homogentisic acid oxidase

**Enzyme and pathway:** Phenylalanine → (phenylalanine hydroxylase, BH4) → tyrosine → (tyrosine transaminase) → 4-hydroxyphenylpyruvate → (4-HPPD) → homogentisic acid → (homogentisate 1,2-dioxygenase, a.k.a. homogentisic acid oxidase; requires Fe2+ and O2) → 4-maleylacetoacetate → fumarylacetoacetate (fumarylacetoacetate hydrolase) → fumarate + acetoacetate. Tyrosine is therefore both glucogenic (fumarate) and ketogenic (acetoacetate). The enzyme is expressed mainly in the liver and kidney.

**Disease: Alkaptonuria (ochronosis)** - Inheritance: autosomal recessive; HGD gene on chromosome 3q. It is a rare disorder, and it is benign early in life. - Pathophysiology: Loss of enzyme function causes homogentisic acid to accumulate. It is excreted in urine, and it also oxidizes and polymerizes into a melanin-like pigment (benzoquinone acetic acid) that deposits in connective tissue, especially cartilage and collagen-rich tissue. - Clinical features: - Urine that turns dark brown or black on standing or with alkalinization (oxidation of homogentisic acid). It may be noticed as dark diapers in infancy. - Ochronosis: blue-black pigmentation of the sclera, ear cartilage, nose, and skin over the hands. Also dark sweat and cerumen. - Arthropathy: onset in the 30s–40s. It affects the spine (low back pain, loss of lumbar lordosis, intervertebral disc calcification) and large joints (knees, hips, shoulders). It resembles premature osteoarthritis. Intervertebral disc calcification on X-ray is a classic finding. - Cardiovascular: aortic stenosis and mitral valve calcification, coronary calcification. - Others: renal and prostate stones. - Diagnosis: Elevated homogentisic acid in urine (urine organic acid analysis, GC-MS), and urine darkening with NaOH. Genetic testing for HGD mutations confirms it. - Treatment: Supportive. This includes a low-protein diet (restricting phenylalanine and tyrosine), vitamin C (limited evidence), and joint replacement as needed. Nitisinone (a 4-HPPD inhibitor) reduces homogentisic acid production. It is approved for alkaptonuria in some regions, and it can cause tyrosinemia and ocular side effects.

**High-yield board pearls:** - Alkaptonuria is not the same as other tyrosine-pathway disorders: - Phenylketonuria: phenylalanine hydroxylase or BH4 deficiency. Presents with a musty odor, intellectual disability, and hypopigmentation. - Tyrosinemia type I: fumarylacetoacetate hydrolase deficiency. Presents with liver failure, a cabbage-like odor, and renal tubular dysfunction. - Tyrosinemia type II: tyrosine transaminase deficiency. Presents with keratitis and palmoplantar keratosis. - Albinism: tyrosinase deficiency. Presents with a lack of melanin. - Classic vignette: A middle-aged adult with back pain and arthritis, dark ear cartilage, and urine that darkens on standing. - Intelligence and lifespan are largely normal. Morbidity is from arthropathy and cardiac valve disease.