The apo-structure of the B. anthracis short-chain dehydrogenase/reductase (SCD/R) has been determined. The protein of unknown specificity shares ~44 % sequence identity with the human mitochondrial 2,4-dienoyl-CoA reductase (PDB IDs: 1W73, 1W8D and 1W6U). Except for the N- and C-terminal extensions of the human enzyme, both proteins exhibit identical fold, which is a single alpha/beta domain with the dinucleotide binding “Rossmann” fold, characteristic for the SCD/R family. The rmsd of their C-alpha positions is 1.3-1.6 Å. The human homolog catalyzes the reduction of 2,4-dienoyl-CoA to enoyl-CoA, which then enters the beta-oxidation cycle. Interestingly, known bacterial 2,4-dienoyl-CoA reductase from E. coli (PDB ID 1PS9) is structurally unrelated to two mentioned proteins and binds a different set of cofactors, FAD, FMN and 4Fe-4S cluster.
Homologous SCD/Rs are homotetramers in the crystal lattice with their coenzyme- and substrate-binding sites being almost entirely exposed to the solvent. This is one of the reasons why there are not big structural perturbations upon association of NADP, binding and processing of the substrate. Indeed, pairwise structural alignment of 3IMF and 1W8D/1W6U indicates that structural changes due to association of the ligands are small in magnitude. However, co-crystallization of the Bacillus homolog with NADP and its structure determination are required to confirm these observations. Identical distortion of the active site region spanning residues (190-200 in 3IMF; 245-255 in 1W8D) may reflect broad substrate specificity of the human and perhaps bacterial SCD/R. Identification of potential substrate(s) of the bacterial enzyme is desired.