Bile acid chains, degradation oxidative

MIESCHER DEGRADATION. Adaptation of the Barbier-Wieland carboxylic acid degradation to pcrmil simultaneous elimination of three carbon atoms, as in degradation of the bile acid side chain to the methyl ketone stage. Conversion of the methyl ester of the bile acid to the tertiary alcohol, followed by dehydration, bromination. dehydrohalogenatinn, and oxidation of the diene yields die required degraded ketone. 

Two pathways have been proposed for degradation of the cholestane side chain in the biosynthesis of bile acids. These differ in the site proposed for the first hydroxylation step in side-chain oxidation and are discussed below for the formation of cholic add. 

Decarboxylation /-Butylhydroperoxide. Copper powder. Dimethyl sulfoxide. Iron. Decarboxylation, oxidative Lead dioxide. Lead tetraacetate. Pyridine-N-oxide. Degradation, bile acid side chain Periodic acid. 

Danielsson and Kazuno have shown that 5j8-ranol is an efficient precursor of cholic acid in bile fistula rats while 26-deoxy-5)S-ranol is not [134]. The mechanism of the side-chain degradation of 5 -ranol is not known but probably an oxidation of the 26-hydroxyl group to a carboxyl group followed by a /S-oxidation. 

Schematically shown are two separate P-oxidation systems, one involved in degradation of straight chain fatty acid derivatives (left side), the other handling 2-melhyl-branched compounds (right side), each of them consisting of four steps that are catalyzed by an acyl-CoA oxidase, a multifimctional protein (MFP) (containing two or more activities) and a thiolase. Only the proteins belonging to the left system are (at least in rodents) induced by peroxisome proliferators and correspond to those initially discovered and characterized in rat liver. In rat, the CoA-esters of bile acid intermediates and pristanic acid are desaturated by separate enzymes (highlighted in italie), while in man only one oxidase appears to be involved. Before the naturally occurring 2R-pristanic acid and 25R-bile acid intermediates can be desaturated, a racemisation reaction is required. The 2-methyl-2-enoyl-CoAs, generated by the oxidases, are thought to be hydrated by the same MFP-2. Under normal conditions, the intermediates are believed to be channeled from...

As discussed above, the peroxisomal fatty acid P-oxidation system is specifically involved in the degradation of a specific group of fatty acids including very-long-chain fatty acids, pristanic acid and di- and trihydroxycholestanoic acid. Several inherited diseases in man have been described in which peroxisomal P-oxidationis impaired at some level as reflected in the differential acciunulation of very-long-chain fatty acids, pristanic acid and the bile acid intermediates in plasma from patients. The following disorders can be distinguished ... 

The degradation of the bile acid side chain is best carried out (Mattox and Kendall, 1950) at the 1 l-keto-12a-bromo oxide stage (VI), since... 

Figure 4 Peroxisomal fatty-acid (FA) /3-oxidation pathways. While saturated long-chain fatty acids (LCFA) are preferentially degrade in mitochondria, saturated very-long-chain fatty acids (VLCFA) and some LCFA are shortened by peroxisomal /3-oxidation. Degradation of pristanic acid, the product of phytanic acid a-oxidation, and the conversion of the cholesterol-derived 27-carbon bile-acid precursors dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA) to 24-carbon bile acids also require this pathway. The mechanism by which these substrates enter peroxisomes is unknown. Four enzymatic reactions serve to shorten the substrates by either two (LCFA, VLCFA) or three (pristanic acid, DHCA, THCA) carbon atoms. The 2-methyl group of the latter substrates is shown in brackets. SCPx thiolase refers to the thiolase activity of sterol carrier protein x.

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