THE MURINE 3-BETA-HYDROXYSTEROID DEHYDROGENASE MULTIGENE FAMILY - STRUCTURE, FUNCTION AND TISSUE-SPECIFIC EXPRESSION

The classical form of the enzyme 5-ene-3 beta-hydroxysteroid dehydroge nase/isomerase (3 beta HSD), expressed in adrenal glands and gonads, c atalyzes the conversion of 5-ene-3 beta-hydroxysteroids to 4-ene-3-ket osteroids, an essential step in the biosynthesis of all active steroid hormones. To date, four distinct mouse 3 beta HSD cDNAs have been iso lated and characterized. These cDNAs are expressed in a tissue-specifi c manner and encode proteins of two functional classes. Mouse 3 beta H SD I and III function as 3 beta-hydroxysteroid dehydrogenases and 5-en -->4-en isomerases using NAD(+) as a cofactor. The enzymatic function of 3 beta HSD II has not been completely characterized. Mouse 3 beta H SD IV functions only as a 3-ketosteroid reductase using NADPH as a cof actor. The predicted amino acid sequences of the four isoforms exhibit a high degree of identity. Forms II and III are 85 and 83% homologous to form I. Form IV is most distant from the other three with 77 and 7 3% sequence identity to I and III, respectively. 3 beta HSD I is expre ssed in the gonads and adrenal glands of the adult mouse. 3 beta HSD I I and III are expressed in the kidney and liver with the expression of form II greater in kidney and form III greater in liver. Form IV is e xpressed exclusively in the kidney. Although the amino acid compositio n of forms I, III and IV predicts proteins of the same molecular weigh t, the proteins have different mobilities on SDS-polyacrylamide gel el ectrophoresis. This characteristic allows for differential identificat ion of the expressed proteins. The four structural genes encoding the different isoforms are closely linked within a segment of mouse chromo some 3 that is conserved on human chromosome 1.