Red cell glucose phosphate isomerase (GPI): a molecular study of three novel mutations associated with hereditary nonspherocytic hemolytic anemia

Repiso, Ada; Oliva, Baldomero; Vives‐Corrons, Joan‐Lluis; Beutler, Ernest; Carreras, José; Climent, F.

doi:10.1002/humu.9466

Cited by 17 publications

(18 citation statements)

References 15 publications

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“…In fact, one of the main characteristics of the mutant dimer is its comparatively low stability. The presented data show that at relatively high temperatures, the mutant enzyme loses activity faster than the wild type, which is in agreement with the reports in hemolysates (12) and cultured fibroblasts from patients affected by the E104D mutation (19,20). Along this line, CD and differential scanning calorimetry data showed that heat denaturation of the wild type occurs at temperatures about 12°C higher than in the mutant enzyme.…”

Section: Discussionsupporting

confidence: 81%

“…The data are consistent with TIM activity of affected individuals being substantially lower than in unaffected individuals; it was also shown that TIM activity in the E104D mutant is thermolabile (12,20). A two-hybrid system in yeast was used to explore the interaction between the two monomers of various mutant enzymes, including E104D (21).…”

supporting

confidence: 52%

“…In studies of hemolysates from patients affected by TIM deficiency, the activity of the enzyme is found to be more than an order of magnitude lower than in normal individuals. Further, this reduction is accompanied by accumulation of dihydroxyacetone phosphate to levels several times higher than those of the controls (7)(8)(9)(10)(11)(12)(13)(14). At high concentrations, dihydroxyacetone phosphate inhibits myo-inositol-3-phosphate synthase (15); this inhibition may be related to the clinical manifestations of TIM deficiencies.…”

mentioning

confidence: 99%

“…HsTIM-Since it has been reported that in cultured fibroblasts and in erythrocytes from patients affected by the E104D mutation, TIM activity is thermolabile (12,20), we assessed the stability of the wild type and mutant enzymes at various temperatures. The incubation of the mutant enzyme at 36°C or above (supplemental Fig.…”

Section: The Stability Of the Dimers And The Formation Of Active Dimementioning

confidence: 99%

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Structural Basis of Human Triosephosphate Isomerase Deficiency

Rodríguez-Almazán

Arreola

Rodríguez-Larrea

et al. 2008

Journal of Biological Chemistry

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Human triosephosphate isomerase deficiency is a rare autosomal disease that causes premature death of homozygous individuals. The most frequent mutation that leads to this illness is in position 104, which involves a conservative change of a Glu for Asp. Despite the extensive work that has been carried out on the E104D mutant enzyme in hemolysates and whole cells, the molecular basis of this disease is poorly understood. Here, we show that the purified, recombinant mutant enzyme E104D, while exhibiting normal catalytic activity, shows impairments in the formation of active dimers and low thermostability and monomerizes under conditions in which the wild type retains its dimeric form. The crystal structure of the E104D mutant at 1.85 Å resolution showed that its global structure was similar to that of the wild type; however, residue 104 is part of a conserved cluster of 10 residues, five from each subunit. An analysis of the available high resolution structures of TIM dimers revealed that this cluster forms a cavity that possesses an elaborate conserved network of buried water molecules that bridge the two subunits. In the E104D mutant, a disruption of contacts of the amino acid side chains in the conserved cluster leads to a perturbation of the water network in which the water-protein and water-water interactions that join the two monomers are significantly weakened and diminished. Thus, the disruption of this solvent system would stand as the underlying cause of the deficiency.

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Section: Discussionsupporting

confidence: 81%

supporting

confidence: 52%

mentioning

confidence: 99%

Section: The Stability Of the Dimers And The Formation Of Active Dimementioning

confidence: 99%

See 2 more Smart Citations

Structural Basis of Human Triosephosphate Isomerase Deficiency

Rodríguez-Almazán

Arreola

Rodríguez-Larrea

et al. 2008

Journal of Biological Chemistry

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“…Residual GPI activity in erythrocytes of around 7% (GPI-Catalonia), in an individual is homozygous for the missense mutation 1648A→G (Lys550→G l u ) i n e x o n 1 8 w a s d e s c r i b e d and residual activity in erythrocytes of around 20% (GPI-Barcelona), was found in a compound heterozygote for two different missense mutations: 341A→T (Asp113→Val) in exon 4 and 663T→G (Asn220→Lys) in exon 7. Molecular modeling using the human crystal structure of GPI as a model was performed to determine how these mutations could affect enzyme structure and function (Repiso et al, 2006). Chinese hamster (CHO) cell lines with ethylmethane sulfonate induced mutations in GPI and consequent loss of GPI activity have been reported.…”

Section: Point Mutation In Glucose-6-phosphate Isomerasementioning

confidence: 99%

Point Mutations That Reduce Erythrocyte Resistance to Oxidative Stress

Volosnikov¹,

Serebryakova²

2012

Point Mutation

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Regulatory role of zinc during aluminium‐induced altered carbohydrate metabolism in rat brain

Singla

Dhawan

2011

J of Neuroscience Research

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Aluminium is considered an environmental neurotoxicant and causes many neurological disorders, whereas zinc is vital for many biological functions. The present study was carried out to investigate the role of Zn, if any, in mitigating the adverse effects inflicted by Al on carbohydrate metabolism in rat brain. Male Sprague-Dawley rats weighing 140-160 g were divided into four different groups: normal control, Al-treated (100 mg/kg b.w./day in drinking water via oral gavage), Zn-treated (227mg/liter in drinking water), and combined Al- and Zn-treated rats. All the treatments were continued for 2 months, and their effects on carbohydrate-metabolizing enzymes were studied. Additionally, expressions of the proteins glycogen synthase kinase-3 (GSK3) and protein phosphatase (PP1), which help in regulating carbohydrate energy metabolism, were also studied. Al treatment resulted in increased activities of the glucose-6-phosphatase (G6P), glucose-6-isomerase (G6I), and lactate dehydrogenase (LDH), whereas the activities of hexokinase and succinate dehydrogenase (SDH) and glycogen content were decreased. Moreover, no significant change was observed in the biochemical parameters upon Zn supplementation alone. However, Zn supplementation to Al-treated rats was able to reduce significantly the Al-induced increased activities of G6P, G6I, and LDH, but it elevated the levels of hexokinase, SDH, and glycogen. Furthermore, Al treatment increased the protein expression of GSK3 and decreased the PP1 expression, which were found to be reversed upon Zn administration. Hence, Zn is effective in regulating theAl-induced alterations in carbohydrate metabolism.

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Red cell glucose phosphate isomerase (GPI): a molecular study of three novel mutations associated with hereditary nonspherocytic hemolytic anemia

Cited by 17 publications

References 15 publications

Structural Basis of Human Triosephosphate Isomerase Deficiency

Structural Basis of Human Triosephosphate Isomerase Deficiency

Point Mutations That Reduce Erythrocyte Resistance to Oxidative Stress

Regulatory role of zinc during aluminium‐induced altered carbohydrate metabolism in rat brain

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