The role of 7,9 - diene systems in cholesterol biosynthesis
The role of 7,9 - diene systems in cholesterol biosynthesis
Studies with cell free preparations of rat liver established that dihydroagnosterol (37) was demethylated aerobically at the 14a-position to give 4,4'-dimethylcholesta-7,9-dienol(90). Under anaerobic conditions the dihydroagnosterol (37) was not metabolised and was recovered unchanged. The metabolism of 4,4'-dimethylcholesta-7,9-dienol (90) was shown to involve further aerobic demethylations at the C-4 position and resulted in cholesta-7,9-dienol (89) being formed. The 4,4'-dimethylcholesta-7,9-dienol (90) was not metabolised under anaerobic conditions. The cholesta-7,9dienol (89) was isomerised to cholesta-8,14-dienol (78) which was then converted to cholesterol (2) by the well known pathway. The one enzyme most likely to be unique in the conversion of dihydroagnosterol (37) to cholesterol (2) is the A7'9 -A8,14 isomerase. This enzyme was found to be completely specific for the 4,4'-nordimethyl sterol. Pathways for the isomeric conversion of A 7 ' 9 to the A 8 ' 14 are discussed and a method for distinguishing them using a deuterated medium, proposed. Subsequent investigations with rat liver homogenate revealed that the removal of the 14a-methyl group from dihydroagnosterol (37) resulted in the formation of 4,4'-dimethylcholesta-7,9,14-trienol (91). This trien (91) was reduced under anaerobic conditions by rat liver, microsomes in the presence of NADPH to give 4,4'-dimethyl cholesta-7,9-dienol (90). Moreover the reduction of thetrien (91) in the presence of 4-3H NADPH resulted in the incorporation of tritium in the product. In addition the 4,4'-dimethylcholesta-7,9,14-trienol (91) and 4,4'-dimethyl cholesta-7,9-dienol (90) were converted to cholesterol (2) thus providing further evidence that they are intermediatesin the biosynthesis of cholesterol (2) from dihydroagnosterol.Preliminary studies using rat skin to study sterol biosynthesis demonstrated that the A8 -A7 sterol isomerase of rat skin appears to show the same stereochemistry of hydrogen removal as in rat liver.
University of Southampton
Tavares, Ignatius Anthony
1977
Tavares, Ignatius Anthony
Tavares, Ignatius Anthony
(1977)
The role of 7,9 - diene systems in cholesterol biosynthesis.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Studies with cell free preparations of rat liver established that dihydroagnosterol (37) was demethylated aerobically at the 14a-position to give 4,4'-dimethylcholesta-7,9-dienol(90). Under anaerobic conditions the dihydroagnosterol (37) was not metabolised and was recovered unchanged. The metabolism of 4,4'-dimethylcholesta-7,9-dienol (90) was shown to involve further aerobic demethylations at the C-4 position and resulted in cholesta-7,9-dienol (89) being formed. The 4,4'-dimethylcholesta-7,9-dienol (90) was not metabolised under anaerobic conditions. The cholesta-7,9dienol (89) was isomerised to cholesta-8,14-dienol (78) which was then converted to cholesterol (2) by the well known pathway. The one enzyme most likely to be unique in the conversion of dihydroagnosterol (37) to cholesterol (2) is the A7'9 -A8,14 isomerase. This enzyme was found to be completely specific for the 4,4'-nordimethyl sterol. Pathways for the isomeric conversion of A 7 ' 9 to the A 8 ' 14 are discussed and a method for distinguishing them using a deuterated medium, proposed. Subsequent investigations with rat liver homogenate revealed that the removal of the 14a-methyl group from dihydroagnosterol (37) resulted in the formation of 4,4'-dimethylcholesta-7,9,14-trienol (91). This trien (91) was reduced under anaerobic conditions by rat liver, microsomes in the presence of NADPH to give 4,4'-dimethyl cholesta-7,9-dienol (90). Moreover the reduction of thetrien (91) in the presence of 4-3H NADPH resulted in the incorporation of tritium in the product. In addition the 4,4'-dimethylcholesta-7,9,14-trienol (91) and 4,4'-dimethyl cholesta-7,9-dienol (90) were converted to cholesterol (2) thus providing further evidence that they are intermediatesin the biosynthesis of cholesterol (2) from dihydroagnosterol.Preliminary studies using rat skin to study sterol biosynthesis demonstrated that the A8 -A7 sterol isomerase of rat skin appears to show the same stereochemistry of hydrogen removal as in rat liver.
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Published date: 1977
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Local EPrints ID: 462678
URI: http://eprints.soton.ac.uk/id/eprint/462678
PURE UUID: 44c07650-24ae-4f7c-a60d-24b93c351041
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Date deposited: 04 Jul 2022 19:40
Last modified: 04 Jul 2022 19:40
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Author:
Ignatius Anthony Tavares
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