Product analysis and inhibition studies of a causative Asn to Ser variant of 4-hydroxyphenylpyruvate dioxygenase suggest a simple route to the treatment of Hawkinsinuria.

Hawkinsinuria is a severe inherited condition that has a significant impact on the health of infants. The disease manifests as metabolic acidosis that significantly slows the growth rate and induces persistent diarrhea and vomiting. Though other causes may exist, an autosomal dominant mutation that alters codon 241 of the 4-hydroxyphenylpyruvate dioxygenase (HPPD) gene from encoding an asparagine to encoding a serine gives rise to the symptoms of the disease. The observed pattern of dominance of this mutation belies the paucity of reports of this disease in the literature and suggests that it may be rarely diagnosed. Diagnosis is based on the presence of 2-amino-3-{[2-(carboxymethyl)-2,5-dihydroxy-1-cyclohex-3-enyl]sulfanyl}propanoic acid (hawkinsin) in the urine. We have made the structurally equivalent mutation in the Streptomyces avermitilis (N245S) and rat (N241S) genes and shown that in both cases the N to S variant enzyme forms quinolacetic acid in place of the native product 2,5-dihydroxyphenylacet...