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Catalytic Site Atlas

CSA LITERATURE entry for 1hti

E.C. nametriose-phosphate isomerase
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz)
CSA Homologues of 1htiThere are 112 Homologs
CSA Entries With UniProtID P60174
CSA Entries With EC Number
PDBe Entry 1hti
PDBSum Entry 1hti
MACiE Entry 1hti

Literature Report

IntroductionTriosephosphate isomerase (TIM) is one of the most extensively characterised enzymes in the chemical literature. TIM catalyses the reversible isomerisation of dihydroxyacetone phosphate (DHAP) to d-glyceraldehyde 3-phosphate (GAP) with exceptionally high efficiency, while suppressing elimination of orthophosphate. It contains a large-scale catalytic loop motion, which alternates in open and closed positions. It is an essential component of the glycolytic pathway. Its deficiency has been shown to enhance levels of dihydroxyacetone phosphate in humans and cause chronic anaemia and neuromuscular impairment. Due to its important place in glycolysis, TIM also forms an attractive target for drug design against parasites that have the ability to survive in the mammalian bloodstream. Among the various diseases currently ravaging the tropical world, those due to such parasites are some of the most serious ones (e.g., malaria and sleeping sickness). Control of these diseases is presently a major problem and has been a focus of attention of various agencies.
MechansimTo accomplish this isomerization, TIM first extracts a pro-R hydrogen from the C1 of DHAP and then stereospecifically introduces a proton onto the C2 atom There are three main mechanisms which have been proposed for conversion of DHAP to GAP by TIM. The first step is agreed to be the abstraction of a CI proton by Glu165 forming enediolate-1 (EDT1). The conversion of EDT1 to enediolate-2 (EDT2) is the subject of some debate, 3 pathways have been proposed: A, B and C. Path B is a direct path by internal proton transfer from O1 to O2. Path A involves formation of an enediol intermediate by transfer of a proton from His95 to the O2 atom in Path A or from Glu165 in Path C. The enediol intermediate is then converted to enediolate by transfer of a proton from O1 by His95 (path A) or Glu165 (path C). The final step is accepted to be a proton transfer from Glu165 to C2 to form the product GAP. It has been shown through molecular modelling that Path C is likely to be the most favoured.

Catalytic Sites for 1hti

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluA165166macie:sideChainActs as a general base in the initial deprotonation of C1 of DHAP, then reprotonates C2 in the final step to produce GAP. It also forms the enediol intermediate by transfer of a proton to O2 and abstraction of a proton from O1.
LysA1314macie:sideChainProtonated amine group hydrogen bonds to increase of increase density of O2 on DHAP to electrostatically stabilise EDT1.
HisA9596macie:sideChainThe hydrogen bond between His 95 and O2 in the carbonyl bond introduces a favorable polarizing effect in the conversion from DHAP to EDT1.
AsnA1112macie:sideChainPlays an electrostatic stabilising role in the first proton abstraction and the last proton transfer step to convert EDT2 to GAP.

Literature References

Notes:In previous CSA entry listed Gly177- can find no reference to this residue as catalytic.
Guallar V
Computational modeling of the catalytic reaction in triosephosphate isomerase.
J Mol Biol 2004 337 227-239
PubMed: 15001364
Cui Q
Catalysis and specificity in enzymes: a study of triosephosphate isomerase and comparison with methyl glyoxal synthase.
Adv Protein Chem 2003 66 315-372
PubMed: 14631822