Elucidation of piericidin A1 biosynthetic locus revealed a thioesterase-dependent mechanism of α-pyridone ring formation

Q. Liu, F. Yao, Heng Chooi, Q. Kang, W. Xu, Y. Li, Y. Shao, Y. Shi, Z. Deng, Y. Tang, D. You

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Piericidins are a class of α-pyridone antibiotics that inhibit mitochondrial respiratory chain and exhibit antimicrobial, antifungal, and antitumor activities. Sequential analysis of Streptomyces piomogeues var. Hangzhouwanensis genome revealed six modular polyketide synthases, an amidotransferase, two methyltransferases, and a monooxygenase for piericidin A1 production. Gene functional analysis and deletion results provide overview of the biosynthesis pathway. Furthermore, in vitro characterization of the terminal polyketide synthase module with the thioesterase domain using β-ketoacyl substrates was performed. That revealed a pathway where the α-pyridone ring formation is dependent on hydrolysis of the product β, δ-diketo carboxylic acid by the C-terminal thioesterase followed by amidation and cyclization. These findings set the stage to investigate unusual enzymatic mechanisms in α-pyridone antibiotics biosynthesis, provide a foundation for genome mining of α-pyridone antibiotics, and produce analogs by molecular engineering. © 2012 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)243-253
JournalChemistry and Biology
Volume19
Issue number2
DOIs
Publication statusPublished - 2012

Fingerprint

Pyridones
Polyketide Synthases
Genes
Biosynthesis
Anti-Bacterial Agents
Genome
Functional analysis
Cyclization
Methyltransferases
Streptomyces
Electron Transport
Carboxylic Acids
Mixed Function Oxygenases
Hydrolysis
piericidin A
Substrates

Cite this

Liu, Q. ; Yao, F. ; Chooi, Heng ; Kang, Q. ; Xu, W. ; Li, Y. ; Shao, Y. ; Shi, Y. ; Deng, Z. ; Tang, Y. ; You, D. / Elucidation of piericidin A1 biosynthetic locus revealed a thioesterase-dependent mechanism of α-pyridone ring formation. In: Chemistry and Biology. 2012 ; Vol. 19, No. 2. pp. 243-253.
@article{b188a2a724914860b3413b72571372ac,
title = "Elucidation of piericidin A1 biosynthetic locus revealed a thioesterase-dependent mechanism of α-pyridone ring formation",
abstract = "Piericidins are a class of α-pyridone antibiotics that inhibit mitochondrial respiratory chain and exhibit antimicrobial, antifungal, and antitumor activities. Sequential analysis of Streptomyces piomogeues var. Hangzhouwanensis genome revealed six modular polyketide synthases, an amidotransferase, two methyltransferases, and a monooxygenase for piericidin A1 production. Gene functional analysis and deletion results provide overview of the biosynthesis pathway. Furthermore, in vitro characterization of the terminal polyketide synthase module with the thioesterase domain using β-ketoacyl substrates was performed. That revealed a pathway where the α-pyridone ring formation is dependent on hydrolysis of the product β, δ-diketo carboxylic acid by the C-terminal thioesterase followed by amidation and cyclization. These findings set the stage to investigate unusual enzymatic mechanisms in α-pyridone antibiotics biosynthesis, provide a foundation for genome mining of α-pyridone antibiotics, and produce analogs by molecular engineering. {\circledC} 2012 Elsevier Ltd. All rights reserved.",
author = "Q. Liu and F. Yao and Heng Chooi and Q. Kang and W. Xu and Y. Li and Y. Shao and Y. Shi and Z. Deng and Y. Tang and D. You",
year = "2012",
doi = "10.1016/j.chembiol.2011.12.018",
language = "English",
volume = "19",
pages = "243--253",
journal = "Chemistry & Biology",
issn = "1074-5521",
publisher = "Cell Press",
number = "2",

}

Elucidation of piericidin A1 biosynthetic locus revealed a thioesterase-dependent mechanism of α-pyridone ring formation. / Liu, Q.; Yao, F.; Chooi, Heng; Kang, Q.; Xu, W.; Li, Y.; Shao, Y.; Shi, Y.; Deng, Z.; Tang, Y.; You, D.

In: Chemistry and Biology, Vol. 19, No. 2, 2012, p. 243-253.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Elucidation of piericidin A1 biosynthetic locus revealed a thioesterase-dependent mechanism of α-pyridone ring formation

AU - Liu, Q.

AU - Yao, F.

AU - Chooi, Heng

AU - Kang, Q.

AU - Xu, W.

AU - Li, Y.

AU - Shao, Y.

AU - Shi, Y.

AU - Deng, Z.

AU - Tang, Y.

AU - You, D.

PY - 2012

Y1 - 2012

N2 - Piericidins are a class of α-pyridone antibiotics that inhibit mitochondrial respiratory chain and exhibit antimicrobial, antifungal, and antitumor activities. Sequential analysis of Streptomyces piomogeues var. Hangzhouwanensis genome revealed six modular polyketide synthases, an amidotransferase, two methyltransferases, and a monooxygenase for piericidin A1 production. Gene functional analysis and deletion results provide overview of the biosynthesis pathway. Furthermore, in vitro characterization of the terminal polyketide synthase module with the thioesterase domain using β-ketoacyl substrates was performed. That revealed a pathway where the α-pyridone ring formation is dependent on hydrolysis of the product β, δ-diketo carboxylic acid by the C-terminal thioesterase followed by amidation and cyclization. These findings set the stage to investigate unusual enzymatic mechanisms in α-pyridone antibiotics biosynthesis, provide a foundation for genome mining of α-pyridone antibiotics, and produce analogs by molecular engineering. © 2012 Elsevier Ltd. All rights reserved.

AB - Piericidins are a class of α-pyridone antibiotics that inhibit mitochondrial respiratory chain and exhibit antimicrobial, antifungal, and antitumor activities. Sequential analysis of Streptomyces piomogeues var. Hangzhouwanensis genome revealed six modular polyketide synthases, an amidotransferase, two methyltransferases, and a monooxygenase for piericidin A1 production. Gene functional analysis and deletion results provide overview of the biosynthesis pathway. Furthermore, in vitro characterization of the terminal polyketide synthase module with the thioesterase domain using β-ketoacyl substrates was performed. That revealed a pathway where the α-pyridone ring formation is dependent on hydrolysis of the product β, δ-diketo carboxylic acid by the C-terminal thioesterase followed by amidation and cyclization. These findings set the stage to investigate unusual enzymatic mechanisms in α-pyridone antibiotics biosynthesis, provide a foundation for genome mining of α-pyridone antibiotics, and produce analogs by molecular engineering. © 2012 Elsevier Ltd. All rights reserved.

U2 - 10.1016/j.chembiol.2011.12.018

DO - 10.1016/j.chembiol.2011.12.018

M3 - Article

VL - 19

SP - 243

EP - 253

JO - Chemistry & Biology

JF - Chemistry & Biology

SN - 1074-5521

IS - 2

ER -