Mechanism-based enzyme inactivators of phytosterol biosynthesis

Wenxu Zhou; Zhihong Song; Ragu Kanagasabai; Jialin Liu; Pruthvi Jayasimha; Archana Sinha; Phani Veeramachanemi; Mathew B. Miller; W. David Nes

doi:10.3390/90400185

Mechanism-based enzyme inactivators of phytosterol biosynthesis

Wenxu Zhou, Zhihong Song, Ragu Kanagasabai, Jialin Liu, Pruthvi Jayasimha, Archana Sinha, Phani Veeramachanemi, Mathew B. Miller, W. David Nes

Chemistry and Biochemistry

Research output: Contribution to journal › Review article › peer-review

13 Scopus citations

Abstract

Current progress on the mechanism and substrate recognition by sterol methyl transferase (SMT), the role of mechanism-based inactivators, other inhibitors of SMT action to probe catalysis and phytosterol synthesis is reported. SMT is a membrane-bound enzyme which catalyzes the coupled C-methylation-deprotonation reaction of sterol acceptor molecules generating the 24-alkyl sterol side chains of fungal ergosterol and plant sitosterol. This C-methylation step can be rate-limiting in the post-lanosterol (fungal) or post-cycloartenol (plant) pathways. A series of sterol analogs designed to impair SMT activity irreversibly have provided deep insight into the C-methylation reaction and topography of the SMT active site and as reviewed provide leads for the development of antifungal agents.

Original language	English
Pages (from-to)	185-203
Number of pages	19
Journal	Molecules
Volume	9
Issue number	4
DOIs	https://doi.org/10.3390/90400185
State	Published - Apr 2004

Keywords

Ergosterol
Sitosterol
Stereochemistry
Sterol biosynthesis inhibitors

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10.3390/90400185

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title = "Mechanism-based enzyme inactivators of phytosterol biosynthesis",

abstract = "Current progress on the mechanism and substrate recognition by sterol methyl transferase (SMT), the role of mechanism-based inactivators, other inhibitors of SMT action to probe catalysis and phytosterol synthesis is reported. SMT is a membrane-bound enzyme which catalyzes the coupled C-methylation-deprotonation reaction of sterol acceptor molecules generating the 24-alkyl sterol side chains of fungal ergosterol and plant sitosterol. This C-methylation step can be rate-limiting in the post-lanosterol (fungal) or post-cycloartenol (plant) pathways. A series of sterol analogs designed to impair SMT activity irreversibly have provided deep insight into the C-methylation reaction and topography of the SMT active site and as reviewed provide leads for the development of antifungal agents.",

keywords = "Ergosterol, Sitosterol, Stereochemistry, Sterol biosynthesis inhibitors",

author = "Wenxu Zhou and Zhihong Song and Ragu Kanagasabai and Jialin Liu and Pruthvi Jayasimha and Archana Sinha and Phani Veeramachanemi and Miller, {Mathew B.} and Nes, {W. David}",

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journal = "Molecules",

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T1 - Mechanism-based enzyme inactivators of phytosterol biosynthesis

AU - Zhou, Wenxu

AU - Song, Zhihong

AU - Kanagasabai, Ragu

AU - Liu, Jialin

AU - Jayasimha, Pruthvi

AU - Sinha, Archana

AU - Veeramachanemi, Phani

AU - Miller, Mathew B.

AU - Nes, W. David

PY - 2004/4

Y1 - 2004/4

N2 - Current progress on the mechanism and substrate recognition by sterol methyl transferase (SMT), the role of mechanism-based inactivators, other inhibitors of SMT action to probe catalysis and phytosterol synthesis is reported. SMT is a membrane-bound enzyme which catalyzes the coupled C-methylation-deprotonation reaction of sterol acceptor molecules generating the 24-alkyl sterol side chains of fungal ergosterol and plant sitosterol. This C-methylation step can be rate-limiting in the post-lanosterol (fungal) or post-cycloartenol (plant) pathways. A series of sterol analogs designed to impair SMT activity irreversibly have provided deep insight into the C-methylation reaction and topography of the SMT active site and as reviewed provide leads for the development of antifungal agents.

AB - Current progress on the mechanism and substrate recognition by sterol methyl transferase (SMT), the role of mechanism-based inactivators, other inhibitors of SMT action to probe catalysis and phytosterol synthesis is reported. SMT is a membrane-bound enzyme which catalyzes the coupled C-methylation-deprotonation reaction of sterol acceptor molecules generating the 24-alkyl sterol side chains of fungal ergosterol and plant sitosterol. This C-methylation step can be rate-limiting in the post-lanosterol (fungal) or post-cycloartenol (plant) pathways. A series of sterol analogs designed to impair SMT activity irreversibly have provided deep insight into the C-methylation reaction and topography of the SMT active site and as reviewed provide leads for the development of antifungal agents.

KW - Ergosterol

KW - Sitosterol

KW - Stereochemistry

KW - Sterol biosynthesis inhibitors

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U2 - 10.3390/90400185

DO - 10.3390/90400185

M3 - Review article

C2 - 18007423

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SN - 1420-3049

VL - 9

SP - 185

EP - 203

JO - Molecules

JF - Molecules

IS - 4

ER -

Mechanism-based enzyme inactivators of phytosterol biosynthesis

Abstract

Keywords

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