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

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

Authors :
Hong-Yan Lin
Xinyun Zhao
Guang-Fu Yang
Junjun Liu
Chang-Guo Zhan
Wen-Chao Yang
Xi Chen
Xiaoning Wang
Source :
Chinese Chemical Letters. 32:1920-1924
Publication Year :
2021
Publisher :
Elsevier BV, 2021.

Abstract

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.

Details

ISSN :
10018417
Volume :
32
Database :
OpenAIRE
Journal :
Chinese Chemical Letters
Accession number :
edsair.doi...........bf92d5fc7137b32d037341f28057496f
Full Text :
https://doi.org/10.1016/j.cclet.2021.02.041