Hereditary Hemolytic Anemia with Triosephosphate Isomerase Deficiency

Schneider, Arthur S.; Valentine, William N.; Hattori, Masao; Heins, Henry L.

doi:10.1056/nejm196502042720503

Cited by 192 publications

(78 citation statements)

References 6 publications

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“…(A2) and the value of k cat,f . [63], kinetic parameters of the isoenzyme which makes up 70k75 % of the total activity in the human erythrocyte (three isoenzymes of TPI have been distinguished) ; b [64], human erythrocyte ; c K eq l p/a, [65], 38 mC; d k cat,f was calculated from the specific activity of the purified (4265i) human erythrocyte enzyme (10236 units/mg at pH 7.6, 30 mC ; [66]) adjusted to 37 mC by multiplication by the temperature correction factor of 1.52 [62] ; TPI is reported to be a dimer with a total M r of 56000 [63] ; e k cat,f is 11.4 times k cat,r in rabbit muscle [62] ; f the concentration of TPI in human erythrocytes, e o , was estimated from the measured human erythrocyte activity (697000 units/litre of erythrocytes, pH 7.6, 37 mC ; [62]) and the value of k cat,f . The parameters used in the model are given in Table A10.…”

Section: Scheme A3 a Minimal Model Of Human Erythrocyte Aldmentioning

confidence: 99%

Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: equations and parameter refinement

Mulquiney

Kuchel

1999

Biochemical Journal

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Over the last 25 years, several mathematical models of erythrocyte metabolism have been developed. Although these models have identified the key features in the regulation and control of erythrocyte metabolism, many important aspects remain unexplained. In particular, none of these models have satisfactorily accounted for 2,3-bisphosphoglycerate (2,3-BPG) metabolism. 2,3-BPG is an important modulator of haemoglobin oxygen affinity, and hence an understanding of the regulation of 2,3-BPG concentration is important for understanding blood oxygen transport. A detailed, comprehensive, and hence realistic mathematical model of erythrocyte metabolism is presented that can explain the regulation and control of 2,3-BPG concentration and turnover. The model is restricted to the core metabolic pathways, namely glycolysis, the 2,3-BPG shunt and the pentose phosphate pathway (PPP), and includes membrane transport of metabolites, the binding of metabolites to haemoglobin and Mg# + , as well as pH effects on key enzymic reactions and binding processes. The

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Section: Scheme A3 a Minimal Model Of Human Erythrocyte Aldmentioning

confidence: 99%

Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: equations and parameter refinement

Mulquiney

Kuchel

1999

Biochemical Journal

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“…The underlying pathogenesis of these diseases remains poorly understood. Triose phosphate isomerase (TPI) deficiency is a severe glycolytic enzymopathy caused by specific missense mutations in the TPI gene that are associated with hemolytic anemia, progressive neuromuscular degeneration, increased susceptibility to infection, and premature death (Schneider et al 1965;Valentine 1966). The TPI protein exists as a homodimer of $26.5-kDa monomers that functions to convert dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P) in glycolysis (Rieder and Rose 1959;Mande et al 1994).…”

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confidence: 99%

“…Although these studies have produced important information about the disease, they have not provided much insight into neurological and degenerative aspects of TPI deficiency. Such studies have measured reduced isomerase activity from patients' erythrocytes, platelets, and lympocytes (Schneider et al 1965;Zanella et al 1985;Orosz et al 2001;Olah et al 2002Olah et al , 2005, as well as brain and muscle tissue (Ationu et al 1999). Studies have also documented markedly elevated DHAP levels, suggesting that the anemia may be caused by toxicity of DHAP or one of its catabolites (Zanella et al 1985;Eber et al 1991;Hollan et al 1997;Karg et al 2000;Olah et al 2002Olah et al , 2005.…”

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confidence: 99%

Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

Seigle

Celotto²,

Palladino

2008

Genetics

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Triose phosphate isomerase (TPI) deficiency glycolytic enzymopathy is a progressive neurodegenerative condition that remains poorly understood. The disease is caused exclusively by specific missense mutations affecting the TPI protein and clinically features hemolytic anemia, adult-onset neurological impairment, degeneration, and reduced longevity. TPI has a well-characterized role in glycolysis, catalyzing the isomerization of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P); however, little is known mechanistically about the pathogenesis associated with specific recessive mutations that cause progressive neurodegeneration. Here, we describe key aspects of TPI pathogenesis identified using the TPI sugarkill mutation, a Drosophila model of human TPI deficiency. Specifically, we demonstrate that the mutant protein is expressed, capable of forming a homodimer, and is functional. However, the mutant protein is degraded by the 20S proteasome core leading to loss-of-function pathogenesis.

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“…Glycolytic enzymopathies result from a disturbance in anaerobic metabolism; however, these diseases remain poorly understood. Familial triosephosphate isomerase (TPI) deficiency, an autosomal recessive disorder, has been reported in numerous pedigrees and results in anemia, neuromuscular wasting, and reduced longevity (Schneider et al 1965;Valentine 1966). The relationship of anemia, neuromuscular degeneration, and glycolytic flux to disease pathogenesis is not clear, and an animal model that captures salient features of TPI deficiency has not been reported.…”

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Drosophila Model of Human Inherited Triosephosphate Isomerase Deficiency Glycolytic Enzymopathy

Celotto

Frank²,

Seigle

et al. 2006

Genetics

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Heritable mutations, known as inborn errors of metabolism, cause numerous devastating human diseases, typically as a result of a deficiency in essential metabolic products or the accumulation of toxic intermediates. We have isolated a missense mutation in the Drosophila sugarkill (sgk) gene that causes phenotypes analogous to symptoms of triosephosphate isomerase (TPI) deficiency, a human familial disease, characterized by anaerobic metabolic dysfunction resulting from pathological missense mutations affecting the encoded TPI protein. In Drosophila, the sgk gene encodes the glycolytic enzyme TPI. Our analysis of sgk mutants revealed TPI impairment associated with reduced longevity, progressive locomotor deficiency, and neural degeneration. Biochemical studies demonstrate that mutation of this glycolytic enzyme gene does not result in a bioenergetic deficit, suggesting an alternate cause of enzymopathy associated with TPI impairment.

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Hereditary Hemolytic Anemia with Triosephosphate Isomerase Deficiency

Cited by 192 publications

References 6 publications

Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: equations and parameter refinement

Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: equations and parameter refinement

Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

Drosophila Model of Human Inherited Triosephosphate Isomerase Deficiency Glycolytic Enzymopathy

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