Inactivation of two-electron reduced medium chain acyl-CoA dehydrogenase by 2-octynoyl-CoA

Zhou, Jian-Zhong; Thorpe, Colin

doi:10.1016/0003-9861(89)90277-4

Cited by 10 publications

(3 citation statements)

References 32 publications

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“…In contrast, several thioesters target the flavin prosthetic group of the dehydrogenase, yielding an enzyme-bound reduced FAD derivative ( − ). One of these, methylenecyclopropylacetyl-CoA (MCPA-CoA; Chart , compound 1 ), is formed during the metabolism of the toxic amino acid methylenecyclopropylalanine (hypoglycin A) found in unripe ackee fruit ().…”

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confidence: 99%

Interaction of 3,4-Dienoyl-CoA Thioesters with Medium Chain Acyl-CoA Dehydrogenase: Stereochemistry of Inactivation of a Flavoenzyme

Wang

Zhou

et al. 2001

Biochemistry

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The medium chain acyl-CoA dehydrogenase is rapidly inhibited by racemic 3,4-dienoyl-CoA derivatives with a stoichiometry of two molecules of racemate per enzyme flavin. Synthesis of R- and S-3,4-decadienoyl-CoA shows that the R-enantiomer is a potent, stoichiometric, inhibitor of the enzyme. alpha-Proton abstraction yields an enolate to oxidized flavin charge-transfer intermediate prior to adduct formation. The crystal structure of the reduced, inactive enzyme shows a single covalent bond linking the C-4 carbon of the 2,4-dienoyl-CoA moiety and the N5 locus of reduced flavin. The kinetics of reversal of adduct formation by release of the conjugated 2,4-diene were evaluated as a function of both acyl chain length and truncation of the CoA moiety. The adduct is most stable with medium chain length allenic inhibitors. However, the adducts with R-3,4-decadienoyl-pantetheine and -N-acetylcysteamine are some 9- and >100-fold more kinetically stable than the full-length CoA thioester. Crystal structures of these reduced enzyme species, determined to 2.4 A, suggest that the placement of H-bonds to the inhibitor carbonyl oxygen and the positioning of the catalytic base are important determinants of adduct stability. The S-3,4-decadienoyl-CoA is not a significant inhibitor of the medium chain dehydrogenase and does not form a detectable flavin adduct. However, the S-isomer is rapidly isomerized to the trans-trans-2,4-conjugated diene. Protein modeling studies suggest that the S-enantiomer cannot approach close enough to the isoalloxazine ring to form a flavin adduct, but can be facilely reprotonated by the catalytic base. These studies show that truncation of CoA thioesters may allow the design of unexpectedly potent lipophilic inhibitors of fatty acid oxidation.

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Interaction of 3,4-Dienoyl-CoA Thioesters with Medium Chain Acyl-CoA Dehydrogenase: Stereochemistry of Inactivation of a Flavoenzyme

Wang

Zhou

et al. 2001

Biochemistry

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“…A few fatty acid derivatives are known to inhibit mediumchain acyl-CoA dehydrogenase (MCAD)1 activity (Freund et al, 1985;Shaw & Engel, 1985;Wenz et al, 1981Wenz et al, , 1985Zhou & Thorpe, 1989). However, an inhibitor that is effective in vivo and also specific for MCAD has not been described.…”

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Spiropentaneacetic acid as a specific inhibitor of medium-chain acyl-CoA dehydrogenase

Tserng

Jin²,

Hoppel³

1991

Biochemistry

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To study the structure-activity relationship between pentanoic acid analogues and the inhibition of fatty acid oxidation, a number of 4-pentenoic and methylenecyclopropaneacetic acid derivatives were prepared. All compounds inhibited palmitoylcarnitine oxidation in rat liver mitochondria, with 50% inhibition occurring at a concentration between 6 and 100 microM. However, only methylenecyclopropaneacetic acid (MCPA) and spiropentaneacetic acid (SPA) showed in vivo inhibitory activity in rats as indicated by the occurrence of dicarboxylic aciduria. Rats treated with SPA excreted metabolites derived only from fatty acid oxidation whereas MCPA-treated rats also excreted metabolites derived from branch-chained amino acid and lysine metabolism. SPA is a specific inhibitor of fatty acid oxidation without affecting amino acid metabolism. The site of inhibition is medium-chain acyl-CoA dehydrogenase (MCAD). In contrast, MCPA inhibited both MCAD and short-chain acyl-CoA dehydrogenase with a stronger inhibition toward the latter. The inhibition of fatty acid oxidation by both inhibitors was partially reversible by glycine or l-carnitine. Since SPA does not form a ring-opened nucleophile such as that proposed for MCPA in the inhibition of FAD prosthetic group in acyl-CoA dehydrogenases, we propose that the irreversible inhibition by SPA occurs by a tight complex without forming a covalent bond to the isoalloxazine ring in FAD.

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“…On the basis of the above result, we further synthesized 2-octynoyl-CoA as an isomerase mechanism-based inhibitor. 2-Octynoyl-CoA has been known as an irreversible inhibitor of MCAD . The effect of 2-octynoyl-CoA on the catalytic activity of the thiolase was investigated by the incubation of the thiolase with 5 mol equiv of 2-octynoyl-CoA at room temperature.…”

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Inactivation of Thiolase by 2-Alkynoyl-CoA via Its Intrinsic Isomerase Activity

Zeng

Deng

et al. 2007

Org. Lett.

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Inactivation of two-electron reduced medium chain acyl-CoA dehydrogenase by 2-octynoyl-CoA

Cited by 10 publications

References 32 publications

Interaction of 3,4-Dienoyl-CoA Thioesters with Medium Chain Acyl-CoA Dehydrogenase: Stereochemistry of Inactivation of a Flavoenzyme

Interaction of 3,4-Dienoyl-CoA Thioesters with Medium Chain Acyl-CoA Dehydrogenase: Stereochemistry of Inactivation of a Flavoenzyme

Spiropentaneacetic acid as a specific inhibitor of medium-chain acyl-CoA dehydrogenase

Inactivation of Thiolase by 2-Alkynoyl-CoA via Its Intrinsic Isomerase Activity

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