Molecular and catalytic properties of mitochondrial (ketogenic) 3-hydroxy-3-methylglutaryl coenzyme A synthase of liver.

Reed, W D; Clinkenbeard, D; Lane, .

doi:10.1016/s0021-9258(19)41602-5

Cited by 85 publications

(18 citation statements)

References 19 publications

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“…Incubations were initiated by addition of S-acrylyl-VV-acetylcysteamine and were performed at 30 °C. Aliquots were withdrawn at the times indicated and assayed for enzyme activity by standard spectrophotometric procedures (Reed et al, 1975). * Values reported by Miziorko et al (1986).…”

Section: Resultsmentioning

confidence: 99%

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Chemical events in chloropropionyl-coenzyme A inactivation of acyl-coenzyme A utilizing enzymes

Miziorko¹,

Behnke²,

Ahmad³

1989

Biochemistry

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Incubation of 3-chloropropionyl-CoA with 3-hydroxy-3-methylglutaryl-CoA synthase results in exchange of the C2 proton with solvent as inactivation of enzyme proceeds. This enzyme is also inhibited by S-acrylyl-N-acetylcysteamine; the limiting rate constant for inactivation by the acrylyl derivative (0.36 min-1) slightly exceeds the value measured for chloropropionyl-CoA (0.31 min-1). These observations support the intermediacy of acrylyl-CoA in the chloropropionyl-CoA-dependent inactivation of hydroxymethylglutaryl-CoA synthase. Inhibition of fatty acid synthase by chloropropionyl-CoA is primarily due to alkylation of a reactive cysteine, although secondary reaction with the enzyme's pantetheinyl sulfhydryl occurs. Modification of fatty acid synthase by S-acrylyl-N-acetylcysteamine occurs at a limiting rate (1.8 min-1) that is comparable to that estimated for chloropropionyl-CoA-dependent inactivation. However, this enzyme lacks the ability to deprotonate C2 of an acyl group such as the chloropropionyl moiety. Since such a step would be required to generate an acrylyl group from chloropropionyl-S-enzyme, it is likely that a typical affinity labeling process accounts for inactivation of fatty acid synthase by chloropropionyl-CoA. HMG-CoA lyase is also inhibited by S-acrylyl-N-acetylcysteamine. In contrast to the ability of this reagent to serve as a mechanism-based inhibitor of hydroxymethylglutaryl-CoA synthase and an affinity label of fatty acid synthase, it acts as a group-specific reagent in modifying HMG-CoA lyase (kappa 2 = 86.7 M-1 min-1).

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Section: Resultsmentioning

confidence: 99%

“…Avian liver mitochondrial HMG-CoA synthase was prepared as previously described (Reed et al, 1975;Miziorko, 1984). Rat mammary fatty acid synthase was prepared according to the procedure of Ahmad et al (1982).…”

mentioning

confidence: 99%

Chemical events in chloropropionyl-coenzyme A inactivation of acyl-coenzyme A utilizing enzymes

Miziorko¹,

Behnke²,

Ahmad³

1989

Biochemistry

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“…The assignment of the acetyl-peptide residue corresponding to position 113 as arginine is in accord with the observation that the tryptic peptide containing the affinitylabeled cysteine has an N-terminus corresponding to position 114 (Figure 3). Despite the fact that cytosolic and mitochondrial HMG-CoA synthases are not immunologically closely related (Reed et al, 1975), there is a high level of homology (>90%) between the acetyl peptide and residues 113-130 of the hamster cytosolic enzyme (Gil et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

“…Chicken liver mitochondrial HMG-CoA synthase was prepared and assayed by the method of Reed et al (1975). Chymotrypsin was purchased from Sigma (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Identification of the site of acetyl-S-enzyme formation on avian liver mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase

Vollmer

Mende‐Mueller²,

Miziorko³

1988

Biochemistry

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Avian liver mitochondrial hydroxymethylglutaryl-CoA synthase contains an active-site cysteine involved in forming the labile acetyl-S-enzyme intermediate. Identification of and assignment of function to this cysteine have been accomplished by use of an experimental strategy that relies upon generation and rapid purification of the S-acetylcysteine-containing active-site peptide under mildly acidic conditions that stabilize the thioester adduct. Automated Edman degradation techniques indicate the peptide's sequence to be Arg-Glu-Ser-Gly-Asn-Thr-Asp-Val-Glu-Gly-Ile-Asp-Thr-Thr-Asn-Ala-Cys-Tyr. The acetylated cysteine corresponds to position 129 in the sequence deduced from cDNA data for the hamster cytosolic enzyme [Gil, G., Goldstein, J.L., Slaughter, C.A., & Brown, M.S. (1986) J. Biol. Chem. 261, 3710-3716]. The acetyl-peptide sequence overlaps that reported for a tryptic peptide that contains a cysteine targeted by the affinity label 3-chloropropionyl-CoA [Miziorko, H. M., & Behnke, C. E. (1985) J. Biol. Chem. 260, 13513-13516]. Thus, availability of these structural data allows unambiguous assignment of the acetylation site on the protein as well as a refinement of the mechanism explaining the previously observed affinity labeling of the enzyme.

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“…The other interesting compound identified in the sesquiterpenoid fraction of the essential oil of C. nervatus is ß-bergamotene,which was shown to be a key intermediate in the biosynthesis of ovalcinin produced by the fungus Pseudoeurotum ovalis (15)(16)(17). Such an antibiotic, antitumor, and immunosupressive compound has not been detected in the sesquiterpenoid fraction of the essential oil of C. nervatus nor in that oiC.…”

Section: Methodsmentioning

confidence: 99%

Chemistry of Sudanese Flora: Cymbopogon nervatus

Modawi¹,

Magar²,

Satti³

et al. 1984

J. Nat. Prod.

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Molecular and catalytic properties of mitochondrial (ketogenic) 3-hydroxy-3-methylglutaryl coenzyme A synthase of liver.

Cited by 85 publications

References 19 publications

Chemical events in chloropropionyl-coenzyme A inactivation of acyl-coenzyme A utilizing enzymes

Chemical events in chloropropionyl-coenzyme A inactivation of acyl-coenzyme A utilizing enzymes

Identification of the site of acetyl-S-enzyme formation on avian liver mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase

Chemistry of Sudanese Flora: Cymbopogon nervatus

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