Bile acid biosynthesis pathways

CYP27A1 catalyzes the side chain oxidation (27-hydroxylation) in bile acid biosynthesis. Because bile acid synthesis is the only elimination pathway for cholesterol, mutations in the CYP27A1 gene lead to abnormal deposition of cholesterol and cholestanol in various tissues. This sterol storage disorder is known as cerebrotendinous xanthomatosis. CYP27B1 is the 1-alpha hydroxylase of vitamin D3 that converts it to the active vitamin form. The function of CYP27C1 is not yet known. 

It is impossible to determine the relative contributions of each of these pathways to total bile-acid biosynthesis, due to the nature of the data. Some values were obtained from patients whose gallbladders had been surgically removed other patients would be atypical due to illness, and many data were obtained from experimental animals, which may metabolise these compounds differently from humans. Also, the exact order of many of the reactions is not known, since the intermediates may act as substrates for more than one enzyme. Further details for these reactions can be found in reviews by Chiang, Moore et al. and Fuchs et al ... 

Fig. 9. The elaboration of the cholesteol nucleus in bile acid synthesis. (Cholic acid and chenodeoxycholic acid biosynthesis pathway).

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

The exact contributions of these alternate pathways to total hepatic bile acid synthesis in normal subjects is not certain, although 26-hydroxylation is usually regarded as the major pathway. In addition, it should be pointed out that current views of hepatic cholic acid and chenodeoxycholic acid synthesis are based primarily oh studies carried out in the rat. More recent studies, which have involved the administration of labeled bile acid intermediates to patients, have suggested that bile acid biosynthesis is more complex than previously thought and that multiple pathways exist to convert cholesterol to bile acids (Vll). 

The possibUity of multiple pathways in bile acid biosynthesis in man has been discussed by Vlahcevic et al. [180-182]. A number of labelled 7 -hydroxylated intermediates in bile acid biosynthesis were administered to bile fistula patients as well as patients with an intact enterohepatic circulation. In accordance with previous work with bile fistula rats, the spedfic activity of the isolated chohc add was in general considerably lower than that of chenodeoxychohc acid. On the basis of this finding, it was suggested that a portion of chohc acid was synthesized via a route not involving initial 7a-hydroxylation of cholesterol. It must then be assumed that the administered intermediate mixes with the endogenous pool of the same steroid. However, due to compartmentation, the metabolic fate of a precursor reaching the hepatocyte might be different from that of the the same compound formed within the cell. Normally, the different precursors are present in the cells in trace amounts... 

Information concerning the relative importance of metabolic pathways may be obtained from studies on inborn errors of metabolism. Two such disorders affecting bile acid biosynthesis have been described, cerebrotendinous xanthomatosis (CTX) and Zellweger s disease (cerebro-hepato-renal syndrome). The primary defect in cerebrotendinous xanthomatosis seems to be the absence of one enzyme involved in bile acid biosynthesis. The basic defect in Zellweger s disease has not yet been defined with certainty. 

Figure 2.17 Suggested pathway of cholesterol metabolism in human brain based on the identification of metabolites in CSR The left hand branch constitutes the initial steps of the acidic pathway of bile acid biosynthesis. 26-Hydroxycholesterol may be synthesized in brain via a reaction catalyzed by CYP27A1 or imported into brain from the circulation (Heverin, Meaney, Liitjohann, et al. [60].) Thus, the ultimate product of this pathway 7a-hydroxy-3-oxocholest-4-en-26-oic may be derived from brain synthesized or imported sterols. The right-hand branch of the pathway represents the initial steps of the 24-hydroxylase pathway of bile acid biosynthesis. The initial enzyme CYP46A1 is uniquely expressed in nervous tissue (Lund, Guileyardo, and Russell [61]). (See color insert.)...

Sanyal S, Bavner A, Haroniti A, Nilsson LM, Lundasen T, Rehnmark S, Witt MR, Einarsson C, Talianidis I, Gustafsson JA, Treuter E (2007) Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis. Proc Natl Acad Sci U S A 104 15665-15670... 

S-Hydroxycholesterols represent an initial metabolite in one of the pathways of bile acid biosynthesis. Although bile acid biosynthesis predominantly occurs in the Uver, this first step in the 24S-hydroxylase pathway is extrahepatic [61], Interestingly, Ferdinandusse et al. [52] and Mano et al. [53] have been able to identify C27 and C24 bile acids in brain by negative ion ESI-MS. Like Mano et al., we have also been able to identify cholic acid in rodent brain [62]. Mano et al. identified both cholic and deoxycholic acids in rat brain cytoplasmic extracts however, when these extracts were treated with guanidine to reduce protein noncovalent interactions, high levels of chenodeoxycholic acid were also found. 

Also included in this report, are two documented alternative biochemical pathways which are known to introduce oxygen functionaly at C-25 (and C-26) directly without using the oxysterol pathway . In the first, sterols may be hydroxylated at C-25 in the liver during bile acid biosynthesis (1). In the second, vitamin D3 is known to be hydroxylated directly at C-25 in mammalian systems (1). These documented instances occur in the animal kingdom. Plant metabolism, especially the biosynthesis of secondary plant metabolites, has not been examined in sufficient detail to indicate the extent to which direct introduction of a hydroxyl group at C-25 might occur. However, a great deal of evidence is available to indicate that many of these side chain oxysterols are produced via the oxysterol pathway . 

Figure 26-7. Biosynthesis and degradation of bile acids. A second pathway in mitochondria involves hy-droxylation of cholesterol by sterol 27-hydroxylase. Asterisk Catalyzed by microbial enzymes.

We begin with an account of the main steps in the biosynthesis of cholesterol from acetate, then discuss the transport of cholesterol in the blood, its uptake by cells, the normal regulation of cholesterol synthesis, and its regulation in those with defects in cholesterol uptake or transport. We next consider other cellular components derived from cholesterol, such as bile acids and steroid hormones. Finally, an outline of the biosynthetic pathways to some of the many compounds derived from isoprene units, which share early steps with the pathway to cholesterol, illustrates the extraordinary versatility of isoprenoid condensations in biosynthesis. 

A number of cytochrome P450 enzymes are involved in the conversion of acetate to sterols and bile acids (Figure 9.6). The participation of P450 enzymes in pathways of cholesterol biosynthesis and elimination demonstrate their important role in cholesterol homeostasis. Lanosterol 14a-desmethylase, encoded by CYP51A1, is a pivotal P450 involved in cholesterol biosynthesis. The synthesis of bile acids from... 

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. 

Swell, L., Biosynthesis of bile acids in man. Multiple pathways to cholic acid and che-nodeoxycholic acid. /. Biol. Chem. 255, 2925-2933 (1980). 

Cholesterol is primarily restricted to eukaryotic cells where it plays a number of roles. Undoubtedly, the most primitive function is as a structural component of membranes. Its metabolism to bile acids and the steroid hormones is relatively recent in the evolutionary sense. In this chapter, the pathway of cholesterol biosynthesis will be divided into segments which correspond to the chemical and biochemical divisions of this biosynthetic route. The initial part of the pathway is the 3-step conversion of acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The next is the reduction of this molecule to mevalonate, considered to be the rate-controlling step in the biosynthesis of polyisoprenoids. From thence, a series of phosphorylation reactions both activate and decarboxylate mevalonate to isopen tenyl pyrophosphate, the true isoprenoid precursor. After a rearrangement to the allylic pyrophosphate, dimethylallyl pyrophosphate, a sequence of l -4 con-... 

XIII) Species differences and alternative pathways in the biosynthesis of bile acids... 

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