SMART: P4Hc domain annotation

P4Hc Prolyl 4-hydroxylase alpha subunit homologues.

SMART accession number:	SM00702
Description:	Mammalian enzymes catalyse hydroxylation of collagen, for example. Prokaryotic enzymes might catalyse hydroxylation of antibiotic peptides. These are 2-oxoglutarate-dependent dioxygenases, requiring 2-oxoglutarate and dioxygen as cosubstrates and ferrous iron as a cofactor.
Interpro abstract (IPR006620):	Mammalian prolyl 4-hydroxylase alpha catalyses the posttranslational formation of 4- hydroxyproline in -xaa-pro-gly-sequences in collagens and other proteins. Prokaryotic enzymes might catalyse hydroxylation of antibiotic peptides. These are 2-oxoglutarate-dependent dioxygenases, requiring 2-oxoglutarate and dioxygen as cosubstrates and ferrous iron as a cofactor [ (PUBMED:11276424) ].
GO process:	oxidation-reduction process (GO:0055114)
GO function:	oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), iron ion binding (GO:0005506), L-ascorbic acid binding (GO:0031418)
Family alignment:	View or

There are 28654 P4Hc domains in 28559 proteins in SMART's nrdb database.

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Evolution (species in which this domain is found)
Taxonomic distribution of proteins containing P4Hc domain.
This tree includes only several representative species. The complete taxonomic breakdown of all proteins with P4Hc domain is also avaliable.

Click on the protein counts, or double click on taxonomic names to display all proteins containing P4Hc domain in the selected taxonomic class.
Cellular role (predicted cellular role)
Binding / catalysis: Proline hydroxylation
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Aravind L, Koonin EV
- The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases.
- Genome Biol. 2001; 2: 7-7
- Display abstract
- BACKGROUND: Protein fold recognition using sequence profile searches frequently allows prediction of the structure and biochemical mechanisms of proteins with an important biological function but unknown biochemical activity. Here we describe such predictions resulting from an analysis of the 2-oxoglutarate (2OG) and Fe(II)-dependent oxygenases, a class of enzymes that are widespread in eukaryotes and bacteria and catalyze a variety of reactions typically involving the oxidation of an organic substrate using a dioxygen molecule. RESULTS: We employ sequence profile analysis to show that the DNA repair protein AlkB, the extracellular matrix protein leprecan, the disease-resistance-related protein EGL-9 and several uncharacterized proteins define novel families of enzymes of the 2OG-Fe(II) oxygenase superfamily. The identification of AlkB as a member of the 2OG-Fe(II) oxygenase superfamily suggests that this protein catalyzes oxidative detoxification of alkylated bases. More distant homologs of AlkB were detected in eukaryotes and in plant RNA viruses, leading to the hypothesis that these proteins might be involved in RNA demethylation. The EGL-9 protein from Caenorhabditis elegans is necessary for normal muscle function and its inactivation results in resistance against paralysis induced by the Pseudomonas aeruginosa toxin. EGL-9 and leprecan are predicted to be novel protein hydroxylases that might be involved in the generation of substrates for protein glycosylation. CONCLUSIONS: Here, using sequence profile searches, we show that several previously undetected protein families contain 2OG-Fe(II) oxygenase fold. This allows us to predict the catalytic activity for a wide range of biologically important, but biochemically uncharacterized proteins from eukaryotes and bacteria.
- Aravind L, Koonin EV
- The DNA-repair protein AlkB, EGL-9, and leprecan define new families of2-oxoglutarate- and iron-dependent dioxygenases.
- Genome Biol. 2001; 2: 7-7
- Display abstract
- BACKGROUND: Protein fold recognition using sequence profile searchesfrequently allows prediction of the structure and biochemical mechanismsof proteins with an important biological function but unknown biochemicalactivity. Here we describe such predictions resulting from an analysis ofthe 2-oxoglutarate (2OG) and Fe(II)-dependent oxygenases, a class ofenzymes that are widespread in eukaryotes and bacteria and catalyze avariety of reactions typically involving the oxidation of an organicsubstrate using a dioxygen molecule. RESULTS: We employ sequence profileanalysis to show that the DNA repair protein AlkB, the extracellularmatrix protein leprecan, the disease-resistance-related protein EGL-9 andseveral uncharacterized proteins define novel families of enzymes of the2OG-Fe(II) oxygenase superfamily. The identification of AlkB as a memberof the 2OG-Fe(II) oxygenase superfamily suggests that this proteincatalyzes oxidative detoxification of alkylated bases. More distanthomologs of AlkB were detected in eukaryotes and in plant RNA viruses,leading to the hypothesis that these proteins might be involved in RNAdemethylation. The EGL-9 protein from Caenorhabditis elegans is necessaryfor normal muscle function and its inactivation results in resistanceagainst paralysis induced by the Pseudomonas aeruginosa toxin. EGL-9 andleprecan are predicted to be novel protein hydroxylases that might beinvolved in the generation of substrates for protein glycosylation.CONCLUSIONS: Here, using sequence profile searches, we show that severalpreviously undetected protein families contain 2OG-Fe(II) oxygenase fold.This allows us to predict the catalytic activity for a wide range ofbiologically important, but biochemically uncharacterized proteins fromeukaryotes and bacteria.
- Friedman L, Higgin JJ, Moulder G, Barstead R, Raines RT, Kimble J
- Prolyl 4-hydroxylase is required for viability and morphogenesis inCaenorhabditis elegans.
- Proc Natl Acad Sci U S A. 2000; 97: 4736-41
- Display abstract
- The genome of Caenorhabditis elegans possesses two genes, dpy-18 andphy-2, that encode alpha subunits of the enzyme prolyl 4-hydroxylase. Wehave generated deletions within each gene to eliminate prolyl4-hydroxylase activity from the animal. The dpy-18 mutant has an aberrantbody morphology, consistent with a role of prolyl 4-hydroxylase information of the body cuticle. The phy-2 mutant is phenotypically wildtype. However, the dpy-18; phy-2 double mutant is not viable, suggestingan essential role for prolyl 4-hydroxylase that is normally accomplishedby either dpy-18 or phy-2. The effects of the double mutation weremimicked by small-molecule inhibitors of prolyl 4-hydroxylase, validatingthe genetic results and suggesting that C. elegans can serve as a modelsystem for the discovery of new inhibitors.
- Kivirikko KI, Myllyla R, Pihlajaniemi T
- Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with fourcosubstrates and a multifunctional subunit.
- FASEB J. 1989; 3: 1609-17
- Display abstract
- Prolyl 4-hydroxylase (EC 1.14.11.2) catalyzes the formation of4-hydroxyproline in collagens by the hydroxylation of proline residues inX-Pro-Gly sequences. The reaction requires Fe2+, 2-oxoglutarate, O2, andascorbate and involves an oxidative decarboxylation of 2-oxoglutarate.Ascorbate is not consumed during most catalytic cycles, but the enzymealso catalyzes decarboxylation of 2-oxoglutarate without subsequenthydroxylation, and ascorbate is required as a specific alternative oxygenacceptor in such uncoupled reaction cycles. A number of compounds inhibitprolyl 4-hydroxylase competitively with respect to some of itscosubstrates or the peptide substrate, and recently many suicideinactivators have also been described. Such inhibitors and inactivatorsare of considerable interest, because the prolyl 4-hydroxylase reactionwould seem a particularly suitable target for chemical regulation of theexcessive collagen formation found in patients with various fibroticdiseases. The active prolyl 4-hydroxylase is an alpha 2 beta 2 tetramer,consisting of two different types of inactive monomer and probablycontaining two catalytic sites per tetramer. The large catalytic site maybe cooperatively built up of both the alpha and beta subunits, but thealpha subunit appears to contribute the major part. The beta subunit hasbeen found to be identical to the enzyme protein disulfide isomerase and amajor cellular thyroid hormone-binding protein and shows partial homologywith a phosphoinositide-specific phospholipase C, thioredoxins, and theestrogen-binding domain of the estrogen receptor. The COOH-terminus ofthis beta subunit has the amino acid sequence Lys-Asp-Glu-Leu, which wasrecently suggested to be necessary for the retention of a polypeptidewithin the lumen of the endoplasmic reticulum. The alpha subunit does nothave this COOH-terminal sequence, and thus one function of the betasubunit in the prolyl 4-hydroxylase tetramer appears to be to retain theenzyme within this cell organelle.
- Chen-Kiang S, Cardinale GJ, Udenfriend S
- Homology between a prolyl hydroxylase subunit and a tissue protein thatcrossreacts immunologically with the enzyme.
- Proc Natl Acad Sci U S A. 1977; 74: 4420-4
- Display abstract
- A protein, enzymatically inactive but immunologically related to prolylhydroxylase (prolyl-glycyl-peptide, 2-oxoglutarate:oxygen oxidoreductase;EC 1.14.11.2) (cross-reacting protein), has been purified to nearhomogeneity from skin of newborn rats. The purified protein has amolecular weight of 60,000 on gel filtration and sodium dodecyl sulfategel electrophoresis, corresponding to that of the smaller of the twodissimilar subunits of the enzyme. The two subunits of prolyl hydroxylasediffer markedly from one another in their amino acid compositions, butcrossreating protein and the smaller subunit are very similar incomposition. On antibody-affinity chromatography both subunits reactedwith the antibody developed against the intact enzyme. Neithercrossreacting protein nor the 60,000 molecular weight subunit was adsorbedonto concanavalin A, which adsorbed the intact enzyme as well as thelarger subunit. It would appear that crossreacting protein is identical toone of the subunits of prolyl hydroxylase or metabolically related to it.
Metabolism (metabolic pathways involving proteins which contain this domain)

Structure (3D structures containing this domain)

3D Structures of P4Hc domains in PDB

PDB code	Main view	Title
2g19		Cellular Oxygen Sensing: Crystal Structure of Hypoxia-Inducible Factor Prolyl Hydroxylase (PHD2)
2g1m		Cellular Oxygen Sensing: Crystal Structure of Hypoxia-Inducible Factor Prolyl Hydroxylase (PHD2)
2hbt		Crystal structure of HIF prolyl hydroxylase EGLN-1 in complex with a biologically active inhibitor
2hbu		Crystal structure of HIF prolyl hydroxylase EGLN-1 in complex with a biologically active inhibitor
2jig		Crystal structure of Chlamydomonas reinhrdtii prolyl-4 hydroxylase type I complexed with zinc and pyridine-2,4-dicarboxylate
2jij		Crystal structure of the apo form of Chlamydomonas reinhardtii prolyl- 4 hydroxylase type I
2v4a		Crystal structure of the SeMet-labeled prolyl-4 hydroxylase (P4H) type I from green algae Chlamydomonas reinhardtii.
2y33		S-nitrosylated PHD2 (GSNO soaked) in complex with Zn(II) and UN9
2y34		S-nitrosylated PHD2 (NO exposed) in complex with Fe(II) and UN9
3dkq		Crystal structure of Putative Oxygenase (YP_001051978.1) from SHEWANELLA BALTICA OS155 at 2.26 A resolution
3gze		Algal prolyl 4-hydroxylase complexed with zinc and (Ser-Pro)5 peptide substrate
3hqr		PHD2:Mn:NOG:HIF1-alpha substrate complex
3hqu		PHD2:Fe:UN9:partial HIF1-alpha substrate complex
3itq		Crystal Structure of a Prolyl 4-Hydroxylase from Bacillus anthracis
3kt1		Crystal structure of Tpa1 from Saccharomyces cerevisiae, a component of the messenger ribonucleoprotein complex
3kt4		Crystal structure of Tpa1 from Saccharomyces cerevisiae, a component of the messenger ribonucleoprotein complex
3kt7		Crystal structure of Tpa1 from Saccharomyces cerevisiae, a component of the messenger ribonucleoprotein complex
3mgu		Saccharomyces cerevisiae Tpa1
3ouh		PHD2-R127 with JNJ41536014
3oui		PHD2-R717 with 40787422
3ouj		PHD2 with 2-Oxoglutarate
4bqw		HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with Mn(II) and 2-(4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid
4bqx		HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with Mn(II) and N-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]glycine (IOX3/UN9)
4bqy		HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with Fe(II) and N-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]alanine
4iw3		Crystal structure of a Pseudomonas putida prolyl-4-hydroxylase (P4H) in complex with elongation factor Tu (EF-Tu)
4j25		Crystal structure of a Pseudomonas putida prolyl-4-hydroxylase (P4H)
4jzr		Structure of Prolyl Hydroxylase Domain-containing Protein (PHD) with Inhibitors
4kbz		Crystal Structure of Hypoxia-Inducible Factor Prolyl Hydroxylase (PHD2) with (S)-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid
4nhk		4NHK
4nhl		4NHL
4nhm		4NHM
4nhx		4NHX
4nhy		4NHY
4uwd		4UWD
5a3u		5A3U
5c5t		5C5T
5c5u		5C5U
5hv0		5HV0
5hv4		5HV4
5iat		5IAT
5iav		5IAV
5iax		5IAX
5l9b		5L9B
5l9r		5L9R
5l9v		5L9V
5la9		5LA9
5las		5LAS
5lat		5LAT
5lb6		5LB6
5lbb		5LBB
5lbc		5LBC
5lbe		5LBE
5lbf		5LBF

Links (links to other resources describing this domain)
INTERPRO IPR006620

P4Hc

Taxonomic distribution of proteins containing P4Hc domain.

3D Structures of P4Hc domains in PDB