Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase
Abstract
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.
- Authors:
-
- 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)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- 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.
- OSTI Identifier:
- 1368252
- Grant/Contract Number:
- AC02-06CH11357; DK042303; CA108874; AGM-12006; ACB-12002
- Resource Type:
- Accepted Manuscript
- Journal Name:
- ACS Chemical Biology
- Additional Journal Information:
- Journal Volume: 11; Journal Issue: 12; Journal ID: ISSN 1554-8929
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Chemical structure; Peptides and proteins; Alkyls; Metabolism; Organic reactions
Citation Formats
Skiba, Meredith A., Sikkema, Andrew P., Fiers, William D., Gerwick, William H., Sherman, David H., Aldrich, Courtney C., and Smith, Janet L. Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase. United States: N. p., 2016.
Web. doi:10.1021/acschembio.6b00759.
Skiba, Meredith A., Sikkema, Andrew P., Fiers, William D., Gerwick, William H., Sherman, David H., Aldrich, Courtney C., & Smith, Janet L. Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase. United States. https://doi.org/10.1021/acschembio.6b00759
Skiba, Meredith A., Sikkema, Andrew P., Fiers, William D., Gerwick, William H., Sherman, David H., Aldrich, Courtney C., and Smith, Janet L. Mon .
"Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase". United States. https://doi.org/10.1021/acschembio.6b00759. https://www.osti.gov/servlets/purl/1368252.
@article{osti_1368252,
title = {Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase},
author = {Skiba, Meredith A. and Sikkema, Andrew P. and Fiers, William D. and Gerwick, William H. and Sherman, David H. and Aldrich, Courtney C. and Smith, Janet L.},
abstractNote = {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.},
doi = {10.1021/acschembio.6b00759},
journal = {ACS Chemical Biology},
number = 12,
volume = 11,
place = {United States},
year = {Mon Oct 10 00:00:00 EDT 2016},
month = {Mon Oct 10 00:00:00 EDT 2016}
}
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