WordNet

street name for lysergic acid diethylamide (同)back breaker, battery-acid, dose, dot, Elvis, loony toons, Lucy in the sky with diamonds, pane, superman, window pane, Zen
any of various water-soluble compounds having a sour taste and capable of turning litmus red and reacting with a base to form a salt
having the characteristics of an acid; "an acid reaction"
any of the enzymes that catalyze biological oxidation

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酸性の / 酸味のある,すっぱい(sour) / (言葉・態度などが)厳しい,しんらつな / 酸 / すっぱいもの / 《俗》=LSD

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/08/13 15:21:44」(JST)

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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.^[1] 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.^[2]

homogentisate
4-maleylacetoacetate

Enzyme Active Site[edit source | edit]

The active site of Homogentisate 1,2-dioxygenase was determined through the crystal structure, which was captured through the work of Titus et al.^[1] 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[edit source | edit]

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.^{[citation needed]} 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.^[2] 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.^{[citation needed]}

Mechanism[edit source | edit]

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.,^[2] 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[edit source | edit]

^ ^a ^b Titus, Greg P; Mueller, HA; Burgner, J; Rodríguez De Córdoba, S; Peñalva, MA; Timm, DE (2000). "Crystal structure of human homogentisate dioxygenase". Nature Structural Biology 7 (7): 542–546. doi:10.1038/76756. PMID 10876237.
^ ^a ^b ^c Borowski, Tomasz; Georgiev, V; Siegbahn, PE (2005). "Catalytic Reaction Mechanism of Homogentisate Dioxygenase: A Hybrid DFT Study". Journal of American Chemical Society 127 (49): 17303–17314. doi:10.1021/ja054433j. PMID 16332080.

External links[edit source | edit]

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)

UpToDate Contents

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5. 慢性肉芽腫性疾患：病因、臨床症状、および診断 chronic granulomatous disease pathogenesis clinical manifestations and diagnosis

English Journal

Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy.

Nemethova M1, Radvanszky J1, Kadasi L1,2, Ascher DB3, Pires DE3, Blundell TL3, Porfirio B4, Mannoni A5, Santucci A6, Milucci L6, Sestini S7, Biolcati G8, Sorge F8, Aurizi C8, Aquaron R9, Alsbou M10, Marques Lourenço C11, Ramadevi K12, Ranganath LR13, Gallagher JA14, van Kan C15, Hall AK16, Olsson B17, Sireau N18, Ayoob H18, Timmis OG18, Le Quan Sang KH19, Genovese F20, Imrich R21, Rovensky J21, Srinivasaraghavan R22, Bharadwaj SK23, Spiegel R24, Zatkova A1.
European journal of human genetics : EJHG.Eur J Hum Genet.2016 Jan;24(1):66-72. doi: 10.1038/ejhg.2015.60. Epub 2015 Mar 25.
Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-
PMID 25804398

Proteomic analysis of Chromobacterium violaceum and its adaptability to stress.

Castro D1,2, Cordeiro IB3,4, Taquita P5, Eberlin MN6, Garcia JS7, Souza GH8, Arruda MA9, Andrade EV10, Filho SA11, Crainey JL12, Lozano LL13, Nogueira PA14, Orlandi PP15.
BMC microbiology.BMC Microbiol.2015 Dec 1;15:272. doi: 10.1186/s12866-015-0606-2.
BACKGROUND: Chromobacterium violaceum (C. violaceum) occurs abundantly in a variety of ecosystems, including ecosystems that place the bacterium under stress. This study assessed the adaptability of C. violaceum by submitting it to nutritional and pH stresses and then analyzing protein expression us
PMID 26627076

Renal and prostate stones composition in alkaptonuria: a case report.

Wolff F, Biaou I, Koopmansch C, Vanden Bossche M, Pozdzik A, Roumeguère T, Cotton F.
Clinical nephrology.Clin Nephrol.2015 Dec;84(12):339-42. doi: 10.5414/CN108608.
Alkaptonuria is a genetic disorder characterized by an accumulation of homogentisic acid due to an enzymatic defect of homogentisate 1,2 dioxygenase. The homogentisic acid is excreted exclusively by both glomerular filtration and tubular secretion leading to the renal parenchyma being exposed to hig
PMID 26396096

Japanese Journal

A Rare Case of Acquired Methemoglobinemia Associated with Alkaptonuria

, , , , , , , ,
Internal Medicine 53(16), 1797-1800, 2014
… Alkaptonuria is a congenital error of metabolism caused by the deficiency of homogentisic acid oxidase, which subsequently results in the accumulation of homogentisic acid (HGA) in body tissues. …
NAID 130004678402

人工関節置換術を行ったアルカプトン尿症性股関節症の１例

宮澤慎一,松下具敬,金子真也,甲斐信生
中国・四国整形外科学会雑誌 19(2), 251-255, 2007
… And the urine turned black after alkalization and homogentisic acid was detected. … 1 year after the total hip arthroplasty, she can walk with a cane without pain and the prosthesis has no loosening.Alcaptonuria is rare hereditary metabolic disorder that results from a deficiency of the enzyme homogentisic acid oxidase. …
NAID 130004438402

Ochronotic Arthropathy Requiring Bilateral Hip and Knee Joint Arthroplasty : Case Study

, , , , , , ,
日本リウマチ・関節外科学会雑誌 25(4), 489-496, 2006-12-31
… Ochronosis is a rare disease caused by an inherited lack of homogentisic acid oxidase. … It is associated with various systemic abnormalities and related to the deposition of homogentisic acid pigment in connective tissues. …
NAID 10018722615

Related Pictures

★リンクテーブル★

リンク元	「ホモゲンチジン酸酸化酵素」「homogentisate 1,2-dioxygenase」
関連記事	「homogentisic acid」

「ホモゲンチジン酸酸化酵素」

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

Search
PMC	articles
PubMed	articles
NCBI	proteins

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