Two enzymes, one function? Comparison of the testosterone-synthesizing enzymes 17β-hydroxysteroid dehydrogenase type 3 and 5

Both 17β-hydroxysteroid dehydrogenase types 3 and 5 (17βHSD3 and 17βHSD5) catalyze the conversion from androstenedione (A4) to testosterone in the body, yet the enzymes differ in many ways. Among the differences are their affiliation to different enzyme superfamilies (short-chain dehydrogenases/reductases (SDR) vs. aldo-keto reductases (AKR), respectively), their substrate specificity, their intracellular location and tissue-specific expression. The enzymes share some physiological substrates, but 17βHSD5 is also part of phase I xenobiotic metabolism, while for human 17βHSD3 no exogenous substrates are known. Both play a role in male (fetal) development and contribute to alternative androgen synthesis pathways, albeit to varying degrees. Moreover, the three-dimensional protein structures and catalytic domains of the two enzymes are not alike. Whereas 17βHSD5 is characterized by a TIM barrel motif, typical for AKRs, the tertiary structure of 17βHSD3 incorporates a Rossmann fold, typical for SDRs. Furthermore, there are differences in terms of their gene inducibility. Interestingly, both enzymes are associated with prostate carcinoma, making them potential targets for prostate cancer therapy. Higher gene and protein expression in the tumor indicate a self-enhancing loop with locally elevated concentrations of anabolic testosterone, which fuels prostate cancer growth. Analogously, altered levels of 17βHSD3 and/or 17βHSD5 are linked to certain other diseases. In this review, we provide an overview of the similarities and differences between these two enzymes.