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

Skiba, Meredith A.; Sikkema, Andrew P.; Fiers, William D.; Gerwick, William H.; Sherman, David H.; Aldrich, Courtney C.; Smith, Janet L.

doi:10.1021/acschembio.6b00759

Title: 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

DOI:https://doi.org/10.1021/acschembio.6b00759· OSTI ID:1368252

Skiba, Meredith A. ^[1]; Sikkema, Andrew P. ^[1]; Fiers, William D. ^[2]; Gerwick, William H. ^[3]; Sherman, David H. ^[1]; Aldrich, Courtney C. ^[2]; Smith, Janet L. ^[1]

Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Minnesota, Minneapolis, MN (United States)
Univ. of California San Diego, La Jolla, CA (United States)

Polyketide metabolites produced by modular type I polyketide synthases (PKS) acquire their chemical diversity through the variety of catalytic domains within modules of the pathway. Methyltransferases are among the least characterized of the catalytic domains common to PKS systems. We determined the domain boundaries and characterized the activity of a PKS C-methyltransferase (C-MT) from the curacin A biosynthetic pathway. The C-MT catalyzes S-adenosylmethionine-dependent methyl transfer to the α-position of β-ketoacyl substrates linked to acyl carrier protein (ACP) or a small-molecule analog but does not act on β-hydroxyacyl substrates or malonyl-ACP. Key catalytic residues conserved in both bacterial and fungal PKS C-MTs were identified in a 2 Å crystal structure and validated biochemically. As a result, analysis of the structure and the sequences bordering the C-MT provides insight into the positioning of this domain within complete PKS modules.

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

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Health; National Inst. of General Medical Sciences; National Cancer Inst.

Grant/Contract Number:: AC02-06CH11357; DK042303; CA108874; AGM-12006; ACB-12002

OSTI ID:: 1368252

Journal Information:: ACS Chemical Biology, Vol. 11, Issue 12; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 31 works

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References (48)

Polyketides, proteins and genes in fungi: programmed nano-machines begin to reveal their secrets Cox, Russell J. Organic & Biomolecular Chemistry, Vol. 5, Issue 13 https://doi.org/10.1039/b704420h	journal	January 2007
The structures of type I polyketide synthases Keatinge-Clay, Adrian T. Natural Product Reports, Vol. 29, Issue 10 https://doi.org/10.1039/c2np20019h	journal	January 2012
The type I fatty acid and polyketide synthases: a tale of two megasynthases Smith, Stuart; Tsai, Shiou-Chuan Natural Product Reports, Vol. 24, Issue 5 https://doi.org/10.1039/b603600g	journal	January 2007
New insights into the formation of fungal aromatic polyketides Crawford, Jason M.; Townsend, Craig A. Nature Reviews Microbiology, Vol. 8, Issue 12 https://doi.org/10.1038/nrmicro2465	journal	November 2010
Iron acquisition in plague: modular logic in enzymatic biogenesis of yersiniabactin by Yersinia pestis Gehring, Amy M.; DeMoll, Edward; Fetherston, Jacqueline D. Chemistry & Biology, Vol. 5, Issue 10 https://doi.org/10.1016/S1074-5521(98)90115-6	journal	October 1998
Lovastatin biosynthesis in Aspergillus terreus: Characterization of blocked mutants, enzyme activities and a multifunctional polyketide synthase gene Hendrickson, Lee; Ray Davis, C.; Roach, Claudia Chemistry & Biology, Vol. 6, Issue 7 https://doi.org/10.1016/S1074-5521(99)80061-1	journal	July 1999
Modulation of Polyketide Synthase Activity by Accessory Proteins During Lovastatin Biosynthesis Kennedy, J. Science, Vol. 284, Issue 5418 https://doi.org/10.1126/science.284.5418.1368	journal	May 1999
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
Biosynthetic Characterization and Chemoenzymatic Assembly of the Cryptophycins. Potent Anticancer Agents from Nostoc Cyanobionts Magarvey, Nathan A.; Beck, Zachary Q.; Golakoti, Trimurtulu ACS Chemical Biology, Vol. 1, Issue 12 https://doi.org/10.1021/cb6004307	journal	December 2006
Cloning and Biochemical Characterization of the Hectochlorin Biosynthetic Gene Cluster from the Marine Cyanobacterium Lyngbya majuscula Ramaswamy, Aishwarya V.; Sorrels, Carla M.; Gerwick, William H. Journal of Natural Products, Vol. 70, Issue 12 https://doi.org/10.1021/np0704250	journal	December 2007
Identification of the Putative Bryostatin Polyketide Synthase Gene Cluster from “ Candidatus Endobugula sertula”, the Uncultivated Microbial Symbiont of the Marine Bryozoan Bugula neritina Sudek, Sebastian; Lopanik, Nicole B.; Waggoner, Laura E. Journal of Natural Products, Vol. 70, Issue 1 https://doi.org/10.1021/np060361d	journal	December 2006
Structural organization of microcystin biosynthesis in Microcystis aeruginosa PCC7806: an integrated peptide–polyketide synthetase system Tillett, Daniel; Dittmann, Elke; Erhard, Marcel Chemistry & Biology, Vol. 7, Issue 10 https://doi.org/10.1016/S1074-5521(00)00021-1	journal	October 2000
Identification and Characterization of the Chaetoviridin and Chaetomugilin Gene Cluster in Chaetomium globosum Reveal Dual Functions of an Iterative Highly-Reducing Polyketide Synthase Winter, Jaclyn M.; Sato, Michio; Sugimoto, Satoru Journal of the American Chemical Society, Vol. 134, Issue 43 https://doi.org/10.1021/ja3090498	journal	October 2012
Elucidation of Gephyronic Acid Biosynthetic Pathway Revealed Unexpected SAM-Dependent Methylations Young, Jeanette; Stevens, D. Cole; Carmichael, Rory Journal of Natural Products, Vol. 76, Issue 12 https://doi.org/10.1021/np400629v	journal	November 2013
Cloning and Heterologous Expression of the Epothilone Gene Cluster Tang, L. Science, Vol. 287, Issue 5453 https://doi.org/10.1126/science.287.5453.640	journal	January 2000
In silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites Ansari, Mohd; Sharma, Jyoti; Gokhale, Rajesh S. BMC Bioinformatics, Vol. 9, Issue 1 https://doi.org/10.1186/1471-2105-9-454	journal	January 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
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
Understanding Programming of Fungal Iterative Polyketide Synthases: The Biochemical Basis for Regioselectivity by the Methyltransferase Domain in the Lovastatin Megasynthase Cacho, Ralph A.; Thuss, Justin; Xu, Wei Journal of the American Chemical Society, Vol. 137, Issue 50 https://doi.org/10.1021/jacs.5b11814	journal	December 2015
Yersiniabactin Synthetase Miller, Deborah Ann; Luo, Lusong; Hillson, Nathan Chemistry & Biology, Vol. 9, Issue 3 https://doi.org/10.1016/S1074-5521(02)00115-1	journal	March 2002
Divergent Mechanistic Routes for the Formation of gem -Dimethyl Groups in the Biosynthesis of Complex Polyketides Poust, Sean; Phelan, Ryan M.; Deng, Kai Angewandte Chemie International Edition, Vol. 54, Issue 8 https://doi.org/10.1002/anie.201410124	journal	January 2015
Methyltransferases excised from trans-AT polyketide synthases operate on N-acetylcysteamine-bound substrates Stevens, D. Cole; Wagner, Drew T.; Manion, Hannah R. The Journal of Antibiotics, Vol. 69, Issue 7 https://doi.org/10.1038/ja.2016.66	journal	June 2016
α-Methylation follows condensation in the gephyronic acid modular polyketide synthase Wagner, Drew T.; Stevens, D. Cole; Mehaffey, M. Rachel Chemical Communications, Vol. 52, Issue 57 https://doi.org/10.1039/C6CC04418B	journal	January 2016
Structure of Curacin A, a Novel Antimitotic, Antiproliferative and Brine Shrimp Toxic Natural Product from the Marine Cyanobacterium Lyngbya majuscula Gerwick, William H.; Proteau, Philip J.; Nagle, Dale G. The Journal of Organic Chemistry, Vol. 59, Issue 6 https://doi.org/10.1021/jo00085a006	journal	March 1994
Crystal Structures of Dehydratase Domains from the Curacin Polyketide Biosynthetic Pathway Akey, David L.; Razelun, Jamie R.; Tehranisa, Jason Structure, Vol. 18, Issue 1 https://doi.org/10.1016/j.str.2009.10.018	journal	January 2010
Terminal Alkene Formation by the Thioesterase of Curacin A Biosynthesis: STRUCTURE OF A DECARBOXYLATING THIOESTERASE Gehret, Jennifer J.; Gu, Liangcai; Gerwick, William H. Journal of Biological Chemistry, Vol. 286, Issue 16 https://doi.org/10.1074/jbc.M110.214635	journal	February 2011
Structural Basis of Functional Group Activation by Sulfotransferases in Complex Metabolic Pathways McCarthy, Jennifer Gehret; Eisman, Eli B.; Kulkarni, Sarang ACS Chemical Biology, Vol. 7, Issue 12 https://doi.org/10.1021/cb300385m	journal	September 2012
GNAT-Like Strategy for Polyketide Chain Initiation Gu, L.; Geders, T. W.; Wang, B. Science, Vol. 318, Issue 5852 https://doi.org/10.1126/science.1148790	journal	November 2007
Metamorphic enzyme assembly in polyketide diversification Gu, Liangcai; Wang, Bo; Kulkarni, Amol Nature, Vol. 459, Issue 7247 https://doi.org/10.1038/nature07870	journal	June 2009
Structural Basis for Cyclopropanation by a Unique Enoyl-Acyl Carrier Protein Reductase Khare, Dheeraj; Hale, Wendi A.; Tripathi, Ashootosh Structure, Vol. 23, Issue 12 https://doi.org/10.1016/j.str.2015.09.013	journal	December 2015
Conformational switch triggered by -ketoglutarate in a halogenase of curacin A biosynthesis Khare, D.; Wang, B.; Gu, L. Proceedings of the National Academy of Sciences, Vol. 107, Issue 32 https://doi.org/10.1073/pnas.1006738107	journal	July 2010
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 Structure of a Ketoreductase Determines the Organization of the β-Carbon Processing Enzymes of Modular Polyketide Synthases Keatinge-Clay, Adrian T.; Stroud, Robert M. Structure, Vol. 14, Issue 4 https://doi.org/10.1016/j.str.2006.01.009	journal	April 2006
Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases Herbst, Dominik A.; Jakob, Roman P.; Zähringer, Franziska Nature, Vol. 531, Issue 7595 https://doi.org/10.1038/nature16993	journal	March 2016
Structural and functional studies of a trans -acyltransferase polyketide assembly line enzyme that catalyzes stereoselective α- and β-ketoreduction: Structure and Function of a PKS α-Ketoreductase Piasecki, Shawn K.; Zheng, Jianting; Axelrod, Abram J. Proteins: Structure, Function, and Bioinformatics, Vol. 82, Issue 9 https://doi.org/10.1002/prot.24561	journal	April 2014
Divergence of multimodular polyketide synthases revealed by a didomain structure Zheng, Jianting; Gay, Darren C.; Demeler, Borries Nature Chemical Biology, Vol. 8, Issue 7 https://doi.org/10.1038/nchembio.964	journal	May 2012
Portability and Structure of the Four-Helix Bundle Docking Domains of trans -Acyltransferase Modular Polyketide Synthases Zeng, Jia; Wagner, Drew T.; Zhang, Zhicheng ACS Chemical Biology, Vol. 11, Issue 9 https://doi.org/10.1021/acschembio.6b00345	journal	July 2016
Structural and Functional Analysis of A-Type Ketoreductases from the Amphotericin Modular Polyketide Synthase Zheng, Jianting; Taylor, Clint A.; Piasecki, Shawn K. Structure, Vol. 18, Issue 8 https://doi.org/10.1016/j.str.2010.04.015	journal	August 2010
Structural Studies of an A2-Type Modular Polyketide Synthase Ketoreductase Reveal Features Controlling α-Substituent Stereochemistry Zheng, Jianting; Piasecki, Shawn K.; Keatinge-Clay, Adrian T. ACS Chemical Biology, Vol. 8, Issue 9 https://doi.org/10.1021/cb400161g	journal	June 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
A Tylosin Ketoreductase Reveals How Chirality Is Determined in Polyketides Keatinge-Clay, Adrian T. Chemistry & Biology, Vol. 14, Issue 8 https://doi.org/10.1016/j.chembiol.2007.07.009	journal	August 2007
Structural and Stereochemical Analysis of a Modular Polyketide Synthase Ketoreductase Domain Required for the Generation of a cis-Alkene Bonnett, Shilah A.; Whicher, Jonathan R.; Papireddy, Kancharla Chemistry & Biology, Vol. 20, Issue 6 https://doi.org/10.1016/j.chembiol.2013.04.014	journal	June 2013
Conservation and Functional Importance of Carbon–Oxygen Hydrogen Bonding in AdoMet-Dependent Methyltransferases Horowitz, Scott; Dirk, Lynnette M. A.; Yesselman, Joseph D. Journal of the American Chemical Society, Vol. 135, Issue 41 https://doi.org/10.1021/ja407140k	journal	October 2013
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
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
Cloning and characterization of a phosphopantetheinyl transferase from Streptomyces verticillus ATCC15003, the producer of the hybrid peptide–polyketide antitumor drug bleomycin Sánchez, César; Du, Liangcheng; Edwards, Daniel J. Chemistry & Biology, Vol. 8, Issue 7 https://doi.org/10.1016/S1074-5521(01)00047-3	journal	July 2001
Functional Characterization of a Dehydratase Domain from the Pikromycin Polyketide Synthase Li, Yang; Dodge, Greg J.; Fiers, William D. Journal of the American Chemical Society, Vol. 137, Issue 22 https://doi.org/10.1021/jacs.5b02325	journal	June 2015

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Insight into Structural Characteristics of Protein-Substrate Interaction in Pimaricin Thioesterase Fan, Shuobing; Wang, Rufan; Li, Chen International Journal of Molecular Sciences, Vol. 20, Issue 4 https://doi.org/10.3390/ijms20040877	journal	February 2019
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Molecular basis of methylation and chain-length programming in a fungal iterative highly reducing polyketide synthase Yang, Xiao-Long; Friedrich, Steffen; Yin, Sen Chemical Science, Vol. 10, Issue 36 https://doi.org/10.1039/c9sc03173a	journal	January 2019
Strobilurin biosynthesis in Basidiomycete fungi Nofiani, Risa; de Mattos-Shipley, Kate; Lebe, Karen E. Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-06202-4	journal	September 2018
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Title: Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase

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