, Jianting; Fage, Christopher D.; Demeler, Borries ACS Chemical Biology, Vol. 8, Issue 6 https://doi.org/10.1021/cb400047s	journal	March 2013
Facile Detection of Acyl and Peptidyl Intermediates on Thiotemplate Carrier Domains via Phosphopantetheinyl Elimination Reactions during Tandem Mass Spectrometry ^† Dorrestein, Pieter C.; Bumpus, Stefanie B.; Calderone, Christopher T. Biochemistry, Vol. 45, Issue 42 https://doi.org/10.1021/bi061169d	journal	October 2006
Top-down mass spectrometry on low-resolution instruments: Characterization of phosphopantetheinylated carrier domains in polyketide and non-ribosomal biosynthetic pathways Meluzzi, Dario; Zheng, Wei Hao; Hensler, Mary Bioorganic & Medicinal Chemistry Letters, Vol. 18, Issue 10 https://doi.org/10.1016/j.bmcl.2007.10.104	journal	May 2008
Architectures, mechanisms and molecular evolution of natural product methyltransferases Liscombe, David K.; Louie, Gordon V.; Noel, Joseph P. Natural Product Reports, Vol. 29, Issue 10 https://doi.org/10.1039/c2np20029e	journal	January 2012
Structure and Reaction Mechanism of Phosphoethanolamine Methyltransferase from the Malaria Parasite Plasmodium falciparum : AN ANTIPARASITIC DRUG TARGET Lee, Soon Goo; Kim, Youngchang; Alpert, Tara D. Journal of Biological Chemistry, Vol. 287, Issue 2 https://doi.org/10.1074/jbc.M111.315267	journal	November 2011
Crystal Structures of Mycolic Acid Cyclopropane Synthases from Mycobacterium tuberculosis Huang, Chih-chin; Smith, Clare V.; Glickman, Michael S. Journal of Biological Chemistry, Vol. 277, Issue 13 https://doi.org/10.1074/jbc.M111698200	journal	March 2002
Structure and Mechanism of the Rebeccamycin Sugar 4′-O-Methyltransferase RebM Singh, Shanteri; McCoy, Jason G.; Zhang, Changsheng Journal of Biological Chemistry, Vol. 283, Issue 33 https://doi.org/10.1074/jbc.M800503200	journal	August 2008
Structure of Geranyl Diphosphate C -Methyltransferase from Streptomyces coelicolor and Implications for the Mechanism of Isoprenoid Modification Köksal, Mustafa; Chou, Wayne K. W.; Cane, David E. Biochemistry, Vol. 51, Issue 14 https://doi.org/10.1021/bi300109c	journal	March 2012
The structure of SpnF, a standalone enzyme that catalyzes [4 + 2] cycloaddition Fage, Christopher D.; Isiorho, Eta A.; Liu, Yungnan Nature Chemical Biology, Vol. 11, Issue 4 https://doi.org/10.1038/nchembio.1768	journal	March 2015
The Crystal Structure of a Mammalian Fatty Acid Synthase Maier, T.; Leibundgut, M.; Ban, N. Science, Vol. 321, Issue 5894 https://doi.org/10.1126/science.1161269	journal	September 2008

Cited By (1)

General chemoenzymatic route to two-stereocenter triketides employing assembly line ketoreductases Zhang, Zhicheng; Cepeda, Alexis J.; Robles, Mireya L. Chemical Communications, Vol. 56, Issue 1 https://doi.org/10.1039/c9cc07966a	journal	January 2020

Figures / Tables (4)

Similar Records

Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase

Journal Article · Mon Oct 10 00:00:00 EDT 2016 · ACS Chemical Biology · OSTI ID:1502222

Skiba, Meredith A.; Sikkema, Andrew P.; Fiers, William D.; +4 more

Biosynthesis of t-Butyl in Apratoxin A: Functional Analysis and Architecture of a PKS Loading Module

Journal Article · Fri Apr 27 00:00:00 EDT 2018 · ACS Chemical Biology · OSTI ID:1502222

Skiba, Meredith A.; Sikkema, Andrew P.; Moss, Nathan A.; +7 more

Anatomy of the β-branching enzyme of polyketide biosynthesis and its interaction with an acyl-ACP substrate

Journal Article · Mon Aug 29 00:00:00 EDT 2016 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1502222

Maloney, Finn P.; Gerwick, Lena; Gerwick, William H.; +2 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
peptides and proteins
metabolism
monomers
chemical structure
alkyls