Triose Phosphate Isomerase: Difference between revisions
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{{STRUCTURE_2ypi|PDB=2ypi|SCENE=}} | {{STRUCTURE_2ypi|PDB=2ypi|SCENE=}} | ||
[[Triose Phosphate Isomerase]] (TPI or TIM) is a ubiquitous dimeric enzyme with a molecular weight of ~54 kD (27 kD per subunit) which catalyzes the reversible interconversion of the triose phosphate isomers dihydroxyacetone phosphate ('''DHAP''') and D-glyceraldehyde-3-phosphate ('''GAP'''), an essential process in the glycolytic pathway. More simply, the enzyme catalyzes the isomerization of a ketose (DHAP) to an aldose (GAP), also referred to as '''PGAL'''. In regards to the two isomers, at equilibrium, roughly 96% of the triose phosphate is in the DHAP isomer form; however, the isomerization reaction proceeds due to the rapid removal of GAP from the subsequent reactions of glycolysis. The TPI structure is shown on the right (PDB entry [[2ypi]]) in complex with GAP ("PGA"), which is bound to each of its two active sites. TPI is an example of a catalytically perfect enzyme, indicating that for almost every enzyme-substrate encounter, a product is formed and that this interaction is limited only by the substrate diffusion rate. In addition to its role in glycolysis, TPI is also involved in several additional metabolic biological processes including gluconeogenesis, the pentose phosphate shunt, and fatty acid biosynthesis. A point mutation to a glutamate residue (Glu104) of TPI results in triose phosphate isomerase deficiency, an autosomal recessive inherited disorder characterized by an increased accumulation of DHAP in erythrocytes. Structurally, this point mutation abolishes TPI’s ability to dimerize, subsequently inhibiting its catalytic activity. | [[Triose Phosphate Isomerase]] (TPI or TIM) is a ubiquitous dimeric enzyme with a molecular weight of ~54 kD (27 kD per subunit) which catalyzes the reversible interconversion of the triose phosphate isomers dihydroxyacetone phosphate ('''DHAP''') and D-glyceraldehyde-3-phosphate ('''GAP'''), an essential process in the glycolytic pathway. More simply, the enzyme catalyzes the isomerization of a ketose (DHAP) to an aldose (GAP), also referred to as '''PGAL'''. In regards to the two isomers, at equilibrium, roughly 96% of the triose phosphate is in the DHAP isomer form; however, the isomerization reaction proceeds due to the rapid removal of GAP from the subsequent reactions of glycolysis. The TPI structure is shown on the right (PDB entry [[2ypi]]) in complex with GAP ("PGA"), which is bound to each of its two active sites. TPI is an example of a catalytically perfect enzyme, indicating that for almost every enzyme-substrate encounter, a product is formed and that this interaction is limited only by the substrate diffusion rate. In addition to its role in glycolysis, TPI is also involved in several additional metabolic biological processes including gluconeogenesis, the pentose phosphate shunt, and fatty acid biosynthesis. A point mutation to a glutamate residue (Glu104) of TPI results in triose phosphate isomerase deficiency, an autosomal recessive inherited disorder characterized by an increased accumulation of DHAP in erythrocytes. Structurally, this point mutation abolishes TPI’s ability to dimerize, subsequently inhibiting its catalytic activity. | ||
== Mechanism == | == Mechanism == | ||
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[[Image:classical2.png|center|thumb|500px| '''Classic Mechanism proposed by Knowles and co-workers''']] | [[Image:classical2.png|center|thumb|500px| '''Classic Mechanism proposed by Knowles and co-workers''']] | ||
TPI carries out the isomerization reaction through an acid-base-mediated mechanism involving '''three catalytic residues''' (<scene name='Triose_Phosphate_Isomerase/Three_catalytic_residues/6'>restore initial scene</scene>), each of which <scene name='Triose_Phosphate_Isomerase/Three_catalytic_residues/14'>contacts the substrate</scene>. First, the DHAP or GAP substrate is initially attracted to the enzyme active site through '''electrostatic interactions''' between the negatively charged phosphate group of the substrate and the positively charged '''Lys12''', | StructureSection load='2ypi' size='500' side='right' caption='testing' scene=Triose_Phosphate_Isomerase/Three_catalytic_residues/6/> TPI carries out the isomerization reaction through an acid-base-mediated mechanism involving '''three catalytic residues''' (<scene name='Triose_Phosphate_Isomerase/Three_catalytic_residues/6'>restore initial scene</scene>), each of which <scene name='Triose_Phosphate_Isomerase/Three_catalytic_residues/14'>contacts the substrate</scene>. First, the DHAP or GAP substrate is initially attracted to the enzyme active site through '''electrostatic interactions''' between the negatively charged phosphate group of the substrate and the positively charged '''Lys12''', | ||
<!--<scene name='Triose_Phosphate_Isomerase/Lys12_shaded/1'>Lys12</scene>,--> | <!--<scene name='Triose_Phosphate_Isomerase/Lys12_shaded/1'>Lys12</scene>,--> | ||
with the resulting interaction stabilizing the substrate. According to the "classic" mechanism, | with the resulting interaction stabilizing the substrate. According to the "classic" mechanism, | ||
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</StructureSection> | </StructureSection> | ||
===Inhibitors of Triose Phosphate Isomerase=== | ===Inhibitors of Triose Phosphate Isomerase=== | ||
