Metabolism of testosterone to 5α-dihydrotestosterone is essential for initiation of the differentiation and development of the urogenital sinus into the prostate. Differentiation of male external genitalia (penis, scrotum and urethra) also strongly depends on the conversion of testosterone to 5α-dihydrotestosterone in the urogenital tubercle, labioscrotal swellings and urogenital folds (1). The irreversible conversion of testosterone to 5α-dihydrotestosterone is catalyzed by the microsomal enzyme 5α-reductase type 2 (SRD5A2) and NADPH dependent.[Figure 4] (11). The cDNA of the gene for 5α-reductase type 2 codes for a protein of 254 amino acid residues with a predicted molecular mass of 28,398 Dalton (12). The NH2-terminal part of the protein contains a subdomain supposedly involved in testosterone binding, while the COOH-terminal region is involved in NADPH-binding (2).
Figure 4. Metabolism of Testosterone to 5α-Dihydrotestosterone by the enzyme 5α-Reductase type 2 (SDR5A2).
The gene is located on chromosome 2 at locus 2p23. Elucidation of the organization of the 5α-reductase type 2 gene revealed 5 coding exons (12). The enzyme has a pH optimum at pH 5.5 in broken cell preparations, but may function optimally in the native state in intact cells at neutral pH and has an apparent Km for testosterone of 4-50 nM. The apparent Km for NADPH is 3-10 M. High expression of 5α-reductase type 2 is observed in prostate tissue. Mutations and deletions in the 5α-reductase type 2 gene have been found to be the molecular basis for the syndrome of 5α-Reductase type 2 deficiency (2).
The 5α-reductase type 1 (SRD5A1) isozyme, also catalyzing the conversion of testosterone to 5α-dihydrotestosterone, differs from the type 2 isozyme in its amino acid composition, kinetics, biochemical properties, substrate specificity, tissue distribution and pH optimum (11, 13). The type 1 enzyme is not involved in androgen dependent male sexual differentiation. The 5α-reductase type 1 cDNA codes for a protein of 259 amino acid residues with a predicted molecular mass of 29,462 Dalton (13). The gene is located on chromosome 5 at locus 5p15 (11). The apparent Km for testosterone is 1-5 mM and for NADPH 3-10 mM. The expression of 5α-reductase type 1 in prostate tissue is relatively low. The difference in pH optima between 5α-reductase type 1 and type 2 enzymes can be used diagnostically for the differential assessment of the individual isoenzymes in genital skin fibroblasts of patients with the syndrome of 5α-reductase deficiency (2, 11).
Male mice with a disruption of the 5α-reductase type 1 gene have a normal phenotype and are fertile. However, female mice with a null allele, have a severe parturition defect, suggesting a role of 5α-reduced androgens synthesized by the type 1 isozyme in normal female physiology (14)