Triosephosphate isomerase

Triosephosphate isomerase (Triosephosphate isomerase, EC 5.3.1.1) or TPI is an enzyme catalyzing reversible interconversion between dihydroxyacetone phosphoric acid (DHAP) and D-glyceraldehyde-3-phosphoric acid (GAP) which are an isomer of the triosephosphate.

TPI plays an important role in glycolytic pathway and is indispensable for production of the energy. TPI is seen in almost all creatures from the animal such as mammals and the insect to fungi, a plant, bacteria. However, some bacteria which do not have glycolytic pathway such as the urea plasma genus do not have TPI.

In Homo sapiens, the loss of TPI is related to progressive serious neuropathy called triosephosphate isomerase deficiency. Triosephosphate isomerase deficiency features chronic hemolytic anemia. There is various mutation to cause this disease, but the glutaminic acid of the 104th residue mutates it to aspartic acid at the most [¹].

Several billions of times quickens a reaction in comparison with TPI being a very efficient enzyme, and taking place in water solutions naturally, too. Because a reaction is very effective, I am called "a complete catalyst". Enter the active center of the enzyme, and speed is limited only at speed to leave a substrate by diffusion [²]; [³].

Mechanism

I form "a crimson oar" as an intermediate. The change of the free energy of each stage including a transition state becomes like a lower figure [²].

The structure of TPI promotes conversion of DHAP and GAP. The nucleophilic glutaminic acid of the 165th residue deprotonates a substrate [⁴], and histidine of the 95th electrophilic residue supplies a proton, and form a crimson oar intermediate [⁵]; [⁶]. The crimson oar disintegrates when deprotonated and takes in a proton from the 165th protonated glutaminic acid and forms GAP. It is homologous mechanism, and the catalyst of the inverse reaction forms the same crimson oar, too [⁷].

TPI is a diffusion limited access. As for 20 times, the formation of DHAP is easy to happen in thermodynamics than the formation of GAP [⁸]. However, in the glycolytic pathway, the consumption of GAP at the next stage of the metabolism lets a reaction advance to the direction of the generation. TPI is inhibited by an active center and connected sulfuric acid, phosphoric acid, ion of the arsenic acid [⁹]. With D-glycerol 1-phosphate which is 2-phosphoglyceric acid and the matrix analog that are transition state analog to other repressors [¹⁰].

TPI dimer judging from the side

Structure

Triosephosphate isomerase

Identifier

Cable address

TIM

Pfam clan

Available protein structure:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

TPI is made of approximately 250 amino acid residue with the dimer of the homology subunit each. The three-dimensional structure of the subunit is eight parallel beta sheet outward in eight alpha helix, inside. In the right figure, the obi expressing the backbone of each subunit is colored with red toward the C-terminus from the N-terminus by blue. The motif of this structure is called α β barrel or TIM barrel and, in folding of the protein, is seen very well. The active center of the barrel leading. The residue of glutaminic acid and histidine affects a catalyst. The sequence of the active site neighborhood is stored in all known TPI.

In TPI, the structure helps a function. Though a residue of glutaminic acid and histidine is located in the correct place to form a crimson oar, I add it and work as a loop for an amino acid chain of 10 or 11 to stabilize an intermediate. This loop comprised of a residue from the 166th to the 176th forms hydrogen bonding to the phosphate group of the substrate. This reaction stabilizes an other transition state of a crimson oar intermediate and the reaction process [⁷].

In addition to enabling a reaction kinetically, the loop of TPI isolates it to prevent that the crimson oar intermediate which is easy to react is dismantled to methylglyoxal and inorganic phosphoric acid. As for the hydrogen bonding between the phosphate group of an enzyme and the substrate, a solid disadvantages such resolution electronically [⁷]. The methylglyoxal is removed by a glyoxalase system to be toxic when I am formed [¹¹].

It is suggested that lysine of the twelfth residue near an active site is indispensable for the function of the enzyme. I help lysine protonated at physiological pH neutralize a negative charge of the phosphate group. When this lysine mutates to a neutral amino acid, TPI loses all functions, but some functions are kept when I mutate to an amino acid with other positive charges [¹²].

Source

^ Orosz, F.; Olah, J. (2008). "Triosephosphate isomerase deficiency: facts and doubts." IUBMB Life 58 (12): 703-715. doi: 10.1080/15216540601115960. PMID 17424909.
^ ^a ^b Albery, W. J.; Knowles, J. R. (1976). "Free-Energy Profile for the Reaction Catalyzed by Triosephosphate Isomerase." Biochemistry 15 (25): 5627-5631. doi: 10.1021/bi00670a031. PMID 999838.
^ Rose, I.A.; Fung, W.J. (1990). "Proton diffusion in the active site of triosephosphate isomerase." Biochemistry 29 (18): 4312-4317. doi: 10.1021/bi00470a008. PMID 2161683.
^ Alber, T.; Banner, D.W.; Wilson, I.A. (1981). "On the three-dimensional structure and catalytic mechanism of triose phosphate isomerase.." Phil. Trans. R. Soc. 293 (1063): 159-171. doi: 10.1098/rstb.1981.0069. PMID 6115415.
^ Nickbarg, E.B.; Davenport, R.C.; Knowles, J.R. (1988). "Triose Phosphate Isomerase: Removal of a Putatively Electrophilic Histidine Residue Results in a Subtle Change in Catalytic Mechanism.." Biochemistry 27 (16): 5948-5960. doi: 10.1021/bi00416a019. PMID 2847777.
^ Komives, E.A.; Chang, L.C. (1991). "Electrophilic Catalysis in Triosephosphate Isomerase: the Role of Histidine-95.." Biochemistry 30 (12): 3011-3019. doi: 10.1021/bi00226a005. PMID 2007138.
^ ^a ^b ^c Knowles, J.R. (1991). "Enzyme catalysis: not different, just better." Nature 350 (6314): 121-124. doi: 10.1038/350121a0. PMID 2005961.
^ Harris, T.K.; Cole, R.N.; Mildvan, A.S. (1998). "Proton Transfer in the Mechanism of Triosephosphate Isomerase.." Biochemistry 37 (47): 16828-16838. doi: 10.1021/bi982089f. PMID 9843453.
^ Lambeir, A.-M.; Opperdoes, F.R.; Wierenga, R.K. (1987). "Kinetic properties of triose-phosphate isomerase from Trypanosama brucei brucei." European Journal of Biochemistry 168 (1): 69-74. doi: 10.1111/j.1432-1033.1987.tb13388.x. PMID 3311744.
^ Lolis, E.; Petsko, G.A. (1990). "Crystallographic Analysis of the Complex between Triosephosphate Isomerase and 2-Phosphoglycolate at 2.5-A Resolution: Implications for Catalysis." Biochemistry 29 (28): 6619-6625. doi: 10.1021/bi00480a010. PMID 2204418.
^ Creighton, D.J.; Hamilton, D.S. (2001). "Brief History of Glyoxalase I and What We Have Learned about Metal Ion-Dependent, Enzyme-Catalyzed Isomerizations.." Archives of Biochemistry and Biophysics 387 (1): 1-10. doi: 10.1006/abbi.2000.2253. PMID 11368170.
^ Lodi, P.J.; Chang, L.C.; Komives, E.A. (1990). "Triosephosphate Isomerase Requires a Positively Charged Active Site: The Role of Lysine-12.." Biochemistry 33 (10): 2809-2814. doi: 10.1021/bi00176a009. PMID 8130193.

http://pdbdev.sdsc.edu: 48346/pdb/molecules/pdb50_6.html

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Triosephosphate isomerase in interactive 3D at Proteopedia
Triosephosphate isomerase (TIM) family in PROSITE

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