Homogentisate 1,2-dioxygenase

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homogentisate 1,2-dioxygenase
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MetaCycmetabolic pathway
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homogentisate 1,2-dioxygenase (homogentisate oxidase)
Identifiers
SymbolHGD
Alt. symbolsAKU
Chr. 3 q21-q23
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StructuresSwiss-model
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Homogentisate 1,2-dioxygenase (homogentisic acid oxidase, homogentisate oxidase, homogentisicase) is an

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
    homogentisate
  • 4-maleylacetoacetate
    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.[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

Homegentisate 1,2 dioxygenase is involved in a type of metabolic diseases, called

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
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

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

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 1-8 of the mechanism
  • Steps 9-11 of the mechanism
    Steps 9-11 of the mechanism

References

  1. ^
    S2CID 6219553
    .
  2. ^
    PMID 16332080
    .

External links
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