Rational proteomics II: Electrostatic nature of cofactor preference in the short-chain oxidoreductase (SCOR) enzyme family

The dominant role of long-range electrostatic interatomic interactions in nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NAD/NADP) cofactor recognition has been shown for enzymes of the short-chain oxidoreductase (SCOR) family. An estimation of cofactor preference based only on the contribution of the electrostatic energy term to the total energy of enzyme-cofactor interaction has been tested for ∼40 known three-dimensional (3D) crystal complexes and ∼330 SCOR enzymes, with cofactor preference predicted by the presence of Asp or Arg recognition residues at specific 3D positions in the β2α3 loop (Duax et al., Proteins 2003;53:931-943). The results obtained were found to be consistent with ∼90% reliable cofactor assignments for those subsets. The procedure was then applied to ∼170 SCOR enzymes with completely uncertain NAD/NADP dependence, due to the lack of Asp and Arg marker residues. The proposed 3D electrostatic approach for cofactor assignment ("3D_βE_el") has been implemented in an automatic screening procedure, and together with the use of marker residues proposed earlier (Duax et al., Proteins 2003;53:931-943), increases the level of reliable predictions for the putative SCORs from ∼70% to ∼90%. It is expected to be applicable for any NAD/NADP-dependent enzyme subset having at least 25-30% sequence identity, with at least one enzyme of known 3D crystal structure.