cholestenone 5alpha-reductase of Human,encoded in the gene SRD5A,is an important key enzyme in the biosynthetic pathway from T to DHT.It catalyzes the reduction of testosterone in position 4 and 5 using NADPH as a hydrogen donor.Up to now,no X-ray structure of this cholestenone 5alpha-reductase or any structurally related enzyme is known.Knowledge of the tertiary structure and possible active sites is,however,essential for understanding the catalysis mechanism and the substrate specificity.With homology modeling techniques,secondary structure prediction tools,molecular dynamics simulations,and energy optimizations,a model with two putative active sites could be created and refined.One active site selected to be the most likely one for the docking of T and DHT is located near the N-terminus of the enzyme.It is widely accepted that residues forming an active site are usually evolutionary conserved within a family of enzymes.Multiple alignments of a multitude of related proteins clearly showed 100% conservation of the amino acid residues that form the first putative active site and therefore strongly support this hypothesis.However,an additional highly conserved region in the amino acid sequence of the enzyme could be detected,which also can be considered a putative (or rudimentary) active site.This site is characterized by a high sequence similarity to the aforementioned site and may give some hints regarding the evolutionary origin of the enzyme.Semiempirical quantum mechanical PM3 calculations have been performed to investigate the thermodynamics and kinetics of the catalysis mechanism.Our models are a basis for developing inhibitors of this enzyme,which is crucial for the cure of BPH.