Sandbox Prolyl Hydroxylase Domain (PHD) Enzyme
From Proteopedia
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=== Structure === | === Structure === | ||
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| - | PHDs have two structural domains: the more variable N-terminal domain and the conserved catalytic C-terminal domain. The catalytic domain core of PHDs consists of eight β-strands in a "jelly-roll" or | + | PHDs have two structural domains: the more variable N-terminal domain and the conserved catalytic C-terminal domain. The catalytic domain core of PHDs consists of eight β-strands in a "jelly-roll" or double stranded β helix <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Jelly_roll_fold/2'>(DSBH) fold motif</scene> supported by three conserved α-helices and other β-strands and loops that pack along the core. Possession of the DSBH 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.<ref>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> |
The <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Active_site/1'>active site</scene>, 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 <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Fe_binding_triad_sequence/1'>triad</scene>, 2-oxoglutarate and a water molecule to form an octahedral geometry. | The <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Active_site/1'>active site</scene>, 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 <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Fe_binding_triad_sequence/1'>triad</scene>, 2-oxoglutarate and a water molecule to form an octahedral geometry. | ||
Revision as of 00:26, 1 May 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 that are 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. [2]
Structure
PHDs have two structural domains: the more variable N-terminal domain and the conserved catalytic C-terminal domain. The catalytic domain core of PHDs consists of eight β-strands in a "jelly-roll" or double stranded β helix supported by three conserved α-helices and other β-strands and loops that pack along the core. Possession of the DSBH 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.[3]
The , 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 , 2-oxoglutarate and a water molecule to form an octahedral geometry.
Function
The dependence of PHD-catalyzed hydroxylation reactions on molecular oxygen concentration led to the most notable role of PHDs as cellular oxygen sensors. Aside from regulation of oxygen homeostasis, other biological functions of the enzyme are being proposed because the results of some studies showed that other factors such as nitric oxide and reactive oxygen species (ROS) possibly control PHD activity. In fact, several functions of the enzyme have been recently identified.
Listed below are the currently identified functions for PHDs in general:
- tumor suppressor
- promoter of cell death (apoptosis)
- regulator of cell differentiation
References
- ↑ Fong, G.H., Takeda, K. "Role and Regulation of Prolyl Hydroxylase Domain Proteins." Cell Death and Differentiation, February 15, 2008, 15, 635-641. PMID:18259202
- ↑ Fong, G.H., Takeda, K. "Role and Regulation of Prolyl Hydroxylase Domain Proteins." Cell Death and Differentiation, February 15, 2008, 15, 635-641. PMID:18259202
- ↑ Fong, G.H., Takeda, K. "Role and Regulation of Prolyl Hydroxylase Domain Proteins." Cell Death and Differentiation, February 15, 2008, 15, 635-641. PMID:18259202
