Reactome | HPD dioxygenates HPP

HPD dioxygenates HPP

Stable Identifier

R-HSA-71163

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

Synonyms

3-(4-hydroxyphenyl)pyruvate + O2 => CO2 + homogentisate, p-hydroxyphenylpyruvate + O2 => homogentisate + CO2

ReviewStatus

5/5

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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 Unpublished crystallographic data indicate that the enzyme is a homodimer (PDB 3ISQ) utilizing Fe2+ and ascorbate (AscH-).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 Dong, J, Xiao, H, Chen, JN, Zheng, BF, Xu, YL, Chen, MX, Yang, WC, Lin, HY, Yang, GF	Structure	2023
34047349	Functional role of residues involved in substrate binding of human 4-hydroxyphenylpyruvate dioxygenase Huang, CW, Hwang, CC, Chang, YL, Liu, JT, Wu, SP, Huang, KL, Huang, WM, Lee, HJ	Biochem J	2021
5487549	The mechanism of enzymic formation of homogentisate from p-hydroxyphenylpyruvate Lindblad, B, Lindstedt, G, Lindstedt, S	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 Lock, EA, Ellis, MK, Gaskin, P, Robinson, M, Auton, TR, Provan, WM, Smith, LL, Prisbylla, MP, Mutter, LC, 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 Rüetschi, U, Cerone, R, Pérez-Cerda, C, Schiaffino, MC, Standing, S, Ugarte, M, Holme, E	Hum Genet	2000
32750420	Identification of key residues determining the binding specificity of human 4-hydroxyphenylpyruvate dioxygenase Liu, YX, Zhao, LX, Ye, T, Gao, S, Li, JZ, Ye, F, Fu, Y	Eur J Pharm Sci	2020