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Introduction and history
Alkaptonuria (AKU) has the distinction of being the disorder that was first designated an inherited metabolic disease, thus leading to the creation and evolution of this branch of medicine. 1 Sir A E Garrod, a chemical pathologist, coined this term for AKU in his lectures to the Royal College of Physicians in 1908. 1 Despite its iconic status, progress in AKU has been slow and there is still no effective treatment for this disease characterised by severe morbidity and significant suffering. Chemical pathology requires indepth understanding of metabolism and with the creation of a metabolic medicine subspeciality in many health systems including the UK, it is appropriate to consider AKU, the archetypal metabolic disease, in this invited review.
Genetic defect
AKU (MIM #203500) is a rare autosomal recessive disorder with a frequency of 1 in 250,000, caused by a deficiency of the enzyme homogentisate 1,2 dioxygenase (HGD; EC 1.13.11.5). 2 This enzyme converts homogentisic acid (HGA) to maleylacetoacetate and has a major role in the catabolism of phenylalanine and tyrosine. The gene defect responsible for AKU was mapped to chromosome 3q13.33 3 and loss of function mutations were identified and confirmed in AKU patients and their families. 4 The HGD gene is 54 363 bp and the protein coding region is organised in 14 exons ranging from 35 to 360 bp to give a 1775 nucleotide transcript that translates as a 445-amino acid protein (NP_000178.2). 5 The crystal structure of the protein showed that it has six subunits that form a dimer of trimers, thus forming a functional hexamer. The subunits contain an N-terminal domain of 280 residues, a C-terminal domain of 140 residues and a central β-sandwich structure. The active site of the enzyme binds iron in a domain that is coordinated by the side chains of His335, Glu341 and His371. 2 6
Metabolic defect
Phenylalanine and tyrosine, from diet and from endogenous protein turnover in vivo, are used to synthesise hormones (such as thyroxine and catecholamines), and melanin as well as new proteins. However, less than 5% of dietary tyrosine is directed to the synthesis of molecules such as hormones, melanin and proteins ( figure 1 ). The majority of dietary tyrosine is metabolised via HGA to malate and...