Synthesis of Triacetic Acid Lactone by the Pigeon Liver Fatty Acid Synthetase Complex

Nixon, J.E.; Putz, Gene R.; Porter, John W.

doi:10.1016/s0021-9258(18)91970-8

Cited by 47 publications

(5 citation statements)

References 27 publications

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“…The reduced level of C02 release must therefore represent slowing down of the condensation steps 2 and 3 of Scheme I. Our studies of the effect of NADP+ on the condensation-C02 exchange reaction (see later) and the reported inhibition of triacetic acid lactone synthesis by NADP+ (Nixon et al, 1968) are consistent with this suggestion. Therefore, the protective effect of NADP+ on the inactivation of enzyme by malonyl-CoA is in slowing down the formation of species i (eq 4, Scheme I).…”

Section: Since [B0supporting

confidence: 81%

Kinetic analysis of the malonyl coenzyme A decarboxylation and the condensation reaction of fatty acid synthesis. Application to the study of malonyl coenzyme A inactivated chicken liver fatty acid synthetase

Srinivasan¹,

Kumar²

1981

Biochemistry

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A kinetic analysis of the decarboxylation of malonyl-CoA and the condensation--CO2 exchange reaction of fatty acid synthesis has been carried out. The analysis supported by experimental evidence defines conditions under which the decarboxylation of malonyl-CoA quantitatively reflects the activity for the condensation reaction between enzyme-bound acyl and malonyl groups. NADP+ decreases the release of 14CO2 from radiolabeled malonyl-CoA by lowering the rates of the processes leading to the formation of triacetic acid lactone. For accurate measurements, the enzyme concentration should be less than 200 micrograms/mL, and malonyl-CoA/enzyme ratios should be 200 or less. Short reaction periods (1 min or less) and inclusion of NADP+ (100 microM) enhance the accuracy of measurements. These analyses have been used to explain the mechanism of malonyl-CoA mediated inactivation of chicken liver fatty acid synthetase and are appropriate for determining the functional condensing site of the polyfunctional polypeptide chains comprising the dimeric enzyme.

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Section: Since [B0supporting

confidence: 81%

Kinetic analysis of the malonyl coenzyme A decarboxylation and the condensation reaction of fatty acid synthesis. Application to the study of malonyl coenzyme A inactivated chicken liver fatty acid synthetase

Srinivasan¹,

Kumar²

1981

Biochemistry

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“…67 The KSs of metazoan FASs prefer fully reduced intermediates; otherwise, incompletely saturated fatty acids would be generated (unnatural chains are accepted at some rate-if NADPH is left out of an in vitro reaction with the metazoan FAS, a triketide pyrone is formed). 69 Some condensation reactions do not occur when KS is acylated by unnatural intermediates. 70 Perhaps the condensation machinery is set up most properly when the natural intermediate has acylated the KS.…”

Section: The Ks Domainmentioning

confidence: 99%

The structures of type I polyketide synthases

2012

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With the recent structural characterization of each of the component enzymes of type I polyketide synthases, scientists are coming tantalizingly close to elucidating the overall architectures and mechanisms of these enormous molecular factories. This review highlights not only what has been revealed about the structures and activities of each of the domains but also the mysteries that remain to be solved.

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“…Initiation of fatty acid synthesis by animal fatty acid synthetases have been postulated to occur when the acetyl group bound at the cysteine SH site of the condensing enzyme condenses with the malonyl group bound at the pantetheine site (Kumar et al, 1972). In the absence of NADPH, the normal process of fatty acid synthesis is circumvented, and the reaction product is triacetic acid lactone, which is presumably formed as a result of condensation between the acetoacetyl moiety bound at the cysteine SH condensing site and the malonyl group bound at the pantetheine site (Nixon et al, 1968). The formation of lactone which presumably occurs through the nucleophilic attack of the enolate group at carbon atom 5 of enzyme-bound triacetic acid on the thiol-bound carboxyl group leading to cyclization could produce distortion of the coordinates of the reactive vicinal thiol groups, cysteine SH and pantetheine SH.…”

Section: Electrophoreticmentioning

confidence: 99%

Inactivation of chicken liver fatty acid synthetase by malonyl coenzyme A. Effects of acetyl coenzyme A and nicotinamide adenine dinucleotide phosphate

Kumar¹,

Srinivasan²

1981

Biochemistry

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Chicken liver fatty acid synthetase complex is irreversibly inactivated by one of the substrates, malonyl-CoA. Acetyl-CoA has a dual role. At concentrations less than or comparable to those of malonyl-CoA, the rate of inactivation is enhanced, whereas at acetyl-CoA/malonyl-CoA ratios greater than 2, the rte of inactivation is slowed down. NADP+ at low concentrations (25 microM) affords considerable protection against malonyl-CoA mediated inactivation whereas NAD+ even at 1.0 mM concentration has no effect. The inactivation process does not lead to the dissociation of the enzyme complex and is accompanied by subtle conformational changes as measured by circular dichroism measurements. Of all the model partial reactions, decarboxylation of malonyl-CoA and the condensation--CO2 exchange are the only reactions which are not catalyzed by the modified species. The process of inactivation is accompanied by enhanced covalent binding of malonyl groups such that approximately 6 mol of the acyl group is bound per mol of the enzyme at complete inactivation. The available evidence suggests that the inactivation of the enzyme results from the binding of malonyl group(s) at or near the condensing site of the enzyme.

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Synthesis of Triacetic Acid Lactone by the Pigeon Liver Fatty Acid Synthetase Complex

Cited by 47 publications

References 27 publications

Kinetic analysis of the malonyl coenzyme A decarboxylation and the condensation reaction of fatty acid synthesis. Application to the study of malonyl coenzyme A inactivated chicken liver fatty acid synthetase

Kinetic analysis of the malonyl coenzyme A decarboxylation and the condensation reaction of fatty acid synthesis. Application to the study of malonyl coenzyme A inactivated chicken liver fatty acid synthetase

The structures of type I polyketide synthases

Inactivation of chicken liver fatty acid synthetase by malonyl coenzyme A. Effects of acetyl coenzyme A and nicotinamide adenine dinucleotide phosphate

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