Vanessa Chaplin/sandbox2: Difference between revisions

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Vanessa Chaplin

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 Metazoans adapt to oxygen levels in the environment by making use of intracellular oxygen levels as signals to regulate the [http://en.wikipedia.org/wiki/Transcription_(genetics) transcription] of genes that are essential under normoxic or [http://en.wikipedia.org/wiki/Hypoxia_(medical) hypoxic] conditions. Central to this mechanism is the oxygen-dependent hydroxylation of specific proline and asparagine residues of  the transcription factor, hypoxia-inducible factor [http://en.wikipedia.org/wiki/HIF1A (HIF)-α] by the HIF-hydroxylase enzymes, which are studied extensively by the [http://people.chem.umass.edu/knapplab/?q=knappchem/index.html Knapp Lab] here at UMass Amherst.<ref name="review">Fong, G.H., Takeda, K.  "Role and Regulation of Prolyl Hydroxylase Domain Proteins."  Cell Death and Differentiation, February 15, 2008, 15, 635-641.  PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18259202 18259202]</ref>
-Of the HIF-hydroxylases, '''Prolyl hydroxylase domain [http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/14/11/ (PHD)]''' is believed to be the main oxygen sensor. PHD2 is a Fe(II)/2-oxoglutarate (OG)-dependent [http://en.wikipedia.org/wiki/Oxygenase dioxygenase] that catalyzes the ''trans''-4-hydroxylation of specific proline residues (in humans, Pro-402 and Pro-564) in [http://en.wikipedia.org/wiki/HIF1A (HIF)-α]. In addition to iron, this enzyme also requires [http://en.wikipedia.org/wiki/Vitamin_C ascorbate] as a cofactor.<ref name="structure">Mcdonough, M.A., Li, V., Flashman, E., et al.  "Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)."  PNAS, June 27, 2006, 103 (26), 9814-9819.  PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16782814 16782814]</ref>
+These HIF-hydroxylase enzymes include Prolyl Hydroxylase Domain isoforms (PHDs) and Factor Inhibition Hypoxia Inducible Factor (FIH). PHDs belong to the same oxygenase superfamily as the [http://en.wikipedia.org/wiki/Collagen collagen] prolyl hydroxylases. Inside the cell, PHD1 is found in the nucleus, while PHD2 is mostly located in the cytoplasm and PHD3 is distributed in both <ref>PMID:12615973</ref>.This distribution contrasts with that of the [http://en.wikipedia.org/wiki/Collagen collagen] prolyl hydroxylases, which reside  in the endoplasmic reticulum. In mammals, the PHD dioxygenase subfamily originally included three [http://en.wiktionary.org/wiki/homolog homolog] members: PHD1 (also known as HPH3 and [http://en.wikipedia.org/wiki/EGLN2 EGLN2]), PHD2 (also known as HPH2 and [http://en.wikipedia.org/wiki/EGLN1 EGLN1]), PHD3 (also known as HPH1 and [http://en.wikipedia.org/wiki/EGLN3 EGLN3]). Recently, a newly identified enzyme called P4H-TM (also named PHD4 and EGLN4) was added to this subfamily. Both PHD1 and PHD2 contain more than 400 [http://en.wikipedia.org/wiki/Amino_acid amino acid] residues while PHD3 has less than 250. All isoforms, however, contain the highly conserved hydroxylase domain in the catalytic carboxy-terminal region. <ref name="review" />. PHDs differ in terms of the proline hydroxylation site. PHD2 hydroxylates Pro-402 or Pro-564 residues in the oxygen degradation domain of [http://en.wikipedia.org/wiki/HIF1A (HIF)-α] whereas PHD3 can only hydroxylate the Pro-564 position.
+Of the HIF-hydroxylases, '''[http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/14/11/ (PHD2)]''' is believed to be the main oxygen sensor. PHD2 is a Fe(II)/2-oxoglutarate (OG)-dependent [http://en.wikipedia.org/wiki/Oxygenase dioxygenase] that catalyzes the ''trans''-4-hydroxylation of specific proline residues (in humans, Pro-402 and Pro-564) in [http://en.wikipedia.org/wiki/HIF1A (HIF)-α]. In addition to iron, this enzyme also requires [http://en.wikipedia.org/wiki/Vitamin_C ascorbate] as a cofactor.<ref name="structure">Mcdonough, M.A., Li, V., Flashman, E., et al.  "Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)."  PNAS, June 27, 2006, 103 (26), 9814-9819.  PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16782814 16782814]</ref>
-PHDs belong to the same oxygenase superfamily as the [http://en.wikipedia.org/wiki/Collagen collagen] prolyl hydroxylases. Inside the cell, PHD1 is found in the nucleus, PHD2 is mostly located in the cytoplasm and PHD3 is distributed in both <ref>PMID:12615973</ref> in contrast to [http://en.wikipedia.org/wiki/Collagen collagen] prolyl hydroxylases, which reside  in the endoplasmic reticulum. In mammals, the PHD dioxygenase subfamily originally includes three [http://en.wiktionary.org/wiki/homolog homolog] members but was recently updated to include another member: PHD1 (also known as HPH3 and [http://en.wikipedia.org/wiki/EGLN2 EGLN2]), PHD2 (also known as HPH2 and [http://en.wikipedia.org/wiki/EGLN1 EGLN1]), PHD3 (also known as HPH1 and [http://en.wikipedia.org/wiki/EGLN3 EGLN3]), and a newly identified enzyme called P4H-TM (also recently named PHD4 and EGLN4). Both PHD1 and PHD2 contain more than 400 [http://en.wikipedia.org/wiki/Amino_acid amino acid] residues while PHD3 has less than 250. All isoforms, however, contain the highly conserved hydroxylase domain in the catalytic carboxy-terminal region. <ref name="review" />. PHDs differ in terms of the proline hydroxylation site. PHD2 hydroxylates Pro-402 and Pro-564 residues in the oxygen degradation domain of [http://en.wikipedia.org/wiki/HIF1A (HIF)-α] whereas PHD3 can only hydroxylate Pro-564 position.
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