The role of malonyl-CoA in isoprenoid biosynthesis

Higgins, Malcolm John Peter (1969). The role of malonyl-CoA in isoprenoid biosynthesis. University of Birmingham. Ph.D.

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The observation that malonyl-CoA is involved in the synthesis of HMG-CoA by a pigeon liver fatty acid synthesising system, has led to uncertainty concerning the origin of the acetoacetyl intermediate for isoprenoid synthesis. A study was undertaken of the utilisation of malonyl-CoA for this purpose.
Initial experiments with crude preparations of rat liver, yeast and the latex of \(Hevea\) \(brasiliensis\) indicated that malonyl-CoA was incorporated into isoprenoid compounds, including mevalonic acid. However, when avidin was added to incubations, fatty acid synthesis from acetate or acetyl-CoA was inhibited while the incorporation into isoprenoids was not affected. This indicated that a biotin dependent carboxylation of acetyl-CoA is not involved in the synthesis of isoprenoid compounds, and that malonyl-CoA was decarboxylated before the incorporation of acetyl-CoA as such. Experiments in which the incorporation of [2-\(^{14}\)C] malonyl-CoA was compared to the incorporation of [1,3-\(^{14}\)C] malonyl-CoA did not resolve this question, but degradation of HMG-CoA and Ergosterol indicated that the incorporation of radioactivity was that to be expected from acetyl-CoA. In accord with these observations, the malonyl-CoA decarboxylase activity could account for the incorporation of malonyl-CoA observed. When this was reduced by isolation conditions in which mitochondrial integrity was preserved, the incorporation into mevalonate was reduced.
An examination of the purification of the pigeon liver fatty acid synthetase showed that HMG-CoA synthesising activity did not copurify with fatty acid synthesising activity.
It was concluded that, in the systems studied, the acetoacetyl intermediate for isoprenoid synthesis arises by the condensation of two molecules of acetyl-CoA without the intervention of malonyl-CoA.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Faculties (to 1997) > Faculty of Science
School or Department: Department of Biochemistry
Funders: Other
Other Funders: Science Research Council
Subjects: Q Science > QP Physiology
Q Science > QR Microbiology


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