Sandbox Prolyl Hydroxylase Domain (PHD) Enzyme
From Proteopedia
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'''Prolyl hydroxylase domain (PHD) enzyme''' [http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/14/11/ (EC 1.14.11.-)] is a Fe(II)/2-oxoglutarate (OG)-dependent [http://en.wikipedia.org/wiki/Oxygenase dioxygenase] that catalyzes the ''trans''-4-hydroxylation of the specific proline residues (in humans, either Pro-402 or 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. | '''Prolyl hydroxylase domain (PHD) enzyme''' [http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/14/11/ (EC 1.14.11.-)] is a Fe(II)/2-oxoglutarate (OG)-dependent [http://en.wikipedia.org/wiki/Oxygenase dioxygenase] that catalyzes the ''trans''-4-hydroxylation of the specific proline residues (in humans, either Pro-402 or 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. | ||
| - | In mammals, this 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 [[EGLN2]]), PHD2 (also known as HPH2 and [[EGLN1]]), PHD3 (also known as HPH1 and [[EGLN3]]), and a newly identified enzyme called P4H-TM (also recently named PHD4 and EGLN4).<ref name="pmid18259202">{{cite journal | author = Fong GH, Takeda K | title = Role and Regulation of Prolyl Hydroxylase Domain Proteins | journal = Cell Death and Differentiation | volume = 15 | issue = | pages = 635–641 | year = 2008 | month = February | pmid = 18259202 | doi = 10.1038/cdd.2008.10 | url = | issn = }}</ref> | + | In mammals, this 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 [[EGLN2]]), PHD2 (also known as HPH2 and [[EGLN1]]), PHD3 (also known as HPH1 and [[EGLN3]]), and a newly identified enzyme called P4H-TM (also recently named PHD4 and EGLN4). Both PHD1 and PHD2 contain more than 400 [[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="pmid18259202">{{cite journal | author = Fong GH, Takeda K | title = Role and Regulation of Prolyl Hydroxylase Domain Proteins | journal = Cell Death and Differentiation | volume = 15 | issue = | pages = 635–641 | year = 2008 | month = February | pmid = 18259202 | doi = 10.1038/cdd.2008.10 | url = | issn = }}</ref> |
=== Structure === | === Structure === | ||
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| - | The protein core of PHDs consists of eight β-strands in a "jelly-roll" or double stranded β helix (DBSH) fold motif supported by three conserved α-helices that pack along the core. | + | The protein core of PHDs consists of eight β-strands in a "jelly-roll" or double stranded β helix (DBSH) fold motif supported by three conserved α-helices and other β-strands that pack along the core. Possession of the DBSH motif is typical of 2-OG-dependent oxygenases. Contained in this core are the three Fe(II)-binding ligands formed by the conserved triad sequence, His-X-Asp/Glu-Xn-His. |
| - | The active site, which is located on a deep cleft between the β-strands comprising the DBSH core, contains | + | The active site, which is located on a deep cleft between the β-strands comprising the DBSH core, contains the essential Fe(II). It is normally coordinated by the conserved two-histidine-one-carboxylate triad, 2-oxoglutarate and a water molecule to form an octahedral geometry. |
=== Function === | === Function === | ||
---- | ---- | ||
Revision as of 21:25, 30 April 2010
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| 2g19, resolution 1.70Å () | |||||||||
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| Ligands: | , | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
One of the CBI Molecules being studied in the University of Massachusetts Amherst Chemistry-Biology Interface Program at UMass Amherst and on display at the Molecular Playground.
Metazoans adapt to oxygen levels in the environment by making use of intracellular oxygen levels as signals to regulate the transcription of genes essential under normoxic or hypoxic conditions. Central to this mechanism is the oxygen-dependent hydroxylation on specific proline and asparagine residues of the transcription factor, hypoxia-inducible factor (HIF)-α.[1]
Prolyl hydroxylase domain (PHD) enzyme (EC 1.14.11.-) is a Fe(II)/2-oxoglutarate (OG)-dependent dioxygenase that catalyzes the trans-4-hydroxylation of the specific proline residues (in humans, either Pro-402 or Pro-564) in (HIF)-α. In addition to iron, this enzyme also requires ascorbate as a cofactor.
In mammals, this dioxygenase subfamily originally includes three homolog members but was recently updated to include another member: PHD1 (also known as HPH3 and EGLN2), PHD2 (also known as HPH2 and EGLN1), PHD3 (also known as HPH1 and EGLN3), and a newly identified enzyme called P4H-TM (also recently named PHD4 and EGLN4). Both PHD1 and PHD2 contain more than 400 amino acid residues while PHD3 has less than 250. All isoforms, however, contain the highly conserved hydroxylase domain in the catalytic carboxy-terminal region. [1]
Structure
The protein core of PHDs consists of eight β-strands in a "jelly-roll" or double stranded β helix (DBSH) fold motif supported by three conserved α-helices and other β-strands that pack along the core. Possession of the DBSH motif is typical of 2-OG-dependent oxygenases. Contained in this core are the three Fe(II)-binding ligands formed by the conserved triad sequence, His-X-Asp/Glu-Xn-His.
The active site, which is located on a deep cleft between the β-strands comprising the DBSH core, contains the essential Fe(II). It is normally coordinated by the conserved two-histidine-one-carboxylate triad, 2-oxoglutarate and a water molecule to form an octahedral geometry.
