Short-chain dehydrogenases/reductases.

Abstract

The family of short-chain dehydrogenases/reductases (SDR) with subunits of typically 250-odd amino acid residues now encompasses 57 different characterised proteins, representing a wide variety of enzyme activities. The first characterised member of this family was the fruit-fly alcohol dehydrogenase (Schwartz and Jörnvall, 1976; Thatcher, 1980). This alcohol dehydrogenase is different from the classical liver alcohol dehydrogenase, which has larger subunits of about 370 residues, is zinc-dependent, and belongs to a family of medium-chain dehydrogenases/reductases (MDR) (Jörnvall et al., 1981; Persson et al., 1994). In the early 80’s, two additional structures were shown to be related to the Drosophila alcohol dehydrogenase (Jörnvall et al., 1981, 1984), thus establishing a new enzyme family. These structures were glucose dehydrogenase (Jany et al., 1984) and ribitol dehydrogenase (Morris et al., 1974; Dothie et al., 1985). Already at this stage, it was seen that the molecular architecture was different between this short-chain dehydrogenase family and the medium-chain dehydrogenases. The coenzyme-binding region is located at the beginning of the C-terminal domain in the medium-chain dehydrogenases, with a classical Rossmann fold (Rossmann et al., 1975) and a conserved Gly-X-Gly-X-X-Gly pattern. In contrast, the short-chain dehydrogenases have a similar pattern of Gly-X-Gly-X-X-X-Gly at the N-terminal region. In addition, secondary structure predictions suggested this region to have a β-turn-α-turn-β motif, compatible with a Rossmann fold (Thatcher & Sawyer, 1980). Consequently, it was early clear that the two different families of dehydrogenases have different molecular architectures. The medium-chain dehydrogenases have an N-terminal, catalytic domain and a C-terminal, coenzyme-binding domain, while in the shortchain dehydrogenases the coenzyme-binding is located N-terminally and the catalytic site toward the C-terminal half of the molecule (Jörnvall et al., 1981).