Triosephosphate isomerase: a highly evolved biocatalyst

Abstract

Triosephosphate isomerase (TIM) is a perfectly evolved enzyme which very fast interconverts dihydroxyacetone phosphate and D: -glyceraldehyde-3-phosphate. Its catalytic site is at the dimer interface, but the four catalytic residues, Asn11, Lys13, His95 and Glu167, are from the same subunit. Glu167 is the catalytic base. An important feature of the TIM active site is the concerted closure of loop-6 and loop-7 on ligand binding, shielding the catalytic site from bulk solvent. The buried active site stabilises the enediolate intermediate. The catalytic residue Glu167 is at the beginning of loop-6. On closure of loop-6, the Glu167 carboxylate moiety moves approximately 2 Å to the substrate. The dynamic properties of the Glu167 side chain in the enzyme substrate complex are a key feature of the proton shuttling mechanism. Two proton shuttling mechanisms, the classical and the criss-cross mechanism, are responsible for the interconversion of the substrates of this enolising enzyme.

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, Leads to Altered Carbohydrate Metabolism in Cancer Cells

“…In the forward direction, the k cat for the enzyme is near 500 s Ϫ1 , and in the reverse direction, it is about 5,000 s Ϫ1 (37). Based on this, the overall equilibrium constant calculated from the total dihydroxyacetone phosphate/glyceraldehyde 3-phosphate ratio is 22 (37 indicates that the contribution from the oxidative branch of the pentose phosphate pathway to the formation of fructose 1,6-bisphosphate is very limited. This also indicates that the contribution from the non-oxidative branch of the pathway is the main source of the formation of fructose 1,6-bisphosphate, especially M3.…”

“…The interconversion of dihydroxyacetone phosphate and glyceraldehyde 3-phosphate is catalyzed by triose-phosphate isomerase, one of the most efficient enzymes (36,37). In the forward direction, the k cat for the enzyme is near 500 s Ϫ1 , and in the reverse direction, it is about 5,000 s Ϫ1 (37).…”

“…The interconversion of dihydroxyacetone phosphate and glyceraldehyde 3-phosphate is catalyzed by triose-phosphate isomerase, one of the most efficient enzymes (36,37). In the forward direction, the k cat for the enzyme is near 500 s Ϫ1 , and in the reverse direction, it is about 5,000 s Ϫ1 (37). Based on this, the overall equilibrium constant calculated from the total dihydroxyacetone phosphate/glyceraldehyde 3-phosphate ratio is 22 (37 indicates that the contribution from the oxidative branch of the pentose phosphate pathway to the formation of fructose 1,6-bisphosphate is very limited.…”

Evidence of a triosephosphate isomerase non-catalytic function critical to behavior and longevity

“…We hypothesized that if the presence of the enzyme was crucial to pathogenesis independent of catalytic activity, we would be able to rescue the disease phenotypes with a catalytically inactive variant of the protein. Lys11 of TPI is a fully conserved catalytic residue known to be required for substrate binding and substitution to Met completely abolishes catalysis (Lodi et al, 1994;Wierenga et al, 2010). We have generated the attP DTPI founder line and have used GE to create Drosophila TPI K11M , encoding a catalytically inactive TPI.…”

The Glycolytic Enzyme Triosephosphate Isomerase of Trichomonas vaginalis Is a Surface-Associated Protein Induced by Glucose That Functions as a Laminin- and Fibronectin-Binding Protein

“…Triosephosphate isomerase (TIM) is a cytoplasmic glycolytic enzyme involved in the reversible interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P), and it plays essential roles in glycolysis (Embden-Meyerhof-Parnas pathway), gluconeogenesis, and the pentose phosphate pathways (15). TIM is an important virulence factor when localized to the cellular surfaces of pathogenic organisms.…”