Triosephosphate isomerase
triosephosphate isomerase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Triose-phosphate isomerase (TPI or TIM) is an
Dihydroxyacetone phosphate | triose phosphate isomerase
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D-glyceraldehyde 3-phosphate | |
triose phosphate isomerase
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Compound C00111 at KEGG Pathway Database.Enzyme 5.3.1.1 at KEGG Pathway Database.Compound C00118 at KEGG Pathway Database.
TPI plays an important role in
In humans, deficiencies in TPI are associated with a progressive, severe neurological disorder called
Triose phosphate isomerase is a highly efficient enzyme, performing the reaction billions of times faster than it would occur naturally in solution. The reaction is so efficient that it is said to be
Mechanism
The mechanism involves the intermediate formation of an enediol. The relative free energy of each ground state and transition state has been determined experimentally, and is displayed in the figure.[2]
The structure of TPI facilitates the conversion between dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GAP). The
TPI is diffusion-limited. In terms of thermodynamics, DHAP formation is favored 20:1 over GAP production.[8] However, in glycolysis, the use of GAP in the subsequent steps of metabolism drives the reaction toward its production. TPI is inhibited by sulfate, phosphate, and arsenate ions, which bind to the active site.[9] Other inhibitors include 2-phosphoglycolate, a transition state analog, and D-glycerol-1-phosphate, a substrate analog.[10]
Structure
Triosephosphate isomerase | |||||||||
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Identifiers | |||||||||
Symbol | TIM | ||||||||
SCOP2 | 1tph / SCOPe / SUPFAM | ||||||||
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Triose phosphate isomerase is a
The structure of triose phosphate isomerase contributes to its function. Besides the precisely placed glutamate and histidine residues to form the enediol, a ten- or eleven-amino acid chain of TPI acts as a loop to stabilize the intermediate. The loop, formed by residues 166 to 176, closes and forms a hydrogen bond to the phosphate group of the substrate. This action stabilizes the enediol intermediate and the other transition states on the reaction pathway.[7]
In addition to making the reaction kinetically feasible, the TPI loop sequesters the reactive enediol intermediate to prevent decomposition to methylglyoxal and inorganic phosphate. The hydrogen bond between the enzyme and the phosphate group of the substrate makes such decomposition stereoelectronically unfavorable.[7] Methylglyoxal is a toxin and, if formed, is removed through the glyoxalase system.[11] The loss of a high-energy phosphate bond and the substrate for the rest of glycolysis makes formation of methylglyoxal inefficient.
Studies suggest that a lysine close to the active site (at position 12) is also crucial for enzyme function. The lysine, protonated at physiological pH, may help neutralize the negative charge of the phosphate group. When this lysine residue is replaced with a neutral amino acid, TPI loses all function, but variants with a different positively charged amino acid retain some function.[12]
See also
- TIM barrel
- Triose Phosphate Isomerase deficiency
- TPI1
- Triosephosphate isomerase in interactive 3D at Proteopedia
- Triosephosphate isomerase (TIM) family in PROSITE
References
External links
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Triosephosphate isomerase