Triose-phosphate isomerase

R. C. Wade, M. E. Davis, B. A. Luty, J. D. Madura, and J. A. McCammon. Gating of the active site of triose phosphate isomerase Brownian dynamics simulations of flexible peptide loops in the enzyme. Biophys. J., 64 9-15, 1993. 

Further steps m glycolysis use the d glyceraldehyde 3 phosphate formed m the aldolase catalyzed cleavage reaction as a substrate Its coproduct dihydroxyacetone phosphate is not wasted however The enzyme triose phosphate isomerase converts dihydroxyacetone phosphate to d glyceraldehyde 3 phosphate which enters the glycol ysis pathway for further transformations... 

Figure 2.20 Motifs that are adjacent in the amino acid sequence are also usually adjacent in the three-dimensional structure. Triose-phosphate isomerase is built up from four P-a-p-a motifs that are consecutive both in the amino acid sequence (a) and in the three-dimensional structure (b).

The enzyme triose phosphate isomerase eatalyzes the intereonversion of D-glyeeraldehyde 3-phosphate and dihydroxyaeetone phosphate. 

FIGURE 6.28 Examples of protein domains with different numbers of layers of backbone strnctnre. (a) Cytochrome c with two layers of a-helix. (b) Domain 2 of phosphoglycerate kinase, composed of a /3-sheet layer between two layers of helix, three layers overall, (c) An nnnsnal five-layer strnctnre, domain 2 of glycogen phosphorylase, a /S-sheet layer sandwiched between four layers of a-helix. (d) The concentric layers of /S-sheet (inside) and a-helix (outside) in triose phosphate isomerase. Hydrophobic residnes are bnried between these concentric layers in the same manner as in the planar layers of the other proteins. The hydrophobic layers are shaded yellow. (Jane Richarelson)... 

Another important parallel /3-array is the eight-stranded parallel j8-barrel, exemplified in the structures of triose phosphate isomerase and pyruvate kinase (Figure 6.30). Each /3-strand in the barrel is flanked by an antiparallel a-helix. The a-helices thus form a larger cylinder of parallel helices concentric with the /3-barrel. Both cylinders thus formed have a right-handed twist. Another parallel /3-structure consists of an internal twisted wall of parallel or mixed /3-sheet protected on both sides by helices or other substructures. This structure is called the doubly wound parallel j8-sbeet because the structure can be... 

Triose phosphate isomerase with substrate analog 2-phosphoglycerate shown in red. 

The triose phosphate isomerase reaction completes the first phase of glycolysis, each glucose that passes through being converted to two molecules of glyceraldehyde-3-phosphate. Although the last two steps of the pathway are... 

FIGURE 19.15 A reaction mechanism for triose phosphate isomerase. 

Triose phosphate isomerase catalyzes the conversion of dihy-droxyacetone-P to glyceraldehyde-3-P. The standard free energy change, AG°, for this reaction is +7.6 kj/mol. However, the observed free energy change (AG) for this reaction in erythrocytes is +2.4 kj/mol. 

Knowles, J., and Albery, W., 1977. Perfection in enzyme catalysis The energetics of triose phosphate isomerase. Accounts of Chemical Research 10 105-111. 

The most convenient method is the formation of two equivalents of (25) by retro-aldol cleavage from commercially available (26) by the combined action of FruA and triose phosphate isomerase (Figure 10.18 inset) [84]. This scheme has been extended into a highly integrated, artificial metabolism for the efficacious in situ preparation of (25) from inexpensive feedstock such as glucose and fructose (two equivalents of... 

Figure 5-6. Examples of tertiary structure of proteins. Top The enzyme triose phosphate isomerase. Note the elegant and symmetrical arrangement of alternating p sheets and a helices. (Courtesy of J Richardson.) Bottom Two-domain structure of the subunit of a homodimeric enzyme, a bacterial class II HMG-CoA reductase. As indicated by the numbered residues, the single polypeptide begins in the large domain, enters the small domain, and ends in the large domain. (Courtesy ofC Lawrence, V Rod well, and C Stauffacher, Purdue University.)...

Dihydroxyacetone phosphate (82) is a substrate for a-glycero-phosphate dehydrogenase, aldolase, and triose phosphate isomerase, and its O-alkyl ethers are intermediates in the biosynthesis of phospholipids. In neutral aqueous solution at 20 °C, dihydroxyacetone phosphate exists as an equilibrium mixture of the keto (82), gem-d o (83), and enol (84) forms, as shown by n.m.r. spectroscopy. The proportion of (82) to (83)... 

Triose phosphate isomerase (TPI) catalyzes the interconversion of glyceralde-hyde-3-phosphate and dihydoxyacetone phosphate and has an important role in glycolysis, gluconeogenesis, fatty acid synthesis, and the hexose monophosphate pathway. Red blood cell TPI activity measured in vitro is approximately 1000 times that of Hx, the least active glycolytic enzyme. TPI is a dimer of identical subunits, each of molecular weight 27,000, and does not utilize cofactors or metal ions. Posttranslational modification of one or both subunits may occur by deamidination, resulting in multiple forms of the enzymes and creating a complex multibanded pattern on electrophoresis. 

Hereditary triose phosphate isomerase (TPI) deficiency is an autosomal recessive disorder that has the most severe clinical manifestations of the erythroenzy-mopathies, including hemolytic anemia, neurological dysfunction, sudden cardiac death, and increased susceptibility to infection. Since the first description by Schneider et al. (S10), more than 25 unrelated families have been reported (Fll). Cases of decreased TPI activities associated with cat cry syndrome and pancytopenia were reported, whereas the correlation between TPI deficiency and these disorders was not clear. Although the degree of anemia is variable, most patients require blood transfusions. Neurological involvement, such as paraparesis, weakness, and hypotonia, is progressive in most cases. No specific therapy is available for the neuropathic manifestations of the disease, and most severely affected children fail to survive beyond the age of 5 years. 

N6. Neubauer, B. A., Pekrun, A., Eber, S. W Lakomek, M and Schroter, W., Relation between genetic defect, altered protein structure, and enzyme function in triose-phosphate isomerase (TPI) deficiency. Eur. J. Pediatr. 151,232a (1992). 

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