Sterol C24-methyltransferase: Mechanistic studies of the C-methylation reaction with 24-fluorocycloartenol

Junqing Wang; Jialin Liu; Zhihong Song; W. David Nes

doi:10.1016/j.bmcl.2007.10.089

Sterol C24-methyltransferase: Mechanistic studies of the C-methylation reaction with 24-fluorocycloartenol

Junqing Wang, Jialin Liu, Zhihong Song, W. David Nes

Chemistry and Biochemistry

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Abstract

The mechanism of the C-methylation reaction was studied with the allylic substrate analog 24-fluorocycloartenol 10 assayed with soybean sterol C24-methyltransferase (SMT). 10 is an effective competitive inhibitor (K_i = 32 μM) of the SMT, and the electron-withdrawing α-fluorine substituent was shown to suppress the rate of the C-methylation reaction by one order of magnitude relative to the natural cycloartenol substrate, k_cat = 0.02 min^-1 versus 0.6 min^-1; alternately 10 can prevent the critical hydride shift of H24 to C25 to afford time-dependent inactivation of SMT (k_inact = 0.32 min^-1).

Original language	English
Pages (from-to)	232-235
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2007.10.089
State	Published - Jan 1 2008

Keywords

24-Fluorocycloartenol
Mechanism-based inactivator
Sterol C24-methyltransferase
Suicide substrate

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10.1016/j.bmcl.2007.10.089

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title = "Sterol C24-methyltransferase: Mechanistic studies of the C-methylation reaction with 24-fluorocycloartenol",

abstract = "The mechanism of the C-methylation reaction was studied with the allylic substrate analog 24-fluorocycloartenol 10 assayed with soybean sterol C24-methyltransferase (SMT). 10 is an effective competitive inhibitor (Ki = 32 μM) of the SMT, and the electron-withdrawing α-fluorine substituent was shown to suppress the rate of the C-methylation reaction by one order of magnitude relative to the natural cycloartenol substrate, kcat = 0.02 min-1 versus 0.6 min-1; alternately 10 can prevent the critical hydride shift of H24 to C25 to afford time-dependent inactivation of SMT (kinact = 0.32 min-1).",

keywords = "24-Fluorocycloartenol, Mechanism-based inactivator, Sterol C24-methyltransferase, Suicide substrate",

author = "Junqing Wang and Jialin Liu and Zhihong Song and Nes, {W. David}",

note = "Funding Information: This work was supported by the National Science Foundation (MCB-0417436) and the Welch Foundation (D-1276). Junqing Wang is a Visiting Professor from the College of Life Science and Technology at Shanxi University, Taiyuan, Shanxi, China. We thank an anonymous reviewer who suggested that the fluoro substituent is predominantly electronic in nature. ",

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doi = "10.1016/j.bmcl.2007.10.089",

language = "English",

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T1 - Sterol C24-methyltransferase

T2 - Mechanistic studies of the C-methylation reaction with 24-fluorocycloartenol

AU - Wang, Junqing

AU - Liu, Jialin

AU - Song, Zhihong

AU - Nes, W. David

N1 - Funding Information: This work was supported by the National Science Foundation (MCB-0417436) and the Welch Foundation (D-1276). Junqing Wang is a Visiting Professor from the College of Life Science and Technology at Shanxi University, Taiyuan, Shanxi, China. We thank an anonymous reviewer who suggested that the fluoro substituent is predominantly electronic in nature.

PY - 2008/1/1

Y1 - 2008/1/1

N2 - The mechanism of the C-methylation reaction was studied with the allylic substrate analog 24-fluorocycloartenol 10 assayed with soybean sterol C24-methyltransferase (SMT). 10 is an effective competitive inhibitor (Ki = 32 μM) of the SMT, and the electron-withdrawing α-fluorine substituent was shown to suppress the rate of the C-methylation reaction by one order of magnitude relative to the natural cycloartenol substrate, kcat = 0.02 min-1 versus 0.6 min-1; alternately 10 can prevent the critical hydride shift of H24 to C25 to afford time-dependent inactivation of SMT (kinact = 0.32 min-1).

AB - The mechanism of the C-methylation reaction was studied with the allylic substrate analog 24-fluorocycloartenol 10 assayed with soybean sterol C24-methyltransferase (SMT). 10 is an effective competitive inhibitor (Ki = 32 μM) of the SMT, and the electron-withdrawing α-fluorine substituent was shown to suppress the rate of the C-methylation reaction by one order of magnitude relative to the natural cycloartenol substrate, kcat = 0.02 min-1 versus 0.6 min-1; alternately 10 can prevent the critical hydride shift of H24 to C25 to afford time-dependent inactivation of SMT (kinact = 0.32 min-1).

KW - 24-Fluorocycloartenol

KW - Mechanism-based inactivator

KW - Sterol C24-methyltransferase

KW - Suicide substrate

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DO - 10.1016/j.bmcl.2007.10.089

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SN - 0960-894X

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SP - 232

EP - 235

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 1

ER -

Sterol C24-methyltransferase: Mechanistic studies of the C-methylation reaction with 24-fluorocycloartenol

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Keywords

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