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The fascinating complexities of steroid-binding enzymes
W L Duax1, J F Griffin, D Ghosh
1Hauptman-Woodward Medical Research Institute, Buffalo, NY 14203, USA. duax@hwi.buffalo.edu
Current Opinion in Structural Biology
|December 1, 1996
Summary
Short chain dehydrogenase/reductase (SDR) enzymes regulate steroid hormones and are key drug targets. Understanding SDR structure and function can lead to potent, tissue-specific inhibitors for various disorders.
Area of Science:
- Biochemistry
- Enzymology
- Molecular Biology
Background:
- Enzymes modulating circulating steroid hormones are crucial for treating steroid-dependent disorders.
- The NADPH-dependent short chain dehydrogenase/reductase (SDR) family plays vital roles in blood pressure, fertility, and growth regulation.
Purpose of the Study:
- To explore the structural and functional characteristics of the SDR enzyme family.
- To identify potential therapeutic targets for steroid-dependent disorders through enzyme inhibition.
Main Methods:
- Analysis of conserved structural features within the SDR family, including the Rossmann fold and catalytic residues.
- Examination of substrate-binding pocket variations to understand binding specificity.
- Review of known examples of SDR inhibition, such as licorice's effect on blood pressure and ulcers.
Main Results:
- Despite minimal amino acid sequence conservation, SDR enzymes share a common dinucleotide-binding Rossmann fold and catalytic tyrosine residue.
- Substrate specificity is determined by variations in the amino acid composition of the substrate-binding pocket.
- Licorice demonstrates the potential for tissue-specific SDR inhibition, impacting both blood pressure and ulcers.
Conclusions:
- Detailed X-ray crystallography of SDR enzymes can reveal critical insights into their function.
- This knowledge will facilitate the rational design of potent and highly selective inhibitors for therapeutic applications.