D-erythrose-4-phosphate dehydrogenase (E4PDH)

D-erythrose-4-phosphate dehydrogenase (E4PDH) is a specialized enzyme that plays a critical role in the de novo biosynthesis of pyridoxal 5'-phosphate (PLP), the active form of Vitamin B6, in various bacterial species such as Escherichia coli (UniProt: P0A9G8). It catalyzes the NAD+-dependent oxidation of D-erythrose 4-phosphate to 4-phospho-D-erythronate, which is an essential precursor in the DXP-independent pathway (PubMed: 9159513). This enzyme is of significant interest in drug discovery because the PLP biosynthetic pathway is present in many pathogenic bacteria but is entirely absent in humans, who must obtain Vitamin B6 through their diet (PubMed: 15544305). Consequently, E4PDH serves as a promising target for the development of novel, narrow-spectrum antibacterial agents that could potentially circumvent existing resistance mechanisms. Inhibition of E4PDH leads to the depletion of PLP, a vital cofactor for over 140 different metabolic enzymes, ultimately resulting in the cessation of bacterial growth and viability. Current research efforts are focused on identifying small-molecule inhibitors that exhibit high selectivity for the bacterial enzyme over human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to minimize potential off-target effects. While no drugs targeting E4PDH are currently in clinical use, it remains a validated metabolic target for addressing the global challenge of antibiotic-resistant infections.

Other names

Erythrose-4-phosphate dehydrogenaseEPDGapBNAD-dependent D-erythrose-4-phosphate dehydrogenase

Inhibition of pyridoxal 5'-phosphate (Vitamin B6) biosynthesis