Citation: Xiaoning Wang, Hongyan Lin, Junjun Liu, Xinyun Zhao, Xi Chen, Wenchao Yang, Guangfu Yang, Chang-guo Zhan. The structure of 4-hydroxylphenylpyruvate dioxygenase complexed with 4-hydroxylphenylpyruvic acid reveals an unexpected inhibition mechanism[J]. Chinese Chemical Letters, ;2021, 32(6): 1920-1924. doi: 10.1016/j.cclet.2021.02.041 shu

The structure of 4-hydroxylphenylpyruvate dioxygenase complexed with 4-hydroxylphenylpyruvic acid reveals an unexpected inhibition mechanism

Xiaoning Wang ^{a, 1} ,
Hongyan Lin ^{b, 1} ,
Junjun Liu ^c ,
Xinyun Zhao ^a ,
Xi Chen ^{a, *,} ,
Wenchao Yang ^{b, *,} ,
Guangfu Yang ^{b, *,} ,
Chang-guo Zhan ^d

a.
College of Chemistry and Material Science, South-Central University for Nationalities, Wuhan 430074, China
b.
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China
c.
School of Pharmacy, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, China
d.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, United States

chen@mail.scuec.edu.cn

tomyang@mail.ccnu.edu.cn

gfyang@mail.ccnu.edu.cn

Received Date: 16 January 2021
Revised Date: 17 February 2021
Accepted Date: 18 February 2021
Available Online: 22 February 2021

Figures(6)

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for both drug and pesticide discovery. As a typical Fe(Ⅱ)-dependent dioxygenase, HPPD catalyzes the complicated transformation of 4-hydroxyphenylpyruvic acid (HPPA) to homogentisic acid (HGA). The binding mode of HPPA in the catalytic pocket of HPPD is a focus of research interests. Recently, we reported the crystal structure of Arabidopsis thaliana HPPD (AtHPPD) complexed with HPPA and a cobalt ion, which was supposed to mimic the pre-reactive structure of AtHPPD-HPPA-Fe(Ⅱ). Unexpectedly, the present study shows that the restored AtHPPD-HPPA-Fe(Ⅱ) complex is still nonreactive toward the bound dioxygen. QM/MM and QM calculations reveal that the HPPA resists the electrophilic attacking of the bound dioxygen by the trim of its phenyl ring, and the residue Phe381 plays a key role in orienting the phenyl ring. Kinetic study on the F381A mutant reveals that the HPPD-HPPA complex observed in the crystal structure should be an intermediate of the substrate transportation instead of the pre-reactive complex. More importantly, the binding mode of the HPPA in this complex is shared with several well-known HPPD inhibitors, suggesting that these inhibitors resist the association of dioxygen (and exert their inhibitory roles) in the same way as the HPPA. The present study provides insights into the inhibition mechanism of HPPD inhibitors.
- 4-Hydroxyphenylpyruvate dioxygenase,
- QM/MM calculation,
- Potential surface scan,
- Substrate self-inhibition
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