4341
T3D4287
Homogentisic acid
Homogentisic acid, also known as melanic acid, is an intermediate in the breakdown or catabolism of tyrosine and phenylalanine. It is generated from the compound p-hydroxyphenylpyruvate through the enzyme p-hydroxyphenylpyruvate dehydrogenase. The resulting homogentisic acid is then broken down into 4-maleylacetoacetate via the enzyme homogentisate 1,2-dioxygenase. Homogentisic acid is also found in other organisms. For instance, it can found in Arbutus unedo (strawberry-tree) honey, in the bacterial plant pathogen Xanthomonas campestris as well as in the yeast Yarrowia lipolytica where it is associated with the production of brown pigments. Homogentisic acid can be oxidatively dimerized to form hipposudoric acid, one of the main constituents of the 'blood sweat' of hippopotamuses. When present in sufficiently high levels, homogentisic acid can function as an osteotoxin and a renal toxin. An osteotoxin is a substance that causes damage to bones and/or joints. A renal toxin causes damage to the kidneys. Chronically high levels of homogentisic acid are associated with alkaptonuria (OMIM: 203500), an inborn error of metabolism. Alkaptonuria is a rare inherited genetic disorder in which the body cannot process the amino acids phenylalanine and tyrosine. It is caused by a mutation in the enzyme homogentisate 1,2-dioxygenase (EC 1.13.11.5), which leads to an accumulation of homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form benzoquinone acetic acid are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid (and benzoquinone acetic acid) causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones and stones in other organs. More specifically, homogentisic acid can be converted to benzoquinone acetic acid (BQA), and the resulting BQA can be readily converted to polymers that resemble the dark skin pigment melanin. These polymers are deposited in the collagen, a connective tissue protein, of particular tissues such as cartilage. This process is called ochronosis (as the tissue looks ochre); ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage.
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
2018-03-21T17:46:15Z
Homogentisic acid
C00544
44747
DB08327
OMD
true
OC(=O)CC1=CC(O)=CC=C1O
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)
InChIKey=IGMNYECMUMZDDF-UHFFFAOYSA-N
168.1467
168.042258744
Endogenous
Solid
0.86
HMDB00130
759