4-Hydroxyphenylpyruvate dioxygenase (HPD) (HPD)

4-Hydroxyphenylpyruvate dioxygenase (HPD) is a key metabolic enzyme that catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate, the second step in the catabolic pathway of tyrosine [1]. The HPD gene is located on the human genomic DNA locus at chromosome 12q24.31 [2]. While loss-of-function mutations in this gene cause rare conditions such as Tyrosinemia type III and Hawkinsinuria, the enzyme is primarily targeted therapeutically to treat Tyrosinemia type I [5]. In Tyrosinemia type I, a downstream enzyme deficiency leads to the accumulation of the toxin succinylacetone; pharmacological inhibition of HPD by nitisinone (NTBC) prevents the formation of this toxin by blocking the pathway upstream [3, 4]. More recently, the HPD genomic locus has become a target for gene-editing technologies like CRISPR/Cas9 and base editing, which aim to provide a permanent knockdown of the enzyme as a one-time treatment for Tyrosinemia type I [6]. Effective inhibition or depletion of HPD requires a low-tyrosine diet to prevent hypertyrosinemia, which can lead to ocular crystals and skin lesions [3]. This target represents a successful application of substrate reduction therapy in metabolic medicine.

Other names

4-hydroxyphenylpyruvic acid oxidase4HPPDHPPDasePPDGLLO4-hydroxyphenylpyruvate dioxygenase gene locus

Competitive inhibition of 4-hydroxyphenylpyruvate dioxygenase to prevent the formation of toxic metabolites upstream of the metabolic block in Tyrosinemia type I.