View source for Biology:Homogentisate 1,2-dioxygenase

{{Short description|Enzyme}}
{{stack begin}}
{{infobox enzyme
| Name       = homogentisate 1,2-dioxygenase
| EC_number  = 1.13.11.5
| CAS_number = 9029-49-6
| GO_code    = 0004411
| image      = Illustration of Homogentisate 1,2-dioxygenase.jpg
| width      =
| caption    = 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. 
}}
{{protein
|Name=homogentisate 1,2-dioxygenase (homogentisate oxidase)
|caption=
|image=
|width=
|HGNCid=4892
|Symbol=HGD
|AltSymbols=AKU
|EntrezGene=3081
|OMIM=607474
|RefSeq=XM_001125882
|UniProt=Q93099
|PDB=
|ECnumber=1.13.11.5
|Chromosome=3
|Arm=q
|Band=21
|LocusSupplementaryData=-q23
}}
{{stack end}}

'''Homogentisate 1,2-dioxygenase''' ('''homogentisic acid oxidase''', '''homogentisate oxidase''', '''homogentisicase''') is an [[Biology:Enzyme|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 [[Chemistry:Tyrosine|tyrosine]] and [[Chemistry:Phenylalanine|phenylalanine]].<ref name=autogenerated1>{{cite journal | vauthors = Titus GP, Mueller HA, Burgner J, Rodríguez De Córdoba S, Peñalva MA, Timm DE | title = Crystal structure of human homogentisate dioxygenase | journal = Nature Structural Biology | volume = 7 | issue = 7 | pages = 542–6 | date = Jul 2000 | pmid = 10876237 | doi = 10.1038/76756 | hdl = 10261/71724 | s2cid = 6219553 | hdl-access = free }}</ref> 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 Fe<sup>2+</sup> and O<sub>2</sub> in order to cleave the aromatic ring of homogentisate.<ref name=autogenerated3>{{cite journal | vauthors = Borowski T, Georgiev V, Siegbahn PE | title = Catalytic reaction mechanism of homogentisate dioxygenase: a hybrid DFT study | journal = Journal of the American Chemical Society | volume = 127 | issue = 49 | pages = 17303–14 | date = Dec 2005 | pmid = 16332080 | doi = 10.1021/ja054433j }}</ref>

<gallery>
Image:Homogentisic acid.svg|homogentisate
Image:4-maleylacetoacetic acid.svg|4-maleylacetoacetate
</gallery>

==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.<ref name=autogenerated1 /> Through the crystal structure the active site was found to contain the following residues; His292, His335, His365, His371, and Glu341. [[Image:Active site2.png|thumb|left|Active Site of HGD containing His335, His371, Glu341, and the Fe<sup>2+</sup> atom|300px]] Homogentisate binds in the active site to Glu341, His335, and His371 via the Fe<sup>2+</sup> 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 [[Medicine:Alkaptonuria|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|date=March 2011}}
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.<ref name=autogenerated3 /> 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|date=March 2011}}

==Mechanism==
Borowski et al. propose a mechanism for HGD in their article featured in the Journal of the American Chemical Society. They base their mechanism on results from hybrid [[Density functional theory|DFT]] calculations with B3LYP functionals using the programs [[Software:Gaussian|Gaussian03]] and [[Software:Jaguar|Jaguar]]. The opening of the aromatic ring in homogentisate is a multi-step process. In the first two steps Fe<sup>2+</sup> coordinates to the carbonyl and ortho phenol oxygens. The iron atom is also coordinated to His335, His371, and Glu341. O<sub>2</sub> then binds to the iron atom,<ref name=autogenerated3 /> subsequently reacting with the aromatic ring to form a peroxo-bridged intermediate.

In the next step, O<sub>2</sub> is cleaved with the formation of an [[Chemistry:Epoxide|epoxide]]. This epoxide intermediate allowing radical reactions to eventually open and oxidize the six-membered ring.

<gallery>
File:Mech01.jpg|Steps 1-8 of the mechanism
File:Mech02.jpg|Steps 9-11 of the mechanism
</gallery>

== References ==
{{Reflist}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1454/  GeneReviews/NCBI/NIH/UW entry on Alkaptonuria]
* [https://www.ncbi.nlm.nih.gov/omim/203500,607474,203500,607474  OMIM entries on Alkaptonuria]
* {{MeshName|Homogentisate+1,2-Dioxygenase}}

{{Monooxygenases}}
{{Amino acid metabolism enzymes}}

[[Category:EC 1.13.11]]

{{Sourceattribution|Homogentisate 1,2-dioxygenase}}