Short‐chain dehydrogenases/reductases (SDRs)

Abstract

Short-chain dehydrogenases/reductases (SDRs) are enzymes of great functional diversity. Even at sequence identities of typically only 15-30%, specific sequence motifs are detectable, reflecting common folding patterns. We have developed a functional assignment scheme based on these motifs and we find five families. Two of these families were known previously and are called ÔclassicalÕ and ÔextendedÕ families, but they are now distinguished at a further level based on coenzyme specificities. This analysis gives seven subfamilies of classical SDRs and three subfamilies of extended SDRs. We find that NADP(H) is the preferred coenzyme among most classical SDRs, while NAD(H) is that preferred among most extended SDRs. Three families are novel entities, denoted ÔintermediateÕ, ÔdivergentÕ and ÔcomplexÕ, encompassing short-chain alcohol dehydrogenases, enoyl reductases and multifunctional enzymes, respectively. The assignment scheme was applied to the genomes of human, mouse, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana and Saccharomyces cerevisiae. In the animal genomes, the extended SDRs amount to around one quarter or less of the total number of SDRs, while in the A. thaliana and S. cerevisiae genomes, the extended members constitute about 40% of the SDR forms. The numbers of NAD(H)-dependent and NADP(H)-dependent SDRs are similar in human, mouse and plant, while the proportions of NAD(H)-dependent enzymes are much lower in fruit fly, worm and yeast. We show that, in spite of the great diversity of the SDR superfamily, the primary structure alone can be used for functional assignments and for predictions of coenzyme preference.Keywords: short-chain dehydrogenases/reductases; genome; coenzyme; sequence patterns; bioinformatics.Short-chain dehydrogenases/reductases (SDRs) are enzymes of 250 residue subunits catalysing NAD(P)(H)-dependent oxidation/reduction reactions. The concept of SDRs was established in 1981 [1], at a time when the only members known were a prokaryotic ribitol dehydrogenase and an insect alcohol dehydrogenase. Since then, the SDR family has grown enormously, both in the number of known members and the diversity of their functions. Already some years ago, over 1000 forms were ascribed to the SDR superfamily [2], and currently at least 3000 members, including species variants, are known with a substrate spectrum ranging from alcohols, sugars, steroids and aromatic compounds to xenobiotics. The N-terminal region binds the coenzymes NAD(H) or NADP(H), while the C-terminal region constitutes the substrate binding part. Although the residue identity is as low as 15-30%, the 3D folds are quite similar, except for the C-terminal regions. The SDRs have been divided into two large families, ÔclassicalÕ and ÔextendedÕ, with different Gly-motifs in the coenzyme-binding regions, and different chain lengths; around 250 residues in classical SDRs and 350 in extended SDRs [3]. Few residues are completely conserved, but several sequence motifs are distinguishable within the families.It is d...

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