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Short-chain dehydrogenases/reductases (SDR): the 2002 update
Udo Oppermann1, Charlotta Filling, Malin Hult
1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177, Stockholm, Sweden. udo.oppermann@mbb.ki.se
Chemico-Biological Interactions
|February 27, 2003
Summary
Short-chain dehydrogenases/reductases (SDR) are a diverse protein family with similar structures but varied functions. New insights into their reaction mechanisms reveal potential as drug targets for diseases like cancer and diabetes.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Short-chain dehydrogenases/reductases (SDR) comprise a large, functionally diverse protein superfamily.
- Over 3000 SDR sequences and 30 3D structures are available, revealing conserved Rossmann-fold patterns despite low sequence identity (15-30%).
Purpose of the Study:
- To elucidate the conserved structural and mechanistic features of the SDR enzyme family.
- To explore the potential of SDR enzymes as pharmacological targets for various diseases.
Main Methods:
- Analysis of sequence motifs for classification and functional assignment.
- Review of recent mutagenetic and structural studies on SDR reaction mechanisms.
- Examination of cellular functions and disease associations of SDR enzymes.
Main Results:
- SDR enzymes share a common alpha/beta fold with a central beta-sheet (Rossmann-fold).
- A conserved catalytic tetrad (Asn-Ser-Tyr-Lys) facilitates a proton relay system, similar to horse liver ADH.
- Sequence motifs enable SDR classification and nomenclature development.
Conclusions:
- SDR enzymes exhibit conserved structural and mechanistic properties despite functional diversity.
- The identified catalytic tetrad and proton relay system provide a framework for understanding SDR mechanisms.
- SDR enzymes represent promising therapeutic targets for hormone-dependent cancers, metabolic disorders (obesity, diabetes), and infectious diseases.