HPD dioxygenates HPP

Stable Identifier
Reaction [transition]
Homo sapiens
p-hydroxyphenylpyruvate + O2 => homogentisate + CO2
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Cytosolic 4-hydroxyphenylpyruvate dioxygenase (HPD, HPPD) catalyzes the reaction of 3-(4-Hydroxyphenyl)pyruvate (HPP, 4-HPPA) with molecular oxygen to form homogentisate and CO2 (Ruetschi et al. 2000, Lindblad et al. 1970). Unpublished crystallographic data indicate that the enzyme is a homodimer (PDB 3ISQ) utilizing Fe2+ and ascorbate (AscH-). Other structures have Co2+ as a cofactor (5EC3, 8IM2; Dong et al., 2023). However, most studies of the catalytic activity assume Fe2+ is the cofactor (e.g., Liu et al., 2020; Huang et al., 2021). Inhibitors of HPD prevent the toxic effects of accumulated metabolites in tyrosinemia type I. Nitisinone was approved in 2002 by the FDA for this purpose (Lock et al., 1998; McKiernan, 2006). Mutations in HPD can lead to tyrosinemia type III (TYRSN3, MIM:276710; reviewed in Scott, 2006).
Literature References
PubMed ID Title Journal Year
16706549 Nitisinone in the treatment of hereditary tyrosinaemia type 1

McKiernan, PJ

Drugs 2006
37794595 Structure-based discovery of pyrazole-benzothiadiazole hybrid as human HPPD inhibitors

Yang, WC, Zheng, BF, Lin, HY, Dong, J, Xiao, H, Chen, MX, Chen, JN, Yang, GF, Xu, YL

Structure 2023
34047349 Functional role of residues involved in substrate binding of human 4-hydroxyphenylpyruvate dioxygenase

Liu, JT, Wu, SP, Hwang, CC, Huang, KL, Lee, HJ, Huang, CW, Chang, YL, Huang, WM

Biochem J 2021
5487549 The mechanism of enzymic formation of homogentisate from p-hydroxyphenylpyruvate

Lindblad, B, Lindstedt, S, Lindstedt, G

J. Am. Chem. Soc. 1970
9728330 From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug

Mutter, LC, Auton, TR, Prisbylla, MP, Gaskin, P, Provan, WM, Ellis, MK, Smith, LL, Robinson, M, Lock, EA, Lee, DL

J Inherit Metab Dis 1998
16602095 The genetic tyrosinemias

Scott, CR

Am J Med Genet C Semin Med Genet 2006
10942115 Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III

Schiaffino, MC, Standing, S, Pérez-Cerda, C, Rüetschi, U, Holme, E, Ugarte, M, Cerone, R

Hum Genet 2000
32750420 Identification of key residues determining the binding specificity of human 4-hydroxyphenylpyruvate dioxygenase

Gao, S, Ye, F, Ye, T, Liu, YX, Li, JZ, Zhao, LX, Fu, Y

Eur J Pharm Sci 2020
Catalyst Activity

4-hydroxyphenylpyruvate dioxygenase activity of HPD:AscH-:Fe2+ dimer [cytosol]

This event is regulated
Orthologous Events
Cross References
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