A SUPER-FAMILY OF MEDIUM-CHAIN DEHYDROGENASES REDUCTASES (MDR) - SUB-LINES INCLUDING XI-CRYSTALLIN, ALCOHOL AND POLYOL DEHYDROGENASES, QUINONE OXIDOREDUCTASES, ENOYL REDUCTASES, VAT-1 AND OTHER PROTEINS/

The protein super-family of medium-chain alcohol dehydrogenases (and g lutathione-dependent formaldehyde dehydrogenase), polyol dehydrogenase s, threonine dehydrogenase, archaeon glucose dehydrogenase, and eye le ns reductase-active zeta-crystallins also includes Escherichia coli qu inone oxidoreductase, Torpedo VAT-1 protein, and enoyl reductases of m ammalian fatty acid and yeast erythronolide synthases. In addition, tw o proteins with hitherto unknown function are shown to belong to this super-family of medium-chain dehydrogenases and reductases (MDR). Alig nment of zeta-crystallins/quinone oxidoreductases/VAT-1 reveals 38 str ictly conserved residues, of which approximately half are glycine resi dues, including those at several space-restricted turn positions and c ritical coenzyme-binding positions in the alcohol dehydrogenases. This indicates a conserved three-dimensional structure at the correspondin g parts of these distantly related proteins and a conserved binding of a coenzyme in the two proteins with hitherto unknown function, thus a scribing a likely oxidoreductase function to these proteins. When all forms are aligned, including enoyl reductases, a zeta-crystallin homol ogue from Leishmania and the two proteins with hitherto unknown functi on, only three residues are strictly conserved among the 106 proteins characterised within the superfamily, and significantly these residues are all glycines, corresponding to Gly66, Gly86 and Gly201 of mammali an class I alcohol dehydrogenase. Notably, these residues are located in different domains. Hence, a distant origin and divergent functions, but related forms and interactions, appear to apply to the entire cha ins of the many prokaryotic and eukaryotic members. Additionally, in t he zeta-crystallins/quinone oxidoreductases, a highly conserved tyrosi ne residue is found. This residue, in the three-dimensional structure of the homologous alcohol dehydrogenase, is positioned at the subunit cleft that contains the active site and could therefore be involved in catalysis. If so, this residue and its role may resemble the pattern of a conserved tyrosine residue in the different family of short-chain dehydrogenases/reductases (SDR).