The HGD gene, responsible for coding the enzyme homogentisate 1,2-dioxygenase (also known as homogentisate oxidase), is situated on chromosome 3, specifically in the region 3q21-q23. This enzyme primarily functions in the liver and kidneys, where it is essential for breaking down the amino acids phenylalanine and tyrosine. Through earlier steps, these amino acids are transformed into homogentisic acid. Homogentisate oxidase then incorporates two oxygen atoms into homogentisic acid, converting it into maleylacetoacetate. Subsequent enzymes further decompose maleylacetoacetate into smaller molecules that the body uses for energy or other purposes.Over 40 different mutations in the HGD gene have been discovered in individuals with alkaptonuria. Many of these mutations result in single amino acid changes in the homogentisate oxidase enzyme. The most prevalent mutation in European populations involves the substitution of methionine with valine at position 368 (Met368Val). These mutations likely disrupt the enzyme's function by altering its structure. Without functional homogentisate oxidase, homogentisic acid accumulates in the body, depositing in connective tissues such as cartilage and skin, causing them to darken and become brittle. Additionally, homogentisic acid appears in urine, turning it black upon exposure to air.
