Biomedical subjects
Publications and source records attributed to M Akhtar.
Cholesterol is biosynthesized from squalene in the presence of tritiated water. Chemical degradation reveals that a considerable percentage of the total radioactivity is present at C-15. This result confirms the previous observations on the involvement of a C-15 hydrogen atom in cholesterol biosynthesis.
1. A mechanism for the removal of the 14alpha-methyl group in ergosterol biosynthesis that involves the intermediacy of an 8,14-diene system is outlined. 2. In accordance with the requirements of this scheme, it is shown that 5alpha-ergosta-8,14-dien-3beta-ol is converted into ergosterol by Saccharomyces cerevisiae.
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Methods for the chemical synthesis of [23-(3)H(2)]lanosterol, [23,25-(3)H(3)]24-methyldihydrolanosterol and [24,28-(3)H(2)]24-methyldihydrolanosterol are described. It is shown that, in the biosynthesis of ergosterol from [26,27-(14)C(2),23-(3)H(2)]lanosterol by the whole cells of Saccharomyces cerevisiae, one of the original C-23 hydrogen atoms is lost and the other is retained at C-23 of ergosterol. It is also shown that 24-methyldihydrolanosterol is converted into ergosterol in good yield and without prior conversion into a 24-methylene derivative. On the basis of these results possible pathways for the formation of the ergosterol side chain from a 24-methylene side chain are discussed.
It is shown that the 7-dehydrocholesterol reductase-catalysed conversion of 7-dehydrocholesterol into cholesterol (II), with a 105000g microsomal pellet of rat liver in the presence of [4-(3)H(2)]NADPH, results in the transfer of radioactivity to the 7alpha-position of cholesterol. When the conversion is carried out in the presence of tritiated water the label is introduced exclusively at the 8beta-position. However, when the conversion of 7-dehydrocholesterol into cholesterol is performed with a 500g supernatant of rat liver homogenate the radioactivity is incorporated at both the 7alpha- and the 8beta-position. Evidence is provided for the presence of an enzyme system in the 500g supernatant that catalyses an equilibration of hydrogen atoms between those at the 4-position of NADPH and those of water. The work with stereospecifically labelled cofactors shows that both the equilibrating system and the 7-dehydrocholesterol reductase utilize the 4B-hydrogen atom of NADPH. In the light of these results a mechanism for the reduction of carbon-carbon double bonds is discussed.
Methods for the preparation of [3alpha-(3)H]ergosta-7,22-dien-3beta-ol (5,6-dihydro-ergosterol), [5,6-(3)H(2)]ergosta-7,22-dien-3beta-ol and [3alpha-(3)H]ergosta-7,22-diene-3beta,5alpha-diol are described. It is shown that 5,6-dihydro[3alpha-(3)H]ergosterol on incubation under aerobic conditions with whole cells of Saccharomyces cerevisiae LK(2)G(12) is efficiently converted into ergosterol. Studies carried out with dihydro[5alpha,6alpha-(3)H(2)]-ergosterol demonstrate that the introduction of the 5,6-double bond in ergosterol biosynthesis is attended by an overall cis-elimination of two hydrogen atoms. To differentiate between a hydroxylation-dehydration mechanism and a dehydrogenation mechanism, the metabolism of [3alpha-(3)H]ergosta-7,22-diene-3beta,5alpha-diol was studied. It was shown that this diol is converted into ergosterol only under aerobic conditions. It is therefore suggested that the introduction of the 5,6-double bond of ergosterol does not occur through a hydroxylation-dehydration mechanism.
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1. Convenient methods for the preparation of tritiated 11-cis-retinol, 11-cis-retinal and rhodopsin are described. Irradiation of labelled rhodopsin in the presence of sodium borohydride resulted in the irreversible binding of the retinyl moiety to the active site. Degradative studies established that the retinyl moiety in this reduced derivative of rhodopsin was attached to the in-amino group of lysine. In connexion with this investigation the synthesis of a number of N-retinylidene- and N-retinyl-amino acids was achieved. Derivatives of lysine with the retinyl moiety attached either to the alpha-amino group or to the in-amino group were also synthesized and characterized. 2. It is suggested that the involvement of a charge-transfer interaction between the retinylidene chromophore and a suitable group -X or -X.H on the opsin best explains the spectroscopic properties of rhodopsin and other visual proteins.
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1. The syntheses of Delta(7)-[4-(14)C]cholestenol (XVI, Scheme 3) and Delta(7)-[6alpha-(3)H]-cholestenol (XII, Scheme 2) are described. 2. The metabolism of doubly labelled Delta(7)-cholestenol (II, Scheme 1) by rat-liver homogenates was studied. 3. During the enzymic conversion of Delta(7)-cholestenol into cholesterol (IV, Scheme 1) the 6alpha-hydrogen atom of the former is lost and the overall reaction corresponds to a cis-elimination. 4. In the light of these results various mechanisms for the conversion of Delta(7)-cholestenol into cholesterol are discussed.