Homogentisate 1,2-dioxygenase (HGD) (HGD)

Homogentisate 1,2-dioxygenase (HGD) is a vital enzyme in the catabolic pathway of the amino acids phenylalanine and tyrosine (UniProt P23730). It specifically catalyzes the oxidative cleavage of the aromatic ring of homogentisate (homogentisic acid) to produce 4-maleylacetoacetate. A deficiency in HGD activity, typically due to genetic mutations, results in Alkaptonuria, a metabolic disorder where homogentisic acid and its oxidized form, benzoquinone acetic acid, accumulate in the body (NIH GARD). This accumulation leads to ochronosis—a bluish-black pigmentation of connective tissues—and severe, early-onset osteoarthritis. While HGD itself is the site of the primary defect in Alkaptonuria, pharmacological intervention currently focuses on inhibiting the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) using Nitisinone to reduce the production of the HGD substrate (PubMed 32814493). Future therapeutic directions may include enzyme replacement therapy or gene editing to restore functional HGD activity.

Other names

Homogentisic acid oxidaseHomogentisicaseHGOHomogentisate oxygenase

Substrate reduction therapy via inhibition of upstream 4-hydroxyphenylpyruvate dioxygenase (HPPD) to prevent homogentisate accumulation; potential for enzyme replacement or gene therapy to restore HGD function (PubMed 32814493).