Bile acid conjugates biosynthesis

The terminal step in the biosynthesis of bile acids from cholesterol is represented by the enzymatic synthesis of water-soluble bile acid conjugates of taurine and/or glycine through a peptide bond, as shown in Fig. 1. 

Besides hormonal steroid conjugates (Figure 2.7), bile alcohol and bile acid conjugates can also be analyzed by shotgun steroidomics. These metabolites are often elevated in abundance in plasma as a consequence of an inborn error of bile acid biosynthesis or as a consequence... 

Glycine participates in the biosynthesis of heme, purines, and creatine and is conjugated to bile acids and to the urinary metabolites of many drugs. 

Biosynthesis of the two primary bile acids is followed by conjugation of their carboxylic group with the amino group of either glycine or taurine, mediated by a cytoplasmic enzyme. By means of this conjugation, the primary bile acids, which initially are barely water-soluble, become anions and are thus rendered hydrophilic. In this way four conjugated bile acids are formed ... 

Biochemical studies with isolated rat hepatocytes have largely been concerned with transport mechanisms [15], secretion of bile acids [17-19], or biosynthesis of bile acids [20]. The capacity of cultured hepatocytes to convert tauro- or glyco-chenodeoxycholate to a- and )8-muricholates [19,21] and to produce bile salts (glycine or taurine conjugates) during the dark phase of the diurnal cycle [21] has been established. Demonstrations of other metabolic transformations by hepatocytes are included in the following sections. 

Bremer and Gloor [40] concluded that enzymes for both reactions were present in hepatic microsomes, but recent studies with microsomes of rat [40-42] and human liver [43] have confirmed the presence of only one enzyme, CoA ligase. The assay system, essentially that for long-chain acyl-CoA ligase [42,43], includes 50 mM NaF, a phosphate buffer (pH 7.5), the enzyme preparation, and constituents of Eqn. 1. Product formation was linear up to 12 min with added protein (between 0.1 and 1.2 mg) from a crude microsomal fraction. Sterol carrier protein [44], cysteine or nicotinamide [38,40] were without effect. This rate-limiting enzyme in the two-step sequence catalyzing conjugation of bile acids exhibits a diurnal variation such that the time of maximum enzyme activity coincides with predicted maximum activity of cholesterol 7a-hydroxylase and the time of maximal biosynthesis of bile acids [45]. The enzyme has not been purified. 

Fig. 1. Biosynthesis of conjugated bile acids. (1) Glycocholic acid. (2) Taurocholic acid.

Although mercapturic acids are normally the major thioether products of lipophilic xenobiotics found in urine of mammals, small amounts of the corresponding S-cysteine conjugates are also frequently excreted. All four thioether products formed during mercapturic acid biosynthesis are routinely excreted in bile. 

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