Triosephosphate isomerase

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triosephosphate isomerase
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Triose-phosphate isomerase (TPI or TIM) is an

catalyzes the reversible interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate
.

Dihydroxyacetone phosphate
triose phosphate isomerase
D-glyceraldehyde 3-phosphate
 
 
 
triose phosphate isomerase

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

fungi, plants, and bacteria. However, some bacteria that do not perform glycolysis, like ureaplasmas
, lack TPI.

In humans, deficiencies in TPI are associated with a progressive, severe neurological disorder called

triose phosphate isomerase deficiency. Triose phosphate isomerase deficiency is characterized by chronic hemolytic anemia. While there are various mutations that cause this disease, most include the replacement of glutamic acid at position 104 with an aspartic acid.[1]

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

diffuse into and out of the enzyme's active site.[2][3]

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]

Free energy changes

The structure of TPI facilitates the conversion between dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GAP). The

substrate,[4] and the electrophilic histidine 95 residue donates a proton to form the enediol intermediate.[5][6] When deprotonated, the enediolate then collapses and, abstracting a proton from protonated glutamate 165, forms the GAP product. Catalysis of the reverse reaction proceeds analogously, forming the same enediol but with enediolate collapse from the oxygen at C2.[7]

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]

Side view of triose phosphate isomerase dimer.

Structure

Triosephosphate isomerase
Identifiers
SymbolTIM
SCOP2
1tph / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Triose phosphate isomerase is a

catalytic mechanism
. The sequence around the active site residues is conserved in all known triose phosphate isomerases.

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

References

External links

  • PDBe-KB provides an overview of all the structure information available in the PDB for Human Triosephosphate isomerase