TRIOSEPHOSPHATE ISOMERASE (TPI) A DIMERIC GLYCOLYTIC ENZYME AS A MODEL OF TIM-BARREL ACTIVE-SITE STRUCTURAL AND CHEMICAL ASPECTS IN THE MONOMER LOOP REGION’S REVERSIBLE CATALYTIC REACTION.

Triosephosphate isomerase (TPI, EC 5.3.1.1) is essential to glycolysis, catalyzes the fifth step in the glycolysis pathway the reversible conversion of dihydroxyacetone phosphate (DHAP) into glyceraldehyde-3-phosphate. TPI is a homodimer formed by two identical dimeric molecules of a single structural locus : 12p13.31. TPI has only 1 functional gene with a molecular mass of 29 kDa, that after refinement are products of a distinct single structural locus. The variant phenotype of identical subunits are expressed in both red cells and circulating lymphocytes, catalyzing the interconversion of one of the two products breakdown by reversible conversion. The TPI substrate by deprotonation the transition state reaction of dihydroxyacetone phosphate (DHAP) substrate yields one product of the glycolytic pathway, is a trend* (Kcat) that persists creating the initial complex microcompartmentation of TPI to give (G3P) glyceraldehyde-3-phosphate which seems to be the isomerase* activity, release is slower than its conversion to DHAP in normal and TPI deficient cells. TIM with its natural substrates has not been () crystalized**. TPI is a dimeric enzyme and contains 7 exons interrupted by six introns.

monomers The crystallographic structure of (HsTPI) human triosephosphate isomerase PDB:1HTI is one dimer per asymmetric unit subunit 1 and subunit 2 are in the open and closed conformations in the 3-dimensional asymmetric space group P 2(1) which is specific to the Monoclinic with minimization on the entire structure in the presence of substrate analogues and its surrounding residues supporting possible regions targeted for drug design.
TPI deficiency (TPID) a disorder of glycolysis, occurring in haplotypes of specific alleles heterogeneous to clinical TPIdeficiency, with a rare homozygous deficiency the resulting genetic defect is the cause of a null variant incompatible with life by abnormally high levels of DHAP which degrades spontaneously into the toxic (MG) methylglyoxal, due to deamidation of asparagine (Asn15-71) to form aspartic and glutamic acid. Loop 6 plays a role in preventing the breakdown yield of methylglyoxal (fMG) one of the of the three products of enzyme-bound enediol(ate) phosphate, towards elimination of (fMG) inorganic phosphate. TPI deficiency is due to the common aberrant dimerization (or the dissociation into inactive monomers) of mutation TPI 1591C, encoding a Glu104-to-Asp (glutamate-to-aspartate) substitution in the TPI variant found in cases of hemolytic anemia coupled with neurodegeneration, the Glu104-to-Asp substitution is the most common disease allele inherited, when compared to wild-type TPI’s three (residues from the same subunit) similar but not identical interactions between the inhibitor and catalytic residues, Glu 167 (or 165) forms a stable dimer and provides the rationale for production of structurally normal enzyme in humans, the E104D mutation, provides the amyloid-resistant structure of human triosephosphate isomerase (HsTPI). Water-protein molecules join two catalytically active monomers which is only in its dimeric form, as monomers of TIM are not functional. Within a hydrophobic catalytic pocket of the native enzymes the binding and catalysis of TPIs in hemolysates, bind to the red cell membrane. Molecular modeling using the human crystal structure of TPI was performed to determine how these mutations could affect enzyme structure and function. The Amyloid secondary structure autoepitopes antigen-driven mechanism works toward recovery of the anti-triosephosphate isomerase mutant TPI peptide** antigens. This is the scheme that allows function-enhancing stability most significantly, the catalysis for deprotonation of DHAP or vice-versa GAP substrates of the TIM-barrel relative to TPI toward turnover of two-part substrate glycolaldehyde / phosphite dianion {GA + HPO32* the transition state for this enolising enzyme substrate pieces.} Km/obsd* group of the whole GAP substrate and H95 (loop 4) is also optimal for small mutational changes in or reflects its compatibility with amino acid residues which stabilizes the enediolate intermediate (GA/HPO) activity from change in the products scheme (a proton transfer mechanism) DHAP/G3P or interconversion of these intermediates.

dhap-g3p

Closed (activated for catalysis) of optimal WT (TPI) molecular modeling PDB 1HTI_B using the human crystal structure of TPI human triosephosphate isomerase (HsTPI) conformation 1hti_b, calculated to the incidence residue Water-protein molecules and the protein cage that interacts within a hydrophobic catalytic pocket isolated and examined which coded for human triose-phosphate isomerase. [EC: 5.3.1.1]….

TPI deficiency (TPID) a disorder of glycolysis, occurring in haplotypes of specific alleles heterogeneous to clinical TPIdeficiency, with a rare homozygous deficiency the resulting genetic defect is the cause of a null variant incompatible with life by abnormally high levels of DHAP which degrades spontaneously into the toxic (MG) methylglyoxal, due to deamidation of asparagine (Asn15-71) to form aspartic and glutamic acid. Loop 6 plays a role in preventing the breakdown yield of methylglyoxal (fMG) one of the of the three products of enzyme-bound enediol(ate) phosphate, towards elimination of (fMG) inorganic phosphate. TPI deficiency is due to the common aberrant dimerization (or the dissociation into inactive monomers) of mutation TPI 1591C, encoding a Glu104-to-Asp (glutamate-to-aspartate) substitution in the TPI variant found in cases of hemolytic anemia coupled with neurodegeneration, the Glu104-to-Asp substitution is the most common disease allele inherited, when compared to wild-type TPI’s three (residues from the same subunit) similar but not identical interactions between the inhibitor and catalytic residues, Glu 167 (or 165) forms a stable dimer and provides the rationale for production of structurally normal enzyme in humans, the E104D mutation, provides the amyloid-resistant structure of human triosephosphate isomerase (HsTPI). Water-protein molecules join two catalytically active monomers which is only in its dimeric form, as monomers of TIM are not functional. Within a hydrophobic catalytic pocket of the native enzymes the binding and catalysis of TPIs in hemolysates, bind to the red cell membrane. Molecular modeling using the human crystal structure of TPI was performed to determine how these mutations could affect enzyme structure and function. The Amyloid secondary structure autoepitopes antigen-driven mechanism works toward recovery of the anti-triosephosphate isomerase mutant TPI peptide** antigens. This is the scheme that allows function-enhancing stability most significantly, the catalysis for deprotonation of DHAP or vice-versa GAP substrates of the TIM-barrel relative to TPI toward turnover of two-part substrate glycolaldehyde / phosphite dianion {GA + HPO32* the transition state for this enolising enzyme substrate pieces.} Km/obsd* group of the whole GAP substrate and H95 (loop 4) is also optimal for small mutational changes in or reflects its compatibility with amino acid residues which stabilizes the enediolate intermediate (GA/HPO) activity from change in the products scheme (a proton transfer mechanism) DHAP/G3P or interconversion of these intermediates.

philo

Structure of human triose phosphate isomerase at the positions of introns in homologous TPI genes from a number of phylogenetically diverse species. The introns motif are identified as calculated in phylogeny.
Phylogenetic trees constructed on the basis of sequence comparisons for triosephosphate isomerases analysis, TIM sequences were constructed based phylogeny with similarity, to those adopting the same structural fold of interest from different species for the taxonomic groups and the K13M mutations involvement in the human triosephosphate isomerase gene family
Interactions in the loop regions combine the effects of His95 and Lys13 for Glu165 (loop 4, 1, and 6) the three crucial catalytic residues in triose phosphate isomerase, all form the enediol intermediate necessary for the interconversion reaction catalyzed by TIM resulting in the natural substrates G3P formation. The introns motif are identified as calculated in phylogenic motifs. Poorly conserved residues as targets for specific•• drug design are expected when compared to (TPI) Triosephosphate isomerase (•). Catalytic residues of the phylogenetic relationship pathways obtained by sequence based methods of specific key amino acids can than be calculated to the incidence residues and other TIMs which may influence the (human) HsTPI equilibrium.
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