The First Defect In Electron Transfer To Mitochondrial P450 Enzymes

Cloning of the cDNAs and genes for the various steroidogenic enzymes and their cofactors permitted identificationoftheprecisegeneticcausesofalltheknown human lesions in steroid biosynthesis and the identification of new diseases (1). There are 2 major classes of steroidogenic enzymes, hydroxysteroid dehydrogenases and cytochromes P450. Each of these classes is divided into 2 maingroups.Thehydroxysteroiddehydrogenasesmaybe either short-chain dehydrogenases or aldo-keto reductases. The short-chain dehydrogenases are familiar to most endocrinologists, and include the 2 isozymes of 3-hydroxysteroid dehydrogenase, the 2 functionally distinct forms of 11-hydroxysteroid dehydrogenase, and the principal forms of 17-hydroxysteroid dehydrogenase. By contrast the aldo-keto reductase enzymes catalyze less familiar reactions, such as 3-hydroxysteroid dehydrogenation and 5-reduction, which are important in the “backdoor pathway” of androgen synthesis (2, 3) and in bile acid synthesis (4). Thus, the hydroxysteroid dehydrogenases are important regulators of steroid activity at the termini of steroidogenic pathways (5), but we will say no more about them here. The cytochrome P450 enzymes are generally more familiar, because they catalyze biosynthetic reactions in the production of steroids, activated vitamin D, leukotrienes, prostaglandins, and bile acids, as well as participating in the degradation of countless drugs and xenobiotic agents. There are 2 distinct groups of vertebrate P450 enzymes: type I enzymes, which are targeted to the mitochondria, andtypeIIenzymes,whicharetargetedtotheendoplasmic reticulum. Enzymes of both classes are about 500-amino acid long, contain a heme group, and undergo a characteristic shift in their absorption spectra at 450 nm when