Abstract
Prolyl hydroxylase domain proteins (PHD isozymes 1-3) regulate levels of the alpha-subunit of the hypoxia inducible factor (HIF) through proline hydroxylation, earmarking HIFalpha for proteosome-mediated degradation. Under hypoxic conditions, HIF stabilization leads to enhanced transcription and regulation of a multitude of processes, including erythropoiesis. Herein, we examine the biochemical characterization of PHD2 variants, Arg371His and Pro317Arg, identified from patients with familial erythrocytosis. The variants display differential effects on catalytic rate and substrate binding, implying that partial inhibition or selective inhibition with regard to HIFalpha isoforms of PHD2 could result in the phenotype displayed by patients with familial erythrocytosis.
MeSH terms
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Amino Acid Motifs
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Amino Acid Substitution
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Arginine / metabolism
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Binding Sites
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Catalysis
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Crystallography, X-Ray
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Genetic Variation*
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Histidine / metabolism
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Humans
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Hydrogen Bonding
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Hydroxylation
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Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Kinetics
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Models, Molecular
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Polycythemia / genetics*
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Polycythemia / metabolism
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Procollagen-Proline Dioxygenase / chemistry*
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Procollagen-Proline Dioxygenase / genetics*
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Procollagen-Proline Dioxygenase / metabolism
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Proline / chemistry
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Proline / metabolism
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Protein Structure, Tertiary
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Recombinant Proteins / chemistry
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / metabolism
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Substrate Specificity
Substances
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Hypoxia-Inducible Factor 1, alpha Subunit
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Isoenzymes
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Recombinant Proteins
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Histidine
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Arginine
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Proline
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Procollagen-Proline Dioxygenase