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To this day, a significant proportion of the human genome remains devoid of functional characterization. In this study, we present evidence that the previously functionally uncharacterized product of the human DHRS10 gene is endowed with 17beta-HSD (17beta-hydroxysteroid dehydrogenase) activity. 17beta-HSD enzymes are primarily involved in the metabolism of steroids at the C-17 position and also of other substrates such as fatty acids, prostaglandins and xenobiotics. In vitro, DHRS10 converts NAD+ into NADH in the presence of oestradiol, testosterone and 5-androstene-3beta,17beta-diol. Furthermore, the product of oestradiol oxidation, oestrone, was identified in intact cells transfected with a construct plasmid encoding the DHRS10 protein. In situ fluorescence hybridization studies have revealed the cytoplasmic localization of DHRS10. Along with tissue expression data, this suggests a role for DHRS10 in the local inactivation of steroids in the central nervous system and placenta. The crystal structure of the DHRS10 apoenzyme exhibits secondary structure of the SDR (short-chain dehydrogenase/reductase) family: a Rossmann-fold with variable loops surrounding the active site. It also reveals a broad and deep active site cleft into which NAD+ and oestradiol can be docked in a catalytically competent orientation.

Type

Journal article

Journal

The Biochemical journal

Publication Date

03/2007

Volume

402

Pages

419 - 427

Addresses

Structural Genomics Consortium, University of Oxford, Oxford OX3 7LD, UK. lukacikp@niddk.nih.gov

Keywords

Cell Line, Cytosol, Humans, NAD, 17-Hydroxysteroid Dehydrogenases, Ligands, Crystallography, X-Ray, Sequence Alignment, Organ Specificity, Gene Expression, Binding Sites, Amino Acid Sequence, Protein Structure, Secondary, Protein Structure, Tertiary, Structural Homology, Protein, Oxidation-Reduction, Kinetics, Models, Molecular, Molecular Sequence Data