MYCOTHIOL-DEPENDENT FORMALDEHYDE DEHYDROGENASE, A PROKARYOTIC MEDIUM-CHAIN DEHYDROGENASE REDUCTASE, PHYLOGENETICALLY LINKS DIFFERENT EUKARYOTIC ALCOHOL DEHYDROGENASES - PRIMARY STRUCTURE, CONFORMATIONAL MODELING AND FUNCTIONAL CORRELATIONS/

Prokaryotic mycothiol-dependent formaldehyde dehydrogenase has been st ructurally characterized by peptide analysis of the 360-residue protei n chain and by molecular modelling and functional correlation with the conformational properties of zinc-containing alcohol dehydrofenases. The structure is found to be a divergent medium-chain dehydrogenase/re ductase (MDR), at a phylogenetic position intermediate between the clu ster of dimeric alcohol dehydrogenases of all classes (including the h uman forms), and several tetrameric reductases/dehydrogenases. Molecul ar modelling and functionally important residues suggest a fold of the mycothiol-dependent formaldehyde dehydrogenase related overall to tha t of MDR alcohol dehydrogenases, with the presence of the catalytic an d structural zinc atoms, but otherwise much altered active-site relati onships compatible with the different substrate specificity, and an al tered loop structure compatible with differences in the quaternary str ucture. Residues typical of glutathione binding in class-III alcohol d ehydrogenase are not present, consistent with that the mycothiol facto r is not closely similar to glutathione. The molecular architecture is different from that of the 'constant' alcohol dehydrogenases (of clas s-III type) and the 'variable' alcohol dehydrogenases (of class-I and class-II types), further supporting the unique structure of mycothiol- dependent formaldehyde dehydrogenase. Borders of internal chain-length differences between this and other MDR enzymes coincide in different combinations, supporting the concept of limited changes in loop region s within this whole family of proteins.