Literature summary for 1.14.11.2 extracted from

Chowdhury, R.; McDonough, M.A.; Mecinovic, J.; Loenarz, C.; Flashman, E.; Hewitson, K.S.; Domene, C.; Schofield, C.J.
Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases (2009), Structure, 17, 981-989.

Search for more literature for 1.14.11.2

Application

Application	Comment	Organism
drug development	the enzyme is a target for design of PHD inhibitors aimed at treating anemia and ischemic disease	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
expression of wild-type and mutant enzymes in Escherichia coli strain BL21(DE3)	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
recombinant catalytic domain of PHD2 in complex with the C-terminal oxygen-dependent degradation domain of HIF-1alpha, 20°C, 100 nl protein solution containing 40 mg/ml protein in 50 mM Tris-HCl, pH 7.5, 1 mM MnCl2, 1 mM NOG, and 0.1 mM HIF-1alpha CODD556-574 mixed with 100 nl of well solution consisting of 0.2 M MgCl2 and 20% PEG 3350, A tPHD2-Fe2+-B-CODD568-574 crystal is obtained by soaking preformed PHD2181-426-Fe2+-B crystals in 50% sodium malonate, pH 7.5, solution containing 10 mM 4R-hydroxylated Pro564 HIF-1alpha CODD556-574(Hyp564) peptide under anaerobic conditions for 72 h. The PHD2-Fe2+-inhibitor complexes crystallize in an apparently homotrimeric form, method optimization, X-ray diffraction structure determination and analysis at 2.0-2.3 A resolution, molecular replacement	Homo sapiens

Crystallization (Comment)

Organism

recombinant catalytic domain of PHD2 in complex with the C-terminal oxygen-dependent degradation domain of HIF-1alpha, 20°C, 100 nl protein solution containing 40 mg/ml protein in 50 mM Tris-HCl, pH 7.5, 1 mM MnCl2, 1 mM NOG, and 0.1 mM HIF-1alpha CODD556-574 mixed with 100 nl of well solution consisting of 0.2 M MgCl2 and 20% PEG 3350, A tPHD2-Fe2+-B-CODD568-574 crystal is obtained by soaking preformed PHD2181-426-Fe2+-B crystals in 50% sodium malonate, pH 7.5, solution containing 10 mM 4R-hydroxylated Pro564 HIF-1alpha CODD556-574(Hyp564) peptide under anaerobic conditions for 72 h. The PHD2-Fe2+-inhibitor complexes crystallize in an apparently homotrimeric form, method optimization, X-ray diffraction structure determination and analysis at 2.0-2.3 A resolution, molecular replacement

Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
additional information	construction of point mutants	Homo sapiens

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Fe2+	HIF prolyl hydroxylases form unusually stable complexes with their Fe2+ cofactor and 2-oxoglutarate cosubstrate	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
hypoxia-inducible transcription factor + 2-oxoglutarate + O2	Homo sapiens	i.e. HIF, oxygen-dependent hydroxylation of proline residues in the alpha subunit of hypoxia-inducible transcription factor is central to the hypoxic response in animals. Prolyl hydroxylation of HIFalpha increases its binding to the von Hippel-Lindau protein, thus signaling for degradation via the ubiquitin-proteasome system	hypoxia-inducible transcription factor trans-4-hydroxy-L-proline + succinate + CO2	-	?
additional information	Homo sapiens	HIF prolyl hydroxylases are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe2+ cofactor and 2-oxoglutarate cosubstrate	?	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	-	sveral isozymes	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant wild-type and mutant enzymes from Escherichia coli strain Bl21(DE3)	Homo sapiens

Reaction

Reaction	Comment	Organism	Reaction ID
procollagen L-proline + 2-oxoglutarate + O2 = procollagen trans-4-hydroxy-L-proline + succinate + CO2	active site structure and action mode, overview	Homo sapiens	a

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
hypoxia-inducible transcription factor + 2-oxoglutarate + O2	i.e. HIF, oxygen-dependent hydroxylation of proline residues in the alpha subunit of hypoxia-inducible transcription factor is central to the hypoxic response in animals. Prolyl hydroxylation of HIFalpha increases its binding to the von Hippel-Lindau protein, thus signaling for degradation via the ubiquitin-proteasome system	Homo sapiens	hypoxia-inducible transcription factor trans-4-hydroxy-L-proline + succinate + CO2	-	?
hypoxia-inducible transcription factor + 2-oxoglutarate + O2	i.e. HIF, the substrate prolyl-residue is bound in a specific conformation and that a significant structural change involving a mobile loop likely occurs concomitant with HIFalpha binding. PHD catalysis involves the mobile region that isolates the hydroxylation site and stabilizes the PHD2-Fe2+-2OG complex. The hydroxylation sites of both NODD and CODD of HIFalpha occur within a conserved LXXLAP motif. In the tPHD2-CODD structure, Leu559CODD, Leu562CODD, and Ala563CODD of the LXXLAP motif form part of the CODD310-helix and make hydrophobic interactions with tPHD2	Homo sapiens	hypoxia-inducible transcription factor trans-4-hydroxy-L-proline + succinate + CO2	-	?
additional information	HIF prolyl hydroxylases are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe2+ cofactor and 2-oxoglutarate cosubstrate	Homo sapiens	?	-	?

Subunits

Subunits	Comment	Organism
monomer	although the PHD2 protein is monomeric in solution, the PHD2-Fe2+-inhibitor complexes crystallize in an apparently homotrimeric form	Homo sapiens

Synonyms

Synonyms	Comment	Organism
HIF prolyl hydroxylase	-	Homo sapiens
PHD	-	Homo sapiens
PHD2	-	Homo sapiens
prolyl hydroxylase domain enzyme	-	Homo sapiens

General Information

General Information	Comment	Organism
physiological function	oxygen-dependent hydroxylation of proline residues in the alpha subunit of hypoxia-inducible transcription factor is central to the hypoxic response in animals. Prolyl hydroxylation of HIFalpha increases its binding to the von Hippel-Lindau protein, thus signaling for degradation via the ubiquitin-proteasome system	Homo sapiens