Correlation in species, cofactor, oligomerization and substrate specificity in short‐chain oxidoreductase enzymes

The Rossmann nucleotide‐binding fold is an abundant, stable fold, which includes the classical short‐chain oxidoreductase (SCOR) sub‐family. SCOR proteins are vital to growth and development of all organisms. Using cofactor identifier sites at adjacent positions in 19,003 SCOR enzymes, we have correlated the divergent evolution of these positions to the oligomerization interfaces and substrate identification loops. Cofactor preferences of 86% of the SCORs are associated with combinations of xR, Dx, Yx or xT. 27 combinations of amino acids in these two positions account for 83% of all SCORs. There is structural information about 22 of these combinations. Proteins with Dx and Yx correlate with NAD binding and xR and xT correlate with NADP binding which are associated with oxidation and reduction reactions respectively. On the basis of structure, cofactor and substrate recognition, 16% of the SCOR proteins can be assigned to families of orthologs for which x‐ray crystal structures have been done. There are 249 groups of proteins where 10 or more proteins contain the same substrate fingerprint that account for 48% of all SCOR proteins.