(+)-Hemipalmitoylcarnitinium Strongly Inhibits Carnitine Palmitoyltransferase-I in Intact Mitochondria

Richard D. Gandour; On tai Leung; Anthony T. Greway; Rona R. Ramsay; Nóirín Nic a' Bháird; Frank R. Fronczek; Bret M. Bellard; G. Kumaravel

doi:10.1021/jm00054a007

(+)-Hemipalmitoylcarnitinium Strongly Inhibits Carnitine Palmitoyltransferase-I in Intact Mitochondria

Richard D. Gandour, On tai Leung^*, Anthony T. Greway, Rona R. Ramsay, Nóirín Nic a' Bháird, Frank R. Fronczek, Bret M. Bellard, G. Kumaravel

^*Corresponding author for this work

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

Abstract

The reaction of the methyl ester of (R)-norcarnitine with 1-bromo-2-heptadecanone produces (+)-6-[(methoxycarbonyl)methyl]-2-pentadecyl-4,4-dimethylmorpholinium bromide, 3, which hydrolyzes to (+)-6-(carboxylatomethyl)-2-pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, HPC) upon treatment with aqueous sodium hydroxide. Single-crystal X-ray analyses have confirmed the structures of (+)-HPC and 3. (+)-HPC inhibits carnitine palmitoyltransferase (CPT-I) activity for the forward reaction (palmitoyl-CoA + carnitine →) in intact mitochondria from rat heart and rat liver. (+)-HPC competitively (versus carnitine) inhibits CPT-I activity in both rat heart and liver mitochondria with K_i = 2.8 ± 0.5 and 4.2 ± 0.7 µM, respectively. As one of the strongest specific inhibitors of CPT-I, HPC is a potential therapeutic agent in myocardial ischemia and Type II diabetes.

Original language	English
Pages (from-to)	237-242
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	36
Issue number	2
DOIs	https://doi.org/10.1021/jm00054a007
Publication status	Published - 1 Jan 1993

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@article{6f099f8aa8144af192d508ed2467bc39,

title = "(+)-Hemipalmitoylcarnitinium Strongly Inhibits Carnitine Palmitoyltransferase-I in Intact Mitochondria",

abstract = "The reaction of the methyl ester of (R)-norcarnitine with 1-bromo-2-heptadecanone produces (+)-6-[(methoxycarbonyl)methyl]-2-pentadecyl-4,4-dimethylmorpholinium bromide, 3, which hydrolyzes to (+)-6-(carboxylatomethyl)-2-pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, HPC) upon treatment with aqueous sodium hydroxide. Single-crystal X-ray analyses have confirmed the structures of (+)-HPC and 3. (+)-HPC inhibits carnitine palmitoyltransferase (CPT-I) activity for the forward reaction (palmitoyl-CoA + carnitine →) in intact mitochondria from rat heart and rat liver. (+)-HPC competitively (versus carnitine) inhibits CPT-I activity in both rat heart and liver mitochondria with Ki = 2.8 ± 0.5 and 4.2 ± 0.7 µM, respectively. As one of the strongest specific inhibitors of CPT-I, HPC is a potential therapeutic agent in myocardial ischemia and Type II diabetes.",

author = "Gandour, {Richard D.} and Leung, {On tai} and Greway, {Anthony T.} and Ramsay, {Rona R.} and {Nic a' Bh{\'a}ird}, N{\'o}ir{\'i}n and Fronczek, {Frank R.} and Bellard, {Bret M.} and G. Kumaravel",

year = "1993",

month = jan,

day = "1",

doi = "10.1021/jm00054a007",

language = "English",

volume = "36",

pages = "237--242",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society (ACS)",

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TY - JOUR

T1 - (+)-Hemipalmitoylcarnitinium Strongly Inhibits Carnitine Palmitoyltransferase-I in Intact Mitochondria

AU - Gandour, Richard D.

AU - Leung, On tai

AU - Greway, Anthony T.

AU - Ramsay, Rona R.

AU - Nic a' Bháird, Nóirín

AU - Fronczek, Frank R.

AU - Bellard, Bret M.

AU - Kumaravel, G.

PY - 1993/1/1

Y1 - 1993/1/1

N2 - The reaction of the methyl ester of (R)-norcarnitine with 1-bromo-2-heptadecanone produces (+)-6-[(methoxycarbonyl)methyl]-2-pentadecyl-4,4-dimethylmorpholinium bromide, 3, which hydrolyzes to (+)-6-(carboxylatomethyl)-2-pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, HPC) upon treatment with aqueous sodium hydroxide. Single-crystal X-ray analyses have confirmed the structures of (+)-HPC and 3. (+)-HPC inhibits carnitine palmitoyltransferase (CPT-I) activity for the forward reaction (palmitoyl-CoA + carnitine →) in intact mitochondria from rat heart and rat liver. (+)-HPC competitively (versus carnitine) inhibits CPT-I activity in both rat heart and liver mitochondria with Ki = 2.8 ± 0.5 and 4.2 ± 0.7 µM, respectively. As one of the strongest specific inhibitors of CPT-I, HPC is a potential therapeutic agent in myocardial ischemia and Type II diabetes.

AB - The reaction of the methyl ester of (R)-norcarnitine with 1-bromo-2-heptadecanone produces (+)-6-[(methoxycarbonyl)methyl]-2-pentadecyl-4,4-dimethylmorpholinium bromide, 3, which hydrolyzes to (+)-6-(carboxylatomethyl)-2-pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, HPC) upon treatment with aqueous sodium hydroxide. Single-crystal X-ray analyses have confirmed the structures of (+)-HPC and 3. (+)-HPC inhibits carnitine palmitoyltransferase (CPT-I) activity for the forward reaction (palmitoyl-CoA + carnitine →) in intact mitochondria from rat heart and rat liver. (+)-HPC competitively (versus carnitine) inhibits CPT-I activity in both rat heart and liver mitochondria with Ki = 2.8 ± 0.5 and 4.2 ± 0.7 µM, respectively. As one of the strongest specific inhibitors of CPT-I, HPC is a potential therapeutic agent in myocardial ischemia and Type II diabetes.

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U2 - 10.1021/jm00054a007

DO - 10.1021/jm00054a007

M3 - Article

C2 - 8423595

AN - SCOPUS:0027476982

SN - 0022-2623

VL - 36

SP - 237

EP - 242

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

(+)-Hemipalmitoylcarnitinium Strongly Inhibits Carnitine Palmitoyltransferase-I in Intact Mitochondria

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