homogentisate 1,2-dioxygenase

ホモゲンチジン酸-1

関

homogentisic acid oxidase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/08 21:45:36」(JST)

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homogentisate 1,2-dioxygenase 3D rendering of Homogentisate Dioxygenase with active site amino acid residues and Iron atom colored. Histidine is the tan color, Glutamate the red color, and Iron is the blue. Identifiers EC number 1.13.11.5 CAS number 9029-49-6 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 homogentisate 1,2-dioxygenase (homogentisate oxidase) Identifiers Symbol HGD Alt. symbols AKU Entrez 3081 HUGO 4892 OMIM 607474 RefSeq XM_001125882 UniProt Q93099 Other data EC number 1.13.11.5 Locus Chr. 3 q21-q23

Homogentisate 1,2-dioxygenase (homogentisic acid oxidase, homogentisicase) is an enzyme, which catalyzes the conversion of homogentisate to 4-maleylacetoacetate. Homogentisate 1,2-dioxygenase or HGD is involved in the catabolism of aromatic rings, more specifically in the breakdown of the amino acids tyrosine and phenylalanine. HGD appears in the metabolic pathway of tyrosine and phenylalanine degradation once the molecule homogentisate is produced. Homogentisate reacts with HGD to produce maleylacetoacetate, which then is further used in the metabolic pathway. HGD requires the use of Fe²⁺ and O₂ in order to cleave the aromatic ring of homogentisate.

• homogentisate

• 4-maleylacetoacetate

Enzyme Active Site

The active site of Homogentisate 1,2-dioxygenase was determined through the crystal structure, which was captured through the work of Titus et al. Through the crystal structure the active site was found to contain the following residues; His292, His335, His365, His371, and Glu341.

Active Site of HGD containing His335, His371, Glu341, and the Fe²⁺ atom

Homogentisate binds in the active site to Glu341, His335, and His371 via the Fe2+ atom. The His292 binds to the hydroxyl group of the aromatic ring. His365 binds to Glu341 via hydrogen bonding to stabilize the amino acid side chains.

Pathology

Homegentisate 1,2 dioxygenase is involved in a type of metabolic diseases, called alkaptonuria. This disorder is due to the inability of the body to deal with homogentisate, which when oxidized by the body will produce the compound known as the ochronotic pigment, which causes a black color, and has several negative effects. This first of these effects is that the patient’s earwax will begin to turn black or red, depends on the patient’s diet, since the blood becomes oxidized and thus turns black due to excess of the ochronotic pigment. The other effect of the ochronotic pigment is that it can accumulate in the body’s connective tissue leading to degenerative arthritis, as the person grows older. Alkaptonuria has another effect in that it can cause the urine to turn black as well if let to sit for long enough to become oxidized, though is this often a method for testing for the genetic defect. The metabolic disease is autosomal recessive, such that both parents must pass the gene on to their children in order for child to have the defect.

Mechanism

Borowski et al. propose a mechanism for HGD in their article featured in the Journal of the American Chemistry. They base their mechanism on results from hybrid DFT calculations with B3LYP functionals using the programs Gaussian03 and Jaguar. The opening of the aromatic ring in homogentisate is a multi-step process. In the first two steps Fe²⁺ coordinates to the carbonyl and ortho phenol oxygens. The iron atom is also coordinated to His335, His371, and Glu341. O₂ then binds to the iron atom., subsequently reacting with the aromatic ring to form a peroxo-bridged intermediate.

In the next step, O₂ is cleaved with the formation of an epoxide. This epoxide intermediate allowing radical reactions to eventually open and oxidize the six-membered ring.

• Steps 1-8 of the mechanism

• Steps 9-11 of the mechanism

References

External links

• GeneReviews/NCBI/NIH/UW entry on Alkaptonuria
• OMIM entries on Alkaptonuria
• Homogentisate 1,2-Dioxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)

English Journal

• Homogentisate 1,2 dioxygenase is expressed in human osteoarticular cells: Implications in alkaptonuria.

• Laschi M, Tinti L, Braconi D, Millucci L, Ghezzi L, Amato L, Selvi E, Spreafico A, Bernardini G, Santucci A.SourceDipartimento di Biotecnologie, Università degli Studi di Siena, Siena Italy.
• Journal of cellular physiology.J Cell Physiol.2012 Sep;227(9):3254-7. doi: 10.1002/jcp.24018.
• Alkaptonuria (AKU) results from defective homogentisate1,2-dioxygenase (HGD), causing degenerative arthropathy. The deposition of ochronotic pigment in joints is so far attributed to homogentisic acid produced by the liver, circulating in the blood and accumulating locally. Human normal and AKU oste
• PMID 22105303

• Novel mutations in the homogentisate 1,2 dioxygenase gene identified in Jordanian patients with alkaptonuria.

• Al-Sbou M.SourceDepartment of Pharmacology, Alkaptonuria Research Office, Faculty of Medicine, Mutah University, P.O. Box: (7), Mutah, karak, 61710, Jordan, malsbou@mutah.edu.jo.
• Rheumatology international.Rheumatol Int.2012 Jun;32(6):1741-6. Epub 2011 Mar 25.
• This study was conducted to identify mutations in the homogentisate 1,2 dioxygenase gene (HGD) in alkaptonuria patients among Jordanian population. Blood samples were collected from four alkaptonuria patients, four carriers, and two healthy volunteers. DNA was isolated from peripheral blood. All 14
• PMID 21437689

Japanese Journal

• Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients

• Am J Hum Genet 62, 776-784, 1998
• NAID 30017635458

Related Links

• HOMOGENTISATE 1,2-DIOXYGENASE; HGD - OMIM ...

TEXT Description The HGD gene encodes homogentisate 1,2-dioxygenase (HGD; EC 1.13.11.5), an enzyme involved in the catabolism of phenylalanine and ...

• Homogentisate 1,2-dioxygenase (IPR005708) < InterPro ...

InterPro provides functional analysis of proteins by classifying them into families and predicting domains and important sites. We combine protein signatures from a number of member databases into a single searchable resource ...

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★リンクテーブル★

リンク元	「ホモゲンチジン酸酸化酵素」「ホモゲンチジン酸-1,2-ジオキシゲナーゼ」
関連記事	「dioxygenase」「homogentisate」

「ホモゲンチジン酸酸化酵素」

　　[★]

英

homogentisic acid oxidase

同

ホモゲンチジン酸-1,2-ジオキシゲナーゼ ホモゲンチジン酸オキシダーゼ homogentisate 1,2-dioxygenase

• チロシン分解系酵素

臨床関連

• アルカプトン尿症

「ホモゲンチジン酸-1,2-ジオキシゲナーゼ」

　　[★]

英

homogentisate 1

• homogentisate 1,2-dioxygenase

関

ホモゲンチジン酸酸化酵素

「dioxygenase」

　　[★]

ジオキシゲナーゼ、二原子酸素添加酵素

「homogentisate」

　　[★]

• ホモゲンチジン酸

関

homogentisic acid