procollagen-proline dioxygenase

プロコラーゲン・プロリンジオキシゲナーゼ

WordNet

1. an amino acid that is found in many proteins (especially collagen)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/02/19 04:52:11」(JST)

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Procollagen-proline dioxygenase
Alpha subunits of procollagen-proline dioxygenase. Image shows substrate binding region (orange) and the binding groove of tyrosine residues (yellow)
Identifiers
EC number	1.14.11.2
CAS number	9028-06-2
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as 2-oxoglutarate-dependent dioxygenases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires 2-oxoglutarate, Fe²⁺, and ascorbate. This particular enzyme catalyzes the formation of (2S, 4R)-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.

Enzyme Mechanism

Procollagen-proline dioxygenase catalyzes the following reaction:

procollagen L-proline + 2-oxoglutarate + O₂ → (2S, 4R)-4-hydroxyproline + succinate + CO₂

The mechanism for the reaction is similar to that of other dioxygenases, and occurs in two distinct stages: In the first, a highly reactive Fe(IV)=O species is produced. Molecular oxygen is bound end-on in an axial position, producing a dioxygen unit. Nucleophilic attack on C2 generates a tetrahedral intermediate, with loss of the double bond in the dioxygen unit and bonds to iron and the alpha carbon of 2-oxoglutarate. Subsequent elimination of CO₂ coincides with the formation of the Fe(IV)=O species. The second stage involves the abstraction of the pro-R hydrogen atom from C-4 of the proline substrate followed by radical combination, which yields hydroxyproline.

As a consequence of the reaction mechanism, one molecule of 2-oxoglutarate is decarboxylated, forming succinate. This succinate is hydrolyzed and replaced with another 2-oxoglutarate after each reaction, and it has been concluded that in the presence of 2-oxoglutarate, enzyme-bound Fe²⁺ is rapidly converted to Fe³⁺, leading to inactivation of the enzyme. Ascorbate is utilized as a cofactor to reduce Fe³⁺ back to Fe²⁺.

Enzyme Structure

A closer view of the substrate binding domain of prolyl hydroxylase. Tyrosine residues, which form the binding groove, are displayed in yellow.

Prolyl hydroxylase is a tetramer with 2 unique subunits. The α subunit is 59 kDa and is responsible for both peptide binding and for catalytic activity. The peptide binding domain spans residues 140-215 of the α subunit, and consists of a concave surface lined with multiple tyrosine residues which interact favorably with the proline-rich substrate. The active site consists of Fe2+ bound to two histidine residues and one aspartate residue, a characteristic shared by most 2-oxoglutarate-dependent dioxygenases. The 55 kDa β subunit is responsible for the enzyme’s localization to and retention in the endoplasmic reticulum. Interestingly, this subunit is identical to the enzyme known as protein disulfide isomerase.

Biological Function

Prolyl hydroxylase catalyzes the formation of hydroxyproline, which is the most abundant post-translational modification in human body. The modification has a significant impact on the stability of collagen, the major connective tissue of the human body. Specifically, hydroxylation increases the melting temperature (T_m) of helical collagen by 16 °C, as compared to unhydroxylated collagen, a difference that allows the protein to be stable at body temperature.

The enzyme acts specifically on proline contained within the X-Pro-Gly motif – where Pro is proline. Because of this motif-specific behavior, the enzyme also acts on other proteins that contain this same sequence. Such proteins include C1q, elastins, PrP, Argonaute 2, and conotoxins, among others.

Disease Relevance

As prolyl hydroxylase requires ascorbate as a cofactor to function, its absence compromises the enzyme’s activity. The resulting decreased hydroxylation leads to the disease condition known as scurvy. Since stability of collagen is compromised in scurvy patients, symptoms include weakening of blood vessels causing purpura, petechiae, and gingival bleeding.

Hypoxia-inducible factor (HIF) is an evolutionarily conserved transcription factor that allows the cell to respond physiologically to decreases in oxygen. A class of prolyl hydroxylases which act specifically on HIF has been identified; hydroxylation of HIF allows the protein to be targeted for degradation. HIF prolyl-hydroxylase has been targeted by a variety of inhibitors that aim to treat stroke, kidney disease, ischemia, anemia, and other important diseases.

Alternate Names

• Protocollagen hydroxylase
• Prolyl hydroxylase
• Prolyl 4-hydroxylase
• Protocollagen prolyl hydroxylase

References

External links

• Procollagen-proline dioxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)
• Fe(2+) 2-oxoglutarate dioxygenase domain in PROSITE

UpToDate Contents

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English Journal

• NOVEL MUTATIONS IN THE WNT1, TMEM38B, P4HB, AND PLS3 GENES IN FOUR UNRELATED CHINESE FAMILIES WITH OSTEOGENESIS IMPERFECTA.

• Cao YJ, Zhang H, Zhang ZL.
• Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2019 Mar;25(3)230-241.
• Osteogenesis imperfecta (OI) is a group of heritable fragile bone diseases, and the majority are caused by pathogenic variants in the COL1A1 and COL1A2 genes. We sought to identify the genetic causes and phenotypes of OI in Chinese patients without COL1A1 or COL1A2 mutations. Twenty-three patients w
• PMID 30913006

• P4HB knockdown induces human HT29 colon cancer cell apoptosis through the generation of reactive oxygen species and inactivation of STAT3 signaling.

• Zhou Y, Yang J, Zhang Q, Xu Q, Lu L, Wang J, Xia W.
• Molecular medicine reports. 2019 Jan;19(1)231-237.
• Colon cancer is the second most lethal malignancy worldwide. A better understanding of colon cancer at the molecular level may increase overall survival rates. Previous studies have indicated that prolyl 4‑hydroxylase, β polypeptide (P4HB) is associated with tumorigenesis in colon cancer; however
• PMID 30431122

• Gamma linolenic acid regulates PHD2 mediated hypoxia and mitochondrial apoptosis in DEN induced hepatocellular carcinoma.

• Cui H, Han F, Zhang L, Wang L, Kumar M.
• Drug design, development and therapy. 2018 ;12()4241-4252.
• Hepatocellular carcinoma (HCC) is one of the known major health problems across the globe, and is sixth ranked among all cancer, due to its high mortality rate. Polyunsaturated fatty acids (PUFAs) play an important role in the formation of a cell membrane, along with the fluidity of the membrane and
• PMID 30587920

Japanese Journal

• STRUCTURAL ROLE OF 3-HYDROXYPROLINE IN COLLAGEN

• MIZUNO Kazunori,HAYASHI Toshihiko,BACHINGER Hans Peter
• Connective tissue 34(1), 45, 2002-04
• … Certain X positions of the GXY repeated sequence of vertebrate collagens are posttranslationally modified by procollagen-proline 3-dioxygenase (EC 1.14.11.7) to trans-3-L-hydroxyprolyl residue (3Hyp). …
• NAID 110004002453

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★リンクテーブル★

リンク元	「プロコラーゲン・プロリンジオキシゲナーゼ」
関連記事	「dioxygenase」「proline」

「プロコラーゲン・プロリンジオキシゲナーゼ」

　　[★]

英

procollagen-proline dioxygenase

「dioxygenase」

　　[★]

ジオキシゲナーゼ、二原子酸素添加酵素

「proline」

　　[★] プロリン, L-proline, Pro, P