Editing Alkaptonuria (section)

==Pathophysiology==
[[File:Homogentisic acid.svg|thumb|right|Chemical [[skeletal formula]] of homogentisic acid, which accumulates in the body fluids of people with alkaptonuria.]]
All people carry in their DNA two copies (one received from each parent) of the gene ''HGD'', which contains the genetic information to produce the enzyme [[homogentisate 1,2-dioxygenase]] (HGD) which can normally be found in numerous tissues in the body (liver, kidney, small intestine, colon, and prostate). In people with alkaptonuria, both copies of the gene contain abnormalities that mean that the body cannot produce an adequately functioning enzyme.<ref name=Zatkova2011>{{cite journal |author =Zatkova A |title=An update on molecular genetics of Alkaptonuria (AKU) |journal=J. Inherit. Metab. Dis. |volume=34 |issue=6 |pages=1127–36 |date=December 2011  |pmid=21720873 |doi=10.1007/s10545-011-9363-z |s2cid=32395461 }}</ref> ''HGD'' mutations are generally found in certain parts ([[exon]]s 6, 8, 10, and 13), but a total of over 100 abnormalities has been described throughout the gene.<ref name=Zatkova2011/> The normal HGD enzyme is a hexamer (it has six subunits) that are organized in two groups of three (two trimers) and contains an [[Ferrous|iron atom]]. Different mutations may affect the structure, function, or solubility of the enzyme.<ref name=Zatkova2011/> Very occasionally, the disease appears to be transmitted in an autosomal-dominant fashion, where a single abnormal copy of ''HGD'' from a single parent is associated with alkaptonuria;  other mechanisms or defects in other genes possibly are responsible in those cases.<ref name=Zatkova2011/>

[[File:Inborn errors of metabolism of phenylalanine and tyrosine.svg|800px|centre|thumb|Pathophysiology of alkaptonuria (AKU) is due to the absence of functional homogentisate dioxygenase (HGD) in the liver.]]
The HGD enzyme is involved in the metabolism (chemical processing) of the [[aromatic amino acids]] [[phenylalanine]] and [[tyrosine]]. Normally, these enter the bloodstream through protein-containing food and the natural turnover of protein in the body. Tyrosine is specifically required for a number of functions, such as [[hormone]]s (e.g. [[thyroxine]], the thyroid hormone), [[melanin]] (the dark pigment in the skin and hair), and certain proteins, but the vast majority (over 95%) is unused and is metabolized through a [[Tyrosine#Degradation|group of enzymes]] that eventually generate [[acetoacetate]] and [[malate]].<ref name=Ranganath/> In alkaptonuria, the HGD enzyme cannot metabolize the homogentisic acid (generated from tyrosine) into [[4-maleylacetoacetate]], and homogentisic acid levels in the blood are 100-fold higher than would normally be expected, despite the fact that a substantial amount is eliminated into the urine by the kidneys.<ref name=Ranganath/>

The homogentisic acid is converted to the related substance benzoquinone acetic acid  which forms [[polymer]]s that resemble the skin pigment melanin. These 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.<ref name=Ranganath/>