Beyond catecholamine biosynthesis (see catecholamine_synthesis pathway), tyrosine has a major degradation route through the homogentisic acid (HGA) pathway. Tyrosine → 4-hydroxyphenylpyruvate (TAT) → HGA (HPPD — 4-hydroxyphenylpyruvate dioxygenase) → maleylacetoacetate → fumarylacetoacetate → fumarate + acetoacetate. Enzyme defects: hereditary tyrosinemia type 1 (FAH deficiency — toxic fumarylacetoacetate accumulates; NITISINONE rescues by blocking HPPD upstream); alkaptonuria (HGD deficiency — HGA accumulates, oxidizes to alkapton causing ochronosis + arthritis; nitisinone is also being investigated here). HPPD is the same enzyme inhibited by mesotrione + nitisinone — the latter repurposed from herbicide development for tyrosinemia.
Organ Systems
nervous
endocrine
digestive
Pathway Steps
tyrosine → 4-hydroxyphenylpyruvate — via tyrosine aminotransferase (TAT). Tyrosine aminotransferase (glucocorticoid-induced) begins tyrosine catabolism; its deficiency causes tyrosinemia type II. Tyrosine is also the branch-point substrate for catecholamines, thyroid hormone, and melanin.
4-hydroxyphenylpyruvate → homogentisic-acid — via HPPD (4-hydroxyphenylpyruvate dioxygenase) — NITISINONE TARGET. HPP dioxygenase is the target of nitisinone, used in tyrosinemia type I to block the pathway upstream of the toxic downstream metabolites (and repurposed for alkaptonuria); the same enzyme class is the triketone-herbicide target.
homogentisic-acid → maleylacetoacetate — via HGD — alkaptonuria deficiency. Homogentisate dioxygenase deficiency causes alkaptonuria — homogentisic acid accumulates, darkening urine on standing and depositing as ochronotic pigment in cartilage and joints over decades.
maleylacetoacetate → fumarate-acetoacetate — via FAH — tyrosinemia type 1 deficiency. Fumarylacetoacetate hydrolase finishes catabolism to fumarate (TCA) + acetoacetate (ketogenic). FAH deficiency is tyrosinemia type I, where accumulating fumarylacetoacetate is hepatotoxic/carcinogenic — treated by nitisinone (blocking upstream) plus diet.