Page last updated: 2024-10-24

peptidyl-proline hydroxylation to 4-hydroxy-L-proline

Definition

Target type: biologicalprocess

The modification of peptidyl-proline to form 4-hydroxy-L-proline; catalyzed by procollagen-proline,2-oxoglutarate-4-dioxygenase. [RESID:AA0030]

Peptidyl-proline hydroxylation to 4-hydroxy-L-proline is a crucial enzymatic process that modifies proline residues within proteins. This post-translational modification is catalyzed by prolyl 4-hydroxylases (P4Hs) which are a family of dioxygenases that require molecular oxygen, ferrous iron, and the cofactor ascorbate (vitamin C) for their activity. The reaction involves the addition of a hydroxyl group to the 4-position of the proline ring, transforming proline into 4-hydroxy-L-proline (Hyp). This modification significantly influences the structure and function of proteins by:

* **Increasing protein stability**: The introduction of a hydroxyl group into the proline ring enhances the rigidity and stability of the protein structure, particularly within collagen triple helix domains.
* **Modulating protein interactions**: The presence of Hyp alters protein-protein interactions, influencing the assembly and function of protein complexes.
* **Regulating protein folding**: Hyp residues play a crucial role in guiding the proper folding of proteins, particularly those involved in extracellular matrix assembly.

The hydroxylation of proline is a tightly regulated process with diverse physiological implications. For example, in collagen biosynthesis, the hydroxylation of proline residues is essential for the formation of stable collagen fibrils. Hydroxylation of proline residues within hypoxia-inducible factor (HIF) proteins regulates their stability and activity, influencing cellular responses to low oxygen conditions.

The enzymatic mechanism of P4Hs involves a series of steps:

1. **Binding of the proline-containing peptide substrate to the P4H enzyme.**
2. **Activation of molecular oxygen by the enzyme's ferrous iron center.**
3. **Hydroxylation of the proline residue at the 4-position.**
4. **Release of the modified peptide and water.**

Defects in P4Hs or deficiencies in the required cofactors can lead to various diseases, including scurvy, osteogenesis imperfecta, and Ehlers-Danlos syndrome. Understanding the intricacies of proline hydroxylation and its impact on protein structure and function is crucial for developing therapeutic strategies for these and other related conditions.
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Proteins (7)

ProteinDefinitionTaxonomy
Prolyl 4-hydroxylase subunit alpha-1[no definition available]Gallus gallus (chicken)
Prolyl 4-hydroxylase subunit alpha-1A prolyl 4-hydroxylase subunit alpha-1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P13674]Homo sapiens (human)
Transmembrane prolyl 4-hydroxylaseA transmembrane prolyl 4-hydroxylase that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9NXG6]Homo sapiens (human)
Prolyl hydroxylase EGLN3A prolyl hydroxylase EGLN3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9H6Z9]Homo sapiens (human)
Egl nine homolog 1An egl nine homolog 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9GZT9]Homo sapiens (human)
Prolyl hydroxylase EGLN2A prolyl hydroxylase EGLN2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96KS0]Homo sapiens (human)
Protein disulfide-isomeraseA protein disulfide-isomerase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P07237]Homo sapiens (human)

Compounds (48)

CompoundDefinitionClassesRoles
2,3-dihydroxybenzoic acid2,3-dihydroxybenzoic acid : A dihydroxybenzoic acid that is benzoic acid substituted by hydroxy groups at positions 2 and 3. It occurs naturally in Phyllanthus acidus and in the aquatic fern Salvinia molesta.

2,3-dihydroxybenzoic acid: RN given refers to parent cpd

dihydroxybenzoic acid : Any member of the class of hydroxybenzoic acids carrying two phenolic hydroxy groups on the benzene ring and its derivatives.
dihydroxybenzoic acidhuman xenobiotic metabolite;
plant metabolite
alpha-ketoglutaric acid2-oxoglutaric acid : An oxo dicarboxylic acid that consists of glutaric acid bearing an oxo substituent at position 2. It is an intermediate metabolite in Krebs cycle.oxo dicarboxylic acidfundamental metabolite
protocatechuic acid3,4-dihydroxybenzoic acid : A dihydroxybenzoic acid in which the hydroxy groups are located at positions 3 and 4.

protocatechuic acid: RN given refers to parent cpd; structure
catechols;
dihydroxybenzoic acid
antineoplastic agent;
EC 1.1.1.25 (shikimate dehydrogenase) inhibitor;
EC 1.14.11.2 (procollagen-proline dioxygenase) inhibitor;
human xenobiotic metabolite;
plant metabolite
4-hydroxybenzoic acid4-hydroxybenzoic acid : A monohydroxybenzoic acid that is benzoic acid carrying a hydroxy substituent at C-4 of the benzene ring.monohydroxybenzoic acidalgal metabolite;
plant metabolite
catecholcatecholsallelochemical;
genotoxin;
plant metabolite
salicylic acidScalp: The outer covering of the calvaria. It is composed of several layers: SKIN; subcutaneous connective tissue; the occipitofrontal muscle which includes the tendinous galea aponeurotica; loose connective tissue; and the pericranium (the PERIOSTEUM of the SKULL).monohydroxybenzoic acidalgal metabolite;
antifungal agent;
antiinfective agent;
EC 1.11.1.11 (L-ascorbate peroxidase) inhibitor;
keratolytic drug;
plant hormone;
plant metabolite
gallic acidgallate : A trihydroxybenzoate that is the conjugate base of gallic acid.trihydroxybenzoic acidantineoplastic agent;
antioxidant;
apoptosis inducer;
astringent;
cyclooxygenase 2 inhibitor;
EC 1.13.11.33 (arachidonate 15-lipoxygenase) inhibitor;
geroprotector;
human xenobiotic metabolite;
plant metabolite
3,4-dihydroxyphenylacetic acid(3,4-dihydroxyphenyl)acetic acid : A dihydroxyphenylacetic acid having the two hydroxy substituents located at the 3- and 4-positions. It is a metabolite of dopamine.

3,4-Dihydroxyphenylacetic Acid: A deaminated metabolite of LEVODOPA.

dihydroxyphenylacetic acid : A dihydroxy monocarboxylic acid consisting of phenylacetic acid having two phenolic hydroxy substituents.
catechols;
dihydroxyphenylacetic acid
human metabolite
glucono-1,4-lactonegamma-lactone
hydroquinonebenzenediol;
hydroquinones
antioxidant;
carcinogenic agent;
cofactor;
Escherichia coli metabolite;
human xenobiotic metabolite;
mouse metabolite;
skin lightening agent
phenylacetic acidphenylacetic acid : A monocarboxylic acid that is toluene in which one of the hydrogens of the methyl group has been replaced by a carboxy group.benzenes;
monocarboxylic acid;
phenylacetic acids
allergen;
Aspergillus metabolite;
auxin;
EC 6.4.1.1 (pyruvate carboxylase) inhibitor;
Escherichia coli metabolite;
human metabolite;
plant growth retardant;
plant metabolite;
Saccharomyces cerevisiae metabolite;
toxin
picolinic acidpicolinic acid : A pyridinemonocarboxylic acid in which the carboxy group is located at position 2. It is an intermediate in the metabolism of tryptophan.

picolinic acid: iron-chelating agent that inhibits DNA synthesis; may interfere with iron-dependent production of stable free organic radical which is essential for ribonucleotide reductase formation of deoxyribonucleotides; RN given refers to parent cpd; structure in Merck Index, 9th ed, #7206
pyridinemonocarboxylic acidhuman metabolite;
MALDI matrix material
pyrogallolbenzenetriol : A triol in which three hydroxy groups are substituted onto a benzene ring.benzenetriol;
phenolic donor
plant metabolite
succinic acidsuccinic acid : An alpha,omega-dicarboxylic acid resulting from the formal oxidation of each of the terminal methyl groups of butane to the corresponding carboxy group. It is an intermediate metabolite in the citric acid cycle.

Succinic Acid: A water-soluble, colorless crystal with an acid taste that is used as a chemical intermediate, in medicine, the manufacture of lacquers, and to make perfume esters. It is also used in foods as a sequestrant, buffer, and a neutralizing agent. (Hawley's Condensed Chemical Dictionary, 12th ed, p1099; McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed, p1851)
alpha,omega-dicarboxylic acid;
C4-dicarboxylic acid
anti-ulcer drug;
fundamental metabolite;
micronutrient;
nutraceutical;
radiation protective agent
isocitric acidisocitric acid : A tricarboxylic acid that is propan-1-ol with a hydrogen at each of the 3 carbon positions replaced by a carboxy group.

isocitric acid: RN given refers to unlabeled parent cpd
secondary alcohol;
tricarboxylic acid
fundamental metabolite
mandelic acidSAMMA: mandelic acid condensation polymer2-hydroxy monocarboxylic acid;
benzenes
antibacterial agent;
human xenobiotic metabolite
2,2'-dipyridyl2,2'-bipyridine : A bipyridine in which the two pyridine moieties are linked by a bond between positions C-2 and C-2'.

2,2'-Dipyridyl: A reagent used for the determination of iron.
bipyridinechelator;
ferroptosis inhibitor
beta-resorcylic acidbeta-resorcylic acid: RN given refers to parent cpd; structure
fusaric acidFusaric Acid: A picolinic acid derivative isolated from various Fusarium species. It has been proposed for a variety of therapeutic applications but is primarily used as a research tool. Its mechanisms of action are poorly understood. It probably inhibits DOPAMINE BETA-HYDROXYLASE, the enzyme that converts dopamine to norepinephrine. It may also have other actions, including the inhibition of cell proliferation and DNA synthesis.aromatic carboxylic acid;
pyridines
2,5-dihydroxybenzoic acid2,5-dihydroxybenzoic acid : A dihydroxybenzoic acid having the two hydroxy groups at the 2- and 5-positions.

2,5-dihydroxybenzoic acid: RN given refers to parent cpd; a oxidative product of saligenin
dihydroxybenzoic acidEC 1.13.11.33 (arachidonate 15-lipoxygenase) inhibitor;
fungal metabolite;
human metabolite;
MALDI matrix material;
mouse metabolite
resorcinolresorcinol : A benzenediol that is benzene dihydroxylated at positions 1 and 3.

resorcinol: RN given refers to parent cpd; structure in Merck Index, 9th ed, #7951
benzenediol;
phenolic donor;
resorcinols
erythropoietin inhibitor;
sensitiser
succinylacetone4,6-dioxoheptanoic acid : A dioxo monocarboxylic acid that is heptanoic acid in which oxo groups replace the hydrogens at positions 4 and 6. It is an abnormal metabolite of the tyrosine metabolic pathway and a marker for type 1 tyrosinaemia.

succinylacetone: inhibitor of heme biosynthesis
beta-diketone;
dioxo monocarboxylic acid
human metabolite
3-hydroxybenzoic acid3-hydroxybenzoic acid : A monohydroxybenzoic acid that is benzoic acid substituted by a hydroxy group at position 3. It has been isolated from Taxus baccata. It is used as an intermediate in the synthesis of plasticisers, resins, pharmaceuticals, etc.

3-hydroxybenzoic acid: RN given refers to parent cpd
monohydroxybenzoic acidbacterial metabolite;
plant metabolite
alpha-resorcylic acid3,5-dihydroxybenzoic acid : A dihydroxybenzoic acid in which the hydroxy groups are located at positions 3 and 5.

alpha-resorcylic acid: RN given refers to parent cpd
dihydroxybenzoic acid;
resorcinols
metabolite
2,5-pyridinedicarboxylic acid2,5-Pyridinedicarboxylic acid: RN given refers to parent cpd

isocinchomeronic acid : A pyridinedicarboxylic acid carrying carboxy groups at positions 2 and 5.
pyridinedicarboxylic acid
gamma-resorcylic aciddihydroxybenzoic acidmetabolite
glycyrrhetinic acidcyclic terpene ketone;
hydroxy monocarboxylic acid;
pentacyclic triterpenoid
immunomodulator;
plant metabolite
salicyluratesalicylurate : A monocarboxylic acid anion that is the conjugate base of salicyluric acid, obtained by deprotonation of the carboxy group; major species at pH 7.3.

salicylurate: RN given refers to parent cpd

salicyluric acid : An N-acylglycine in which the acyl group is specified as 2-hydroxybenzoyl.
N-acylglycine;
secondary carboxamide
human xenobiotic metabolite;
uremic toxin
2,4-pyridinedicarboxylic acidlutidinic acid : A pyridinedicarboxylic acid carrying carboxy groups at positions 2 and 4.pyridinedicarboxylic acid
oleanolic acidhydroxy monocarboxylic acid;
pentacyclic triterpenoid
plant metabolite
daminozidedaminozide: induces tumorsstraight-chain fatty acid
ursolic acidhydroxy monocarboxylic acid;
pentacyclic triterpenoid
geroprotector;
plant metabolite
betulinic acidhydroxy monocarboxylic acid;
pentacyclic triterpenoid
anti-HIV agent;
anti-inflammatory agent;
antimalarial;
antineoplastic agent;
EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor;
plant metabolite
maslinic acid(2Alpha,3beta)-2,3-dihydroxyolean-12-en-28-oic acid: from Luehea divaricata and Agrimonia eupatoriadihydroxy monocarboxylic acid;
pentacyclic triterpenoid
anti-inflammatory agent;
antineoplastic agent;
antioxidant;
plant metabolite
3,4-dihydroxymandelic acid3,4-dihydroxymandelic acid : A catechol that is the 3,4-dihydroxy derivative of mandelic acid; a metabolite of L-dopa.

3,4-dihydroxymandelic acid: metabolite of L-dopa; RN given refers to parent cpd without isomeric designation
2-hydroxy monocarboxylic acid;
catechols
antioxidant;
drug metabolite;
human metabolite;
mouse metabolite
3,4-dihydroxyphenylpropionic acid3-(3,4-dihydroxyphenyl)propanoic acid : A monocarboxylic acid that is 3-phenylpropionic acid substituted by hydroxy groups at positions 3 and 4. Also known as dihydrocaffeic acid, it is a metabolite of caffeic acid and exhibits antioxidant activity.

3,4-dihydroxyphenylpropionic acid: metabolite of caffeic acid; RN given refers to parent cpd; structure
(dihydroxyphenyl)propanoic acidantioxidant;
human xenobiotic metabolite
fumaric acidfumaric acid : A butenedioic acid in which the C=C double bond has E geometry. It is an intermediate metabolite in the citric acid cycle.

fumaric acid: see also record for ferrous fumarate; use FUMARATES for general fumaric acid esters
butenedioic acidfood acidity regulator;
fundamental metabolite;
geroprotector
5-carboxy-8-hydroxyquinoline5-carboxy-8-hydroxyquinoline: a JmjC histone demethylase inhibitor; structure in first sourcequinolines
isoliquiritigeninchalconesantineoplastic agent;
biological pigment;
EC 1.14.18.1 (tyrosinase) inhibitor;
GABA modulator;
geroprotector;
metabolite;
NMDA receptor antagonist
caffeic acidtrans-caffeic acid : The trans-isomer of caffeic acid.caffeic acidgeroprotector;
mouse metabolite
oxalylglycineN-oxalylglycine : An amino dicarboxylic acid that is iminodiacetic acid with an oxo substituent. It is used as an inhibitor of alpha-ketoglutarate dependent (EC 1.14.11.*) enzymes.

oxalylglycine: structure given in first source
amino dicarboxylic acid;
N-acylglycine
EC 1.14.11.* (oxidoreductase acting on paired donors, 2-oxoglutarate as one donor, incorporating 1 atom each of oxygen into both donors) inhibitor
galangin5,7-dihydroxyflavonol: antimicrobial from the twigs of Populus nigra x Populus deltoides; structure in first source

galangin : A 7-hydroxyflavonol with additional hydroxy groups at positions 3 and 5 respectively; a growth inhibitor of breast tumor cells.
7-hydroxyflavonol;
trihydroxyflavone
antimicrobial agent;
EC 3.1.1.3 (triacylglycerol lipase) inhibitor;
plant metabolite
fg-4592roxadustat : An N-acylglycine resulting from the formal condensation of the amino group of glycine with the carboxy group of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid. It is an inhibitor of hypoxia inducible factor prolyl hydroxylase (HIF-PH).

roxadustat: structure in first source
aromatic ether;
isoquinolines;
N-acylglycine
EC 1.14.11.2 (procollagen-proline dioxygenase) inhibitor;
EC 1.14.11.29 (hypoxia-inducible factor-proline dioxygenase) inhibitor
jnj 42041935
ascorbic acidAscorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant.

L-ascorbate : The L-enantiomer of ascorbate and conjugate base of L-ascorbic acid, arising from selective deprotonation of the 3-hydroxy group. Required for a range of essential metabolic reactions in all animals and plants.

L-ascorbic acid : The L-enantiomer of ascorbic acid and conjugate acid of L-ascorbate.

vitamin C : Any member of a group of vitamers that belong to the chemical structural class called butenolides that exhibit biological activity against vitamin C deficiency in animals. The vitamers include L-ascorbic acid and its salt, ionized and oxidized forms.
ascorbic acid;
vitamin C
coenzyme;
cofactor;
flour treatment agent;
food antioxidant;
food colour retention agent;
geroprotector;
plant metabolite;
skin lightening agent
2-[[[4-hydroxy-2-oxo-1-(phenylmethyl)-3-quinolinyl]-oxomethyl]amino]acetic acidquinolines
bay 85-3934
gsk1278863daprodustat : A member of the class of barbiturates that is barbituric acid substituted by cyclohexyl groups at positions 1 and 3, and by a (carboxymethyl)aminocarbonyl group at position 5. It is an inhibitor of hypoxia-inducible factor prolyl hydroxylase developed by GlaxoSmithKline for the treatment of anaemia in patients with chronic kidney disease.

GSK1278863: a HIF prolyl hydroxylase inhibitor