Triose Phosphate Isomerase: Difference between revisions

Although a highly studied enzyme, there are relatively few effective inhibitors of TPI.  From a pharmaceutical perspective, if TPI structures differ greatly between humans and microorganisms such as ''Plasmodium'' or ''Trypanosoma'', whose growth rely heavily or entirely on glycolysis, inhibition may be a strong therapeutic target.<ref>PMID:15911278</ref> Two irreversible inhibitors, halo-acetone phosphate and glycidol phosphate, act by labeling active site residues. Early biochemical studies involving glycidol phosphate have revealed the labeled residue to be the active site glutamate. There are several weak reversible inhibitors of TPI including [http://en.wikipedia.org/wiki/3-Phosphoglyceric_acid 3-Phosphoglycerate], [http://en.wikipedia.org/wiki/Glycerol_3-phosphate glycerol phosphate] and [http://en.wikipedia.org/wiki/Phosphoenolpyruvic_acid phosphoenol pyruvate], with ''K''_i values ranging from 0.2-1.3 mM.<ref>PMID:15911278</ref>  Additionally, several transition state analogues have been used to study the mechanism of TPI, including phosphoglycolohydroxamate (PGH)(''K''_i = 6-14 μM) and the phosphoglycolic acid (PGA)(''K''_i = 3 μM) and 2(''N''-formyl-''N''-hydroxy)aminoethyl phosphonate (IPP) <ref>PMID:15911278</ref>. PGA, believed to bind TPI as a trianion, undergoes tight active site binding through electrostatic interactions with both the neutral His95 and protonated Glu165 side chains, while PGH (binding in the ''cis'' conformation) and IPP function by mimicking structural features of the cognate DHAP and GAP substrates, respectively<ref>PMID:12522213</ref>.