4341 Homogentisic acid Homogentisic acid is an intermediate of the metabolic breakdown of tyrosine and phenylalanine; it occurs in the urine in cases of alkaptonuria. (OMIN 203500) Homogentisic acid is the primary precursor of melanin synthesis in Vibrio cholerae. 451-13-8 780 C8H8O4 White powder. 153°C 850 mg/mL at 25°C Extremely high levels of homogentisic acid are found in patients with the inborn error of metabolism (IEM) called Alkaptonuria. Homogentisic acid spontaneously undergoes oxidation into benzoquinone acetic acid (BQA), which polymerizes forming plasma soluble melanins (PSM). The PSM darkens many tissues (ochronosis - as the tissue looks like ochre), and produces widespread degenerative changes in cartilage and other connective tissues, joints, blood vessels, heart valves and the kidneys. Ochronotic tissue is stiff and unusually brittle. The accumulation of PSM in chondrocytes (the cells that form cartilage) leads to profound alterations in the levels of proteins involved in cell defense, protein folding, and cell organization. An increased post-translational oxidation of proteins, which also involved high molecular weight protein aggregates, has been found to be particularly evident in chondrocytes from patients with alkaptonuria. No indication of carcinogenicity to humans (not listed by IARC). Homogentisic acid is only toxic under chronic exposure. One of the first symptoms of alkaptonuria is darkening of urine on standing (due to the oxidation of homogentisic acid). In most pediatric patients, darkening of urine is the only feature suggesting alkaptonuria. Most patients are usually asymptomatic until age 30. Scleral pigmentation usually starts around age 30. Skin pigmentation becomes obvious by the time patients reach age 40. One of the first sites to be affected is the ear cartilage. There may be discoloration of the forehead, cheeks, axilla, genitalia, palms, nails and soles. Ochronotic arthropathy starts around the 4th decade. Weight-bearing joints like the knees and the intervertebral joints in the spine, as well as the shoulder joints, are involved, with narrowing of joint spaces and disc calcifications. Arthritis is the only disabling effect of this condition and occurs in almost all patients as age advances. Ochronotic arthropathy can be so severe as to require total joint replacement. Pigment deposits can be seen in the larynx, tonsils, esophagus, dura mater, eardrums, trachea, and bronchi. Aortic or mitral valvulitis, calcification of coronary arteries and atherosclerotic plaques are seen after the age of 50 years. Apart from treatment of the complications (such as pain relief using NSAIDs and joint replacement for the cartilage damage), vitamin C has been used to reduce the ochronosis and lowering of the homogentisic acid levels may be attempted with a low-protein diet. Recently the drug nitisinone has been found to suppress homogentisic acid production. Nitrisinone inhibits the enzyme, 4-hydroxyphenylpyruvate dioxygenase, responsible for converting tyrosine to homogentisic acid, thereby blocking the production and accumulation of homogentisic acid. Nitisinone treatment has been shown to cause a 95% reduction in plasma and urinary homogentisic acid. 2014-08-29T06:15:36Z 2026-04-03T00:35:15Z Homogentisic acid C00544 44747 DB08327 OMD true OC(=O)CC1=C(O)C=CC(O)=C1 C8H8O4 InChI=1S/C8H8O4/c9-6-1-2-7(10)5(3-6)4-8(11)12/h1-3,9-10H,4H2,(H,11,12) IGMNYECMUMZDDF-UHFFFAOYSA-N 168.1467 168.042258744 Endogenous Solid 0.86 HMDB00130 759 CHEM003247 DTXSID1060005 2-(2,5-dihydroxyphenyl)acetic acid