Polyketide Ring Expansion Mediated by a Thioesterase, Chain Elongation and Cyclization Domain, in Azinomycin Biosynthesis: Characterization of AziB and AziG

Shogo Mori; Dinesh Simkhada; Huitu Zhang; Megan S. Erb; Yang Zhang; Howard Williams; Dmytro Fedoseyenko; William K. Russell; Doyong Kim; Nathan Fleer; Steven E. Ealick; Coran M.H. Watanabe

doi:10.1021/acs.biochem.5b01050

Polyketide Ring Expansion Mediated by a Thioesterase, Chain Elongation and Cyclization Domain, in Azinomycin Biosynthesis: Characterization of AziB and AziG

Shogo Mori, Dinesh Simkhada, Huitu Zhang, Megan S. Erb, Yang Zhang, Howard Williams, Dmytro Fedoseyenko, William K. Russell, Doyong Kim, Nathan Fleer, Steven E. Ealick, Coran M.H. Watanabe

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

The azinomycins are a family of potent antitumor agents with the ability to form interstrand cross-links with DNA. This study reports on the unusual biosynthetic formation of the 5-methyl naphthoate moiety, which is essential for effective DNA association. While sequence analysis predicts that the polyketide synthase (AziB) catalyzes the formation of this naphthoate, 2-methylbenzoic acid, a truncated single-ring product, is formed instead. We demonstrate that the thioesterase (AziG) acts as a chain elongation and cyclization (CEC) domain and is required for the additional two rounds of chain extension to form the expected product.

Original language	English (US)
Pages (from-to)	704-714
Number of pages	11
Journal	Biochemistry
Volume	55
Issue number	4
DOIs	https://doi.org/10.1021/acs.biochem.5b01050
State	Published - Feb 2 2016
Externally published	Yes

ASJC Scopus subject areas

Biochemistry

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Mori, S., Simkhada, D., Zhang, H., Erb, M. S., Zhang, Y., Williams, H., Fedoseyenko, D., Russell, W. K., Kim, D., Fleer, N., Ealick, S. E., & Watanabe, C. M. H. (2016). Polyketide Ring Expansion Mediated by a Thioesterase, Chain Elongation and Cyclization Domain, in Azinomycin Biosynthesis: Characterization of AziB and AziG. Biochemistry, 55(4), 704-714. https://doi.org/10.1021/acs.biochem.5b01050

Mori, S, Simkhada, D, Zhang, H, Erb, MS, Zhang, Y, Williams, H, Fedoseyenko, D, Russell, WK, Kim, D, Fleer, N, Ealick, SE & Watanabe, CMH 2016, 'Polyketide Ring Expansion Mediated by a Thioesterase, Chain Elongation and Cyclization Domain, in Azinomycin Biosynthesis: Characterization of AziB and AziG', Biochemistry, vol. 55, no. 4, pp. 704-714. https://doi.org/10.1021/acs.biochem.5b01050

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abstract = "The azinomycins are a family of potent antitumor agents with the ability to form interstrand cross-links with DNA. This study reports on the unusual biosynthetic formation of the 5-methyl naphthoate moiety, which is essential for effective DNA association. While sequence analysis predicts that the polyketide synthase (AziB) catalyzes the formation of this naphthoate, 2-methylbenzoic acid, a truncated single-ring product, is formed instead. We demonstrate that the thioesterase (AziG) acts as a chain elongation and cyclization (CEC) domain and is required for the additional two rounds of chain extension to form the expected product.",

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doi = "10.1021/acs.biochem.5b01050",

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T1 - Polyketide Ring Expansion Mediated by a Thioesterase, Chain Elongation and Cyclization Domain, in Azinomycin Biosynthesis

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AU - Mori, Shogo

AU - Simkhada, Dinesh

AU - Zhang, Huitu

AU - Erb, Megan S.

AU - Zhang, Yang

AU - Williams, Howard

AU - Fedoseyenko, Dmytro

AU - Russell, William K.

AU - Kim, Doyong

AU - Fleer, Nathan

AU - Ealick, Steven E.

AU - Watanabe, Coran M.H.

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N2 - The azinomycins are a family of potent antitumor agents with the ability to form interstrand cross-links with DNA. This study reports on the unusual biosynthetic formation of the 5-methyl naphthoate moiety, which is essential for effective DNA association. While sequence analysis predicts that the polyketide synthase (AziB) catalyzes the formation of this naphthoate, 2-methylbenzoic acid, a truncated single-ring product, is formed instead. We demonstrate that the thioesterase (AziG) acts as a chain elongation and cyclization (CEC) domain and is required for the additional two rounds of chain extension to form the expected product.

AB - The azinomycins are a family of potent antitumor agents with the ability to form interstrand cross-links with DNA. This study reports on the unusual biosynthetic formation of the 5-methyl naphthoate moiety, which is essential for effective DNA association. While sequence analysis predicts that the polyketide synthase (AziB) catalyzes the formation of this naphthoate, 2-methylbenzoic acid, a truncated single-ring product, is formed instead. We demonstrate that the thioesterase (AziG) acts as a chain elongation and cyclization (CEC) domain and is required for the additional two rounds of chain extension to form the expected product.

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Polyketide Ring Expansion Mediated by a Thioesterase, Chain Elongation and Cyclization Domain, in Azinomycin Biosynthesis: Characterization of AziB and AziG

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