Structures important in mammalian 11 beta- and 17 beta-hydroxysteroid dehydrogenases

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Hydroxysteroid dehydrogenases (HSDs) are crucial enzymes in steroid metabolism.
• Understanding the 3D structure of HSDs is key to elucidating their function and regulation.

Purpose of the Study:

• To model the 3D structures of human 11 beta- and 17 beta-hydroxysteroid dehydrogenases.
• To analyze the NAD(H)/NADP(H) binding sites and catalytic sites of various HSD types.
• To investigate structural conservation and potential regulatory mechanisms.

Main Methods:

• X-ray crystallographic structures of related enzymes (rat/human dihydropteridine reductase, Streptomyces hydrogenans 20 beta-hydroxysteroid dehydrogenase) were used for modeling.
• Analysis incorporated data from Drosophila alcohol dehydrogenase mutants.
• Comparative structural analysis of conserved residues and stabilizing features.

Main Results:

• Modeled structures revealed conserved residues at the "anchor site" and stabilizing features in 11 beta- and 17 beta-hydroxysteroid dehydrogenase type 1, despite low sequence identity.
• Similar conservation was observed in 11 beta- and 17 beta-hydroxysteroid dehydrogenase type 2.
• A highly conserved alpha-helix with tyrosine and lysine residues was identified at the catalytic site of 17 beta-HSDs.

Conclusions:

• Conserved structural elements suggest shared functional mechanisms among HSDs.
• Interactions involving the alpha-helix F dimerization surface may regulate HSD activity through protein or membrane associations.