Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5

Lilan Zhang; Chun Chi Chen; Tzu Ping Ko; Jian Wen Huang; Yingying Zheng; Weidong Liu; Iren Wang; Satish R. Malwal; Xinxin Feng; Ke Wang; Chun Hsiang Huang; Shang Te Danny Hsu; Andrew H.J. Wang; Eric Oldfield; Rey Ting Guo

doi:10.1002/anie.201511388

Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5

Lilan Zhang, Chun Chi Chen, Tzu Ping Ko, Jian Wen Huang, Yingying Zheng, Weidong Liu, Iren Wang, Satish R. Malwal, Xinxin Feng, Ke Wang, Chun Hsiang Huang, Shang Te Danny Hsu, Andrew H.J. Wang, Eric Oldfield, Rey Ting Guo

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

18 Citations (Scopus)

Abstract

The structure of MoeN5, a unique prenyltransferase involved in the biosynthesis of the antibiotic moenomycin, is reported. MoeN5 catalyzes the reaction of geranyl diphosphate (GPP) with the cis-farnesyl group in phosphoglycolipid 5 to form the (C₂₅) moenocinyl-sidechain-containing lipid 7. GPP binds to an allylic site (S1) and aligns well with known S1 inhibitors. Alkyl glycosides, glycolipids, can bind to both S1 and a second site, S2. Long sidechains in S2 are "bent" and co-locate with the homoallylic substrate isopentenyl diphosphate in other prenyltransferases. These observations support a MoeN5 mechanism in which 5 binds to S2 with its C6-C11 group poised to attack C1 in GPP to form the moenocinyl sidechain, with the more distal regions of 5 aligning with the distal glucose in decyl maltoside. The results are of general interest because they provide the first structures of MoeN5 and a structural basis for its mechanism of action, results that will facilitate the design of new antibiotics.

Original language	English
Pages (from-to)	4716-4720
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	55
Issue number	15
DOIs	https://doi.org/10.1002/anie.201511388
Publication status	Published - Apr 4 2016
Externally published	Yes

Keywords

biosynthesis
drug discovery
enzyme mechanisms
isoprenoids
protein structure

ASJC Scopus subject areas

Catalysis
General Chemistry

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10.1002/anie.201511388

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Zhang, L., Chen, C. C., Ko, T. P., Huang, J. W., Zheng, Y., Liu, W., Wang, I., Malwal, S. R., Feng, X., Wang, K., Huang, C. H., Hsu, S. T. D., Wang, A. H. J., Oldfield, E., & Guo, R. T. (2016). Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5. Angewandte Chemie - International Edition, 55(15), 4716-4720. https://doi.org/10.1002/anie.201511388

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title = "Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5",

abstract = "The structure of MoeN5, a unique prenyltransferase involved in the biosynthesis of the antibiotic moenomycin, is reported. MoeN5 catalyzes the reaction of geranyl diphosphate (GPP) with the cis-farnesyl group in phosphoglycolipid 5 to form the (C25) moenocinyl-sidechain-containing lipid 7. GPP binds to an allylic site (S1) and aligns well with known S1 inhibitors. Alkyl glycosides, glycolipids, can bind to both S1 and a second site, S2. Long sidechains in S2 are {"}bent{"} and co-locate with the homoallylic substrate isopentenyl diphosphate in other prenyltransferases. These observations support a MoeN5 mechanism in which 5 binds to S2 with its C6-C11 group poised to attack C1 in GPP to form the moenocinyl sidechain, with the more distal regions of 5 aligning with the distal glucose in decyl maltoside. The results are of general interest because they provide the first structures of MoeN5 and a structural basis for its mechanism of action, results that will facilitate the design of new antibiotics.",

keywords = "biosynthesis, drug discovery, enzyme mechanisms, isoprenoids, protein structure",

author = "Lilan Zhang and Chen, {Chun Chi} and Ko, {Tzu Ping} and Huang, {Jian Wen} and Yingying Zheng and Weidong Liu and Iren Wang and Malwal, {Satish R.} and Xinxin Feng and Ke Wang and Huang, {Chun Hsiang} and Hsu, {Shang Te Danny} and Wang, {Andrew H.J.} and Eric Oldfield and Guo, {Rey Ting}",

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doi = "10.1002/anie.201511388",

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T1 - Moenomycin Biosynthesis

T2 - Structure and Mechanism of Action of the Prenyltransferase MoeN5

AU - Zhang, Lilan

AU - Chen, Chun Chi

AU - Ko, Tzu Ping

AU - Huang, Jian Wen

AU - Zheng, Yingying

AU - Liu, Weidong

AU - Wang, Iren

AU - Malwal, Satish R.

AU - Feng, Xinxin

AU - Wang, Ke

AU - Huang, Chun Hsiang

AU - Hsu, Shang Te Danny

AU - Wang, Andrew H.J.

AU - Oldfield, Eric

AU - Guo, Rey Ting

PY - 2016/4/4

Y1 - 2016/4/4

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AB - The structure of MoeN5, a unique prenyltransferase involved in the biosynthesis of the antibiotic moenomycin, is reported. MoeN5 catalyzes the reaction of geranyl diphosphate (GPP) with the cis-farnesyl group in phosphoglycolipid 5 to form the (C25) moenocinyl-sidechain-containing lipid 7. GPP binds to an allylic site (S1) and aligns well with known S1 inhibitors. Alkyl glycosides, glycolipids, can bind to both S1 and a second site, S2. Long sidechains in S2 are "bent" and co-locate with the homoallylic substrate isopentenyl diphosphate in other prenyltransferases. These observations support a MoeN5 mechanism in which 5 binds to S2 with its C6-C11 group poised to attack C1 in GPP to form the moenocinyl sidechain, with the more distal regions of 5 aligning with the distal glucose in decyl maltoside. The results are of general interest because they provide the first structures of MoeN5 and a structural basis for its mechanism of action, results that will facilitate the design of new antibiotics.

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KW - drug discovery

KW - enzyme mechanisms

KW - isoprenoids

KW - protein structure

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ER -

Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5

Abstract

Keywords

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