Hereditary Hemolytic Anemia with Hexokinase Deficiency

Valentine, William N.; Oski, Frank A.; Paglia, Donald E.; Baughan, Marjorie A.; Schneider, Arthur S.; Naiman, J. Lawrence

doi:10.1056/nejm196701052760101

Cited by 173 publications

(53 citation statements)

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“…Hexokinase (HK), 1 or ATP:D-hexose 6-phosphotransferase, is a member of the kinase family of tissue-specific isoenzymes (EC 2.7.1.1). Reduction in its activity causes illnesses in humans like hemolytic anemia (1,2) and cardiomyopathy (3).…”

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confidence: 99%

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The High Resolution Crystal Structure of Yeast Hexokinase PII with the Correct Primary Sequence Provides New Insights into Its Mechanism of Action

Kuser¹,

Krauchenco²,

Antunes³

et al. 2000

Journal of Biological Chemistry

112

154

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Hexokinase is the first enzyme in the glycolytic pathway, catalyzing the transfer of a phosphoryl group from ATP to glucose to form glucose 6-phosphate and ADP. Two yeast hexokinase isozymes are known, namely PI and PII. The crystal structure of yeast hexokinase PII from Saccharomyces cerevisiae without substrate or competitive inhibitor is determined and refined in a tetragonal crystal form at 2.2-Å resolution. The folding of the peptide chain is very similar to that of Schistosoma mansoni and previous yeast hexokinase models despite only 30% sequence identity between them. Distinct differences in conformation are found that account for the absence of glucose in the binding site. Comparison of the current model with S. mansoni and yeast hexokinase PI structures both complexed with glucose shows in atomic detail the rigid body domain closure and specific loop movements as glucose binds. A hydrophobic channel formed by strictly conserved hydrophobic residues in the small domain of the hexokinase is identified. The channel's mouth is close to the active site and passes through the small domain to its surface. The possible role of the observed channel in proton transfer is discussed.

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confidence: 99%

“…Reduction in its activity causes illnesses in humans like hemolytic anemia (1,2) and cardiomyopathy (3). Mutations in glucokinase (hexokinase IV) are associated with early onset non-insulin-dependent diabetes mellitus (4,5).…”

mentioning

confidence: 99%

The High Resolution Crystal Structure of Yeast Hexokinase PII with the Correct Primary Sequence Provides New Insights into Its Mechanism of Action

Kuser¹,

Krauchenco²,

Antunes³

et al. 2000

Journal of Biological Chemistry

112

154

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“…It is well established that several glycolytic enzymes are present at a higher activity level in younger red cells. This is true of those enzymes which also had higher levels in our patients after G H therapy: hexokinase (14, 35, 37), 3-phosphoglycerate mutase (14,34), glucose phosphate isomerase (14,34), triosephosphate isomerase (14,34), enolase (14,34), pyruvate kinase (14,34,35,37), glucose 6-phosphate dehydrogenase (14,34,35,37), and phosphofructokinase (14,34). A moderately elevated activity was also found in 3-phosphoglycerate kinase (14).…”

Section: Discussionmentioning

confidence: 55%

“…Elevated enzyme activities due to de novo synthesis of the enzyme protein after G H administration have been reported (16,23). Judging from a previous study (35), the observed rise of hexokinase activity correlates approximately to the rise of reticulocyte count and may thus be fully explained by the erythropoietic action of GH. However, the possibility that G H also exerted a direct stimulatory effect on nucleated red cell enzyme synthesis cannot definitively be excluded.…”

Section: Discussionmentioning

confidence: 82%

Action of Growth Hormone on Erythropoiesis: Changes in Red Blood Cell Enzyme Activities in Growth-retarded Patients with and without Growth Hormone Deficiency

1976

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ExtractFifteen red cell enzyme activities of growth-retarded patients with and without growth hormone (GH) deficiency were investigated before and after GH administration. The 15 enzymes were Hexokinase, phosphoglucomutase, glucose phosphate isomerase, phosphofructokinase, fructose diphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase, triosephosphate isomerase, 2,3-diphosphoglycerate mutase, 3-phosphoglycerate kinase, 3-phosphoglycerate mutase, enolase, pyruvate kinase, glycose-6-phosphate dehydrogenase, 6-phosphogluconic dehydrogenase, glutathione reductase.Sixty-six subjects were studied: 30 normal control subjects (group N) and 36 patients (aged 5-23 years) with short stature. Complete endocrine evaluation showed 21 (group I ) to have GH deficiency (10 patients with isolated GH deficiency) and 15 (group II) to have normal hypothalamic and pituitary function except for two patients with a moderate hypothyroidism. Both had been receiving thyroid hormone treatment for a long time before our studies. All 36 patients were treated with 2 mg human growth hormone intramuscularly for 7 days.Before GH treatment no significant difference was observed between hematologic data in group I (GH deficiency) and group II (no GH deficiency). After GH therapy there was a significant increase in reticulocyte count in both groups of patients with short stature. The mean pretreatment value in group I was 1.294% k 0.084 (SEM); the mean post-treatment value was 2.081% 0.287 (SEM), P < 0.005. The mean pretreatment value in group II was 1.0% 0.184 (SEM); the mean post-treatment value was 1.407% 0.193 (SEM), P < 0.01.In group II (no GH devidiency) mean pretreatment erythrocyte enzyme activities were not significantly different from those activities observed in normal control subjects (group N). However, in patients who lacked GH, the pretreatment activities of five red cell enzymes (glucose phosphate isomerase, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, 2,3-diphosphoglycerate mutase, 3-phosphoglycerate kinase) were significantly decreased before GH administration compared with the values in normal control subjects. The reduction in a further red cell enzyme (3-phosphoglycerate mutase) was statistically not significant.With GH treatment eight red cell enzyme activities showed a significant increase, one of them (hexokinase) significantly rising in both groups of patients. The remaining seven erythrocyte enzymes (3-phosphoglycerate mutase, glucose phosphate isomerase, triosephosphate isomerase, 2,3-diphosphoglycerate mutase, enolase, pyruvate kinase, glucose-6-phosphate dehydrogenase) exhibited significantly elevated activities only in patients lacking GH. In three of these enzymes the increase was significantly above the control value.Enzyme activities which were significantly decreased before GH administration rose significantly after GH therapy except for two enzyme activities (3-phosphoglycerate kinase and glyceraldehyde-3-phosphate dehydrogenase). The data may suggest the presence of a younger red ...

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“…Hexokinase deficiency of human erythrocytes was first related to hereditary nonspherocytic hemolytic anemia in 1967 by Valentine et al (2). The hexokinase activity of the patienit's erythrocytes was only slightly decreased, but was markedly lowered when the degree of reticulocytosis was taken into account.…”

Section: Introductionmentioning

confidence: 99%

Human erythrocyte hexokinase deficiency. Characterization of a mutant enzyme with abnormal regulatory properties.

Rijksen¹,

Staal²

1978

J. Clin. Invest.

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A B S T R A C T In the erythrocytes of a patient with hereditary nonspherocytic hemolytic anemia, a homozygous expression of hexokinase deficiency was detected. The mutant enzyme was characterized by normal kinetic parameters with respect to its substrates, glucose and MgATP2-, normal pH optimum, normal heat stability at 40°C, but abnormal behavior with respect to its regulation by glucose-1,6-diphosphate and inorganic phosphate, and an altered electrophoretic pattern. Interpretation of the results revealed the presence of two different hexokinases type I in normal human erythrocytes: one enzyme with a high affinity for glucose-1,6-diphosphate, the inhibition of which is regulated by inorganic phosphate; and another enzyme with a lower affinity for the inhibitor, not regulated by inorganic phosphate. The former enzyme was not detectable in the erythrocytes of the patient, whereas the presence of the latter enzyme could be demonstrated.

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Hereditary Hemolytic Anemia with Hexokinase Deficiency

Cited by 173 publications

References 15 publications

The High Resolution Crystal Structure of Yeast Hexokinase PII with the Correct Primary Sequence Provides New Insights into Its Mechanism of Action

The High Resolution Crystal Structure of Yeast Hexokinase PII with the Correct Primary Sequence Provides New Insights into Its Mechanism of Action

Action of Growth Hormone on Erythropoiesis: Changes in Red Blood Cell Enzyme Activities in Growth-retarded Patients with and without Growth Hormone Deficiency

Human erythrocyte hexokinase deficiency. Characterization of a mutant enzyme with abnormal regulatory properties.

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