Homogentisate 1,2-dioxygenase
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| Image:HGD.jpg | |
| 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. | |
| 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 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.[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.[1]
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.[1] Through the crystal structure the active site was found to contain the following residues; His292, His335, His365, His371, and Glu341.
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.[1] 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.[1] 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.[1]
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.[1] 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.[1]
References
External links
 | This biochemistry article is a stub. You can help WikiDoc by expanding it. |
Oxidoreductases: monooxygenases (EC 1.13) | |
|---|---|
| 1.13.11 - two atoms of oxygen | Catechol dioxygenase - Homogentisate 1,2-dioxygenase - Cysteine dioxygenase - 4-Hydroxyphenylpyruvate dioxygenase - Indoleamine 2,3-dioxygenase - Lipoxygenase (5) |
| 1.13.12 - one atom of oxygen | Firefly luciferase |
| 1.13.99 - other | Inositol oxygenase |
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
