Divergence of multimodular polyketide synthases revealed by a didomain structure

Jianting Zheng; Darren C. Gay; Borries Demeler; Mark A. White; Adrian T. Keatinge-Clay

doi:10.1038/nchembio.964

Divergence of multimodular polyketide synthases revealed by a didomain structure

Jianting Zheng, Darren C. Gay, Borries Demeler, Mark A. White, Adrian T. Keatinge-Clay

Chemistry and Biochemistry

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

69 Scopus citations

Abstract

The enoylreductase (ER) is the final common enzyme from modular polyketide synthases (PKSs) to be structurally characterized. The 3.0 Å-resolution structure of the didomain comprising the ketoreductase (KR) and ER from the second module of the spinosyn PKS reveals that ER shares an ∼600- Å² interface with KR distinct from that of the related mammalian fatty acid synthase (FAS). In contrast to the ER domains of the mammalian FAS, the ER domains of the second module of the spinosyn PKS do not make contact across the two-fold axis of the synthase. This monomeric organization may have been necessary in the evolution of multimodular PKSs to enable acyl carrier proteins to access each of their cognate enzymes. The isolated ER domain showed activity toward a substrate analog, enabling us to determine the contributions of its active site residues.

Original language	English
Pages (from-to)	615-621
Number of pages	7
Journal	Nature Chemical Biology
Volume	8
Issue number	7
DOIs	https://doi.org/10.1038/nchembio.964
State	Published - Jul 2012

Funding

We thank A.F. Monzingo for helping with in-house diffraction experiments and C.D. Fage for helping optimize crystals. Synchrotron data were obtained at the ALS Beamlines 8.2.1 and 5.0.2. Financial support was provided by Welch Foundation Grant F-1712 (A.T.K.-C.) as well as the Sealy and Smith Foundation grant to the Sealy Center for Structural Biology and Molecular Biophysics (M.A.W.). The development of the UltraScan software is supported by the US National Institutes of Health through grant RR022200 (B.D.). Supercomputer time allocations were provided through the US National Science Foundation grant TG-MCB070038 (B.D.). We acknowledge the support of the San Antonio Cancer Institute grant P30 CA054174 for the Center for Analytical Ultracentrifugation of Macromolecular Assemblies at the University of Texas Health Science Center at San Antonio.

Funders	Funder number
P30 CA054174
TG-MCB070038
RR022200
F-1712
University of Texas Health Science Center at San Antonio

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title = "Divergence of multimodular polyketide synthases revealed by a didomain structure",

abstract = "The enoylreductase (ER) is the final common enzyme from modular polyketide synthases (PKSs) to be structurally characterized. The 3.0 {\AA}-resolution structure of the didomain comprising the ketoreductase (KR) and ER from the second module of the spinosyn PKS reveals that ER shares an ∼600- {\AA}2 interface with KR distinct from that of the related mammalian fatty acid synthase (FAS). In contrast to the ER domains of the mammalian FAS, the ER domains of the second module of the spinosyn PKS do not make contact across the two-fold axis of the synthase. This monomeric organization may have been necessary in the evolution of multimodular PKSs to enable acyl carrier proteins to access each of their cognate enzymes. The isolated ER domain showed activity toward a substrate analog, enabling us to determine the contributions of its active site residues.",

author = "Jianting Zheng and Gay, \{Darren C.\} and Borries Demeler and White, \{Mark A.\} and Keatinge-Clay, \{Adrian T.\}",

note = "Funding Information: We thank A.F. Monzingo for helping with in-house diffraction experiments and C.D. Fage for helping optimize crystals. Synchrotron data were obtained at the ALS Beamlines 8.2.1 and 5.0.2. Financial support was provided by Welch Foundation Grant F-1712 (A.T.K.-C.) as well as the Sealy and Smith Foundation grant to the Sealy Center for Structural Biology and Molecular Biophysics (M.A.W.). The development of the UltraScan software is supported by the US National Institutes of Health through grant RR022200 (B.D.). Supercomputer time allocations were provided through the US National Science Foundation grant TG-MCB070038 (B.D.). We acknowledge the support of the San Antonio Cancer Institute grant P30 CA054174 for the Center for Analytical Ultracentrifugation of Macromolecular Assemblies at the University of Texas Health Science Center at San Antonio.",

year = "2012",

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AU - Gay, Darren C.

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AU - White, Mark A.

AU - Keatinge-Clay, Adrian T.

N1 - Funding Information: We thank A.F. Monzingo for helping with in-house diffraction experiments and C.D. Fage for helping optimize crystals. Synchrotron data were obtained at the ALS Beamlines 8.2.1 and 5.0.2. Financial support was provided by Welch Foundation Grant F-1712 (A.T.K.-C.) as well as the Sealy and Smith Foundation grant to the Sealy Center for Structural Biology and Molecular Biophysics (M.A.W.). The development of the UltraScan software is supported by the US National Institutes of Health through grant RR022200 (B.D.). Supercomputer time allocations were provided through the US National Science Foundation grant TG-MCB070038 (B.D.). We acknowledge the support of the San Antonio Cancer Institute grant P30 CA054174 for the Center for Analytical Ultracentrifugation of Macromolecular Assemblies at the University of Texas Health Science Center at San Antonio.

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N2 - The enoylreductase (ER) is the final common enzyme from modular polyketide synthases (PKSs) to be structurally characterized. The 3.0 Å-resolution structure of the didomain comprising the ketoreductase (KR) and ER from the second module of the spinosyn PKS reveals that ER shares an ∼600- Å2 interface with KR distinct from that of the related mammalian fatty acid synthase (FAS). In contrast to the ER domains of the mammalian FAS, the ER domains of the second module of the spinosyn PKS do not make contact across the two-fold axis of the synthase. This monomeric organization may have been necessary in the evolution of multimodular PKSs to enable acyl carrier proteins to access each of their cognate enzymes. The isolated ER domain showed activity toward a substrate analog, enabling us to determine the contributions of its active site residues.

AB - The enoylreductase (ER) is the final common enzyme from modular polyketide synthases (PKSs) to be structurally characterized. The 3.0 Å-resolution structure of the didomain comprising the ketoreductase (KR) and ER from the second module of the spinosyn PKS reveals that ER shares an ∼600- Å2 interface with KR distinct from that of the related mammalian fatty acid synthase (FAS). In contrast to the ER domains of the mammalian FAS, the ER domains of the second module of the spinosyn PKS do not make contact across the two-fold axis of the synthase. This monomeric organization may have been necessary in the evolution of multimodular PKSs to enable acyl carrier proteins to access each of their cognate enzymes. The isolated ER domain showed activity toward a substrate analog, enabling us to determine the contributions of its active site residues.

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DO - 10.1038/nchembio.964

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Divergence of multimodular polyketide synthases revealed by a didomain structure

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