The synthesis of a full complement of bile acids requires at least 16 enzymes that catalyze 17 reactions (Figure 1) (1). One enzyme, sterol 27-hydroxylase, acts on two different substrates, cholesterol and a pathway intermediate. The expression of selected enzymes in the pathway is regulated by nuclear hormone receptors and other transcription factors to ensure that a constant supply of bile acids is available in an ever-changing dietary environment. The importance of cholesterol catabolism via this pathway is underscored by inherited mutations that impair bile acid synthesis and cause a spectrum of human disease, ranging from liver failure in early childhood to progressive neuropathy in adults. The overall biochemical steps leading to synthesis of a bile acid include: i) initiation of synthesis by 7oc-hydroxylation of sterol precursors, ii) further modifications to the ring structures, iii) oxidation and shortening of the side chain, and iv) conjugation of the bile acid with an amino acid. Synthesis does not progress through a linear order of steps as many sterol intermediates serve as substrates for more than one enzyme. This randomness in turn generates a large number of bile acids with different detergent and regulatory properties, which together ensure complete solubilization of hydrophobic nutrients in the small intestine and tight control of synthesis in the liver.
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