Taxonomic distribution of proteins containing P4Hc domains

The tree below includes only several representative species and genera. The complete taxonomic breakdown of all proteins containing P4Hc domains can be accessed here. Click the counts or percentage values to display the corresponding proteins.

The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases.

Aravind L, Koonin EV
Genome Biol. 2001; 2: 7-7

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.

The DNA-repair protein AlkB, EGL-9, and leprecan define new families of2-oxoglutarate- and iron-dependent dioxygenases.

Aravind L, Koonin EV
Genome Biol. 2001; 2: 7-7

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.

Prolyl 4-hydroxylase is required for viability and morphogenesis inCaenorhabditis elegans.

Friedman L, Higgin JJ, Moulder G, Barstead R, Raines RT, Kimble J
Proc Natl Acad Sci U S A. 2000; 97: 4736-41

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.

Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with fourcosubstrates and a multifunctional subunit.

Kivirikko KI, Myllyla R, Pihlajaniemi T
FASEB J. 1989; 3: 1609-17

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.

Homology between a prolyl hydroxylase subunit and a tissue protein thatcrossreacts immunologically with the enzyme.

Chen-Kiang S, Cardinale GJ, Udenfriend S
Proc Natl Acad Sci U S A. 1977; 74: 4420-4

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.