HPD

HPD Full Name

4-hydroxyphenylpyruvate dioxygenase

HPD Introduction

4-Hydroxyphenylpyruvate dioxygenase (HPD) is a non-heme iron-dependent enzyme that catalyzes the second committed step in the tyrosine catabolic pathway. Encoded by the HPD gene on chromosome 12q24.31, HPD is predominantly expressed in the liver, with lower levels in the kidney, and localizes to the cytosol. The enzyme converts 4-hydroxyphenylpyruvate (HPP) to homogentisate (2,5-dihydroxyphenylacetate) through a complex oxidative decarboxylation and hydroxylation reaction that involves molecular oxygen and requires both ferrous iron and ascorbate as cofactors. This reaction is a key step in the complete degradation of the aromatic amino acid tyrosine to fumarate and acetoacetate.

Figure 1. Strcuture of 4-hydroxyphenylpyruvate dioxygenase.

Catalytic Mechanism and Structural Features
HPD is a homodimeric enzyme belonging to the α/β-hydrolase superfamily. Each subunit contains a catalytic ferrous iron atom coordinated by a conserved 2-histidine-1-carboxylate facial triad motif (His183, His267, Glu349 in the human enzyme). The reaction mechanism proceeds through a high-valent Fe(IV)-oxo intermediate that attacks the aromatic ring of HPP, initiating a NIH-shift rearrangement that incorporates one atom of molecular oxygen into the aromatic ring while the other oxygen atom is released as water. The reaction requires ascorbate to maintain the iron center in its reduced, catalytically active Fe(II) state. The product homogentisate is then further metabolized by homogentisate 1,2-dioxygenase (HGD) in the next step of the pathway.

HPD in Inborn Errors of Metabolism and Drug Development
Hereditary deficiency of HPD activity causes tyrosinemia type III (OMIM #276710), a rare autosomal recessive disorder characterized by elevated blood tyrosine levels and urinary excretion of 4-hydroxyphenylpyruvate and related metabolites. Clinical features range from asymptomatic biochemical abnormalities to intellectual disability, ataxia, seizures, and intermittent ataxia. Diagnosis is confirmed by plasma amino acid analysis, urinary organic acid profiling, and molecular genetic testing. Therapeutically, HPD is the molecular target of nitisinone (NTBC, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione), a potent and specific HPD inhibitor used as first-line therapy for hereditary tyrosinemia type I (caused by fumarylacetoacetate hydrolase deficiency). By blocking the pathway upstream of the toxic metabolite fumarylacetoacetate, nitisinone prevents liver failure and hepatocellular carcinoma in affected patients. HPD inhibitors are also under investigation for alkaptonuria, a disease caused by downstream HGD deficiency.

Alternate Names for HPD

HPD; 4-hydroxyphenylpyruvate dioxygenase; PPD; 4 HPPD; 4HPPD; GLOD3; glyoxalase domain containing 3; 4 HPPD; 4 hydroxyphenylpyruvate dioxygenase; 4 hydroxyphenylpyruvic acid oxidase; 4HPPD; GLOD3; glyoxalase domain containing 3; HPPDase; PPD; OTTHUMP00000