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1/3. HK Utrecht: missense mutation in the active site of human hexokinase associated with hexokinase deficiency and severe nonspherocytic hemolytic anemia.

    hexokinase deficiency is a rare autosomal recessive disease with a clinical phenotype of severe hemolysis. We report a novel homozygous missense mutation in exon 15 (c.2039C>G, HK [hexokinase] Utrecht) of HK1, the gene that encodes red blood cell-specific hexokinase-R, in a patient previously diagnosed with hexokinase deficiency. The Thr680Ser substitution predicted by this mutation affects a highly conserved residue in the enzyme's active site that interacts with phosphate moieties of adenosine diphosphate, adenosine triphosphate (ATP), and inhibitor glucose-6-phosphate. We correlated the molecular data to the severe clinical phenotype of the patient by means of altered enzymatic properties of partially purified hexokinase from the patient, notably with respect to Mg(2 )-ATP binding. These kinetic properties contradict those obtained from a recombinant mutant brain hexokinase-I with the same Thr680Ser substitution. This contradiction thereby stresses the valuable contribution of studying patients with hexokinase deficiency to achieve a better understanding of hexokinase's key role in glycolysis.
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keywords = glycolysis
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2/3. Clinical features and biochemical aspects of red blood cells in Hb Hirosaki.

    Hb Hirosaki is a new unstable variant in which CE 1 phenylalanine of alpha-chain is substituted by leucine. Seven patients with hemolytic anemia were found in one family and Hb Hirosaki was detected in four of them. In clinical feature some differences of severity were observed between child and adult patients. The child cases showed relatively severe symptoms with repeated hemolytic crises and drug sensitivity. Otherwise most of adult cases had only mild hemolytic process throughout their past life. The variety of clinical severity suggests that the expression of abnormal gene may be various in this disorder. The mode of inheritance seemed to be autosomal dominant and all the cases in this report were heterozygous state. Macrocytic and hypochromic anemia was characteristic in most cases and red blood cells containing heinz bodies were dominant in peripheral blood from the splenectomized patients. Accelerated glycolysis and enhanced ATPase activity were outstanding features in the metabolism of erythrocyte in this disorder. The instability of reduced glutathione was also found in three of five cases.
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keywords = glycolysis
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3/3. Platelet functions and energy metabolism in a patient with hexokinase deficiency.

    We have studied the regeneration of adenosine triphosphate (ATP) in the glycolytic pathway in platelets with a 75% reduction in hexokinase (HK) activity and have investigated aggregation and Ca2 secretion. HK-deficient platelets had a normal glycolytic flux in the resting state, but responded insufficiently to stimulation with thrombin (5 U/ml). In contrast, glycogen contents and glycogenolysis were normal. When the metabolic adenine nucleotides were labeled with 14C-adenine, the patient's platelets showed a normal adenylate energy charge and a normal level of 14C-ATP. However, the inhibitor of mitochondrial energy generation, CN-, induced a weaker fall in 14C-ATP in the patient's platelets than in the controls. Analysis of secretion markers revealed decreased amounts of granule-bound ATP and secretable Ca2 , whereas granule-bound adenosine diphosphate (ADP), beta-thromboglobulin, N-acetyl-beta-D-glucosaminidase, and beta-glucuronidase were within the normal range. Aggregation and Ca2 secretion induced by 5 U/ml thrombin were normal and were not changed in the presence of inhibitors of mitochondrial and glycogenolytic energy generation. Aggregation was also normal at 0.1 U/ml thrombin and was independent of these inhibitors, but Ca2 secretion was greatly impaired when mitochondrial and glycogenolytic ATP resynthesis was abolished. These findings indicate that a severe reduction in HK activity causes insufficient acceleration of the glycolytic flux during stimulation with thrombin. This leads to impaired dense granule secretion in conditions where secretion depends on concurrent ATP resynthesis and glycolysis is rate limiting.
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ranking = 1
keywords = glycolysis
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