Alkaptonuria is one of the earliest known diseases resulting from an "inborn error of metabolism" as described by Archibald Garrod in 1909. It is caused by biallelic mutations in the HGD gene , which encodes for a key metabolic enzyme, homogentisate 1,2dioxygenase, responsible for the breakdown of homogentisic acid (2,5dihydroxyphenylacetic acid; HGA, chemical structure in Supplementary Fig. ). In the tyrosine-phenylalanine catabolic pathway , HGA is released from the liver and circulates at high levels in AKU patients. HGA is hypothesized to oxidize to BQA (Supplementary Fig. )