Multifunctional roles of bile acid biosynthetic enzymes and the isolation of a new vitamin D 25-hydroxylase

摘要

Research over the past three decades has led to the annotation of the pathways by which cholesterol is converted into conjugated bile acids in the liver1. At least 16 enzymes that catalyse 17 different reactions participate in these metabolic pathways (Figure 1). The transformation of cholesterol mediated by these enzymes renders the once almost insoluble molecule (Ksp = 2 mg/L) highly soluble (Ksp = 670 g/L) and readily excreted from the body via the bile. With the elucidation of the bile acid pathways has come the realization that many of the participating enzymes play multiple biosynthetic roles (Table 1). For example, three sterol hydroxylases involved in transformations of the side chain of cholesterol during bile acid synthesis also produce oxysterols, which are ligands for nuclear hormone receptors and potent regulators of cholesterol synthesis3. Three enzymes act on both intermediates in the bile acid pathway as well as other steroids, serving for the most part to inactivate steroids and thus terminate signalling through classic steroid hormone receptors. Enzymes in bile acid synthesis also metabolize very long chain fatty acids , such as dietary pristanic acid, and in agreement with the dual functional roles of these proteins, gene mutations that impair these enzyme activities cause defects in hepatic bile acid synthesis5 and the accumulation of very long chain fatty acids leading to neurological dysfunction.