Homogentisate 1,2-dioxygenase

protein
Name=homogentisate 1,2-dioxygenase (homogentisate oxidase)
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.

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350px
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

Homogentisate 1,2-dioxygenase 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 break down of the amino acids tyrosine and phenylalanine.cite journal | author = Titus, Greg P | title = Crystal structure of human homogentisate dioxygenase | journal = Nature Structural Biology | volume = 7 | issue = 7 | pages = 542–546 | year = 2000 | pmid = | doi = | issn = ] 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.cite journal | author = Borowski, Tomasz | title = Catalytic Reaction Mechanism ofHomogentisate Dioxygenase: A Hybrid DFT Study | journal = Journal of American Chemical Society | volume = 127 | issue = | pages = 17303–17314 | year = 2005 | pmid = | doi = | issn = ]

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 and et al. Through the crystal structure the active site was found to contain the following residues; His292, His335, His365, His371, and Glu341. 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.http://en.wikipedia.org/wiki/Alkaptonuria] 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 thusly 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 forchild to have the defect.

Mechanism

Borowski et al. propose a mechanism for HGD in their article featured in the Journal of the American Chemistry. The authors propose this mechanism based on computational data using the programs Gaussian03 and Jaguar to perform a hybrid DFT with B3LYP exchange-correlation functional. DFT or Density functional theory is a quantum mechanics method for determining the ground state of compounds. The mechanism for 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. After this step O₂ binds to the iron atom. In the next step the O₂ reacts with the aromatic ring to form a peroxo-bridged intermediate. This is when there is a C-O-O-Fe in the molecule, and thus called peroxo-bridged because of the oxygen bound to another oxygen. The next major step is that the O₂ is cleaved. This causes the eventual formation of an epoxide ring attached to the 6-member ring. The other oxygen atom from the O₂ then attacks the double bond oxygen on the 6-member ring. This oxygen is then removed from the iron atom.The next step involves the epoxide ring breaking to allow the oxygen to form a double bond, and causing the previously attacked oxygen double bond on the ring to reform. The final step is then to deprotonated the hydroxyl group and form the ketone. Thus forming maleylacetoacetate.

References

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