Glyceraldehyde 3-phosphate dehydrogenase (Leishmania mexicana) (LmGAPDH)

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) from Leishmania mexicana is a critical enzyme in the glycolytic pathway, responsible for the oxidative phosphorylation of glyceraldehyde 3-phosphate into 1,3-bisphosphoglycerate (UniProt: P40924). In kinetoplastid parasites like Leishmania, glycolysis occurs within specialized organelles called glycosomes and is the primary source of ATP, making the enzymes of this pathway essential for survival (PubMed: 7966307). LmGAPDH is a validated drug target because its inhibition leads to a rapid drop in intracellular ATP levels, resulting in parasite death. Although GAPDH is highly conserved, structural biology has revealed distinct features in the parasite enzyme, such as a unique hydrophobic pocket near the NAD+ binding site and differences in the S-loop region, which can be exploited for selective drug design (PDB: 1GYP; PubMed: 9873501). Research has focused on developing small-molecule inhibitors, including adenosine derivatives and various natural products like chalcones, to specifically target LmGAPDH while sparing the human ortholog. Successfully targeting this enzyme could provide a new class of treatments for leishmaniasis, a neglected tropical disease that currently lacks ideal therapeutic options.

Other names

Glyceraldehyde-3-phosphate dehydrogenaseGAPDHG3PGlyceraldehyde-3-phosphate dehydrogenase (phosphorylating)

Inhibition of the glycolytic flux by blocking the conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate, leading to ATP depletion and parasite death.