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On June 12th 2017, the research groups of Prof. Hongwei Guo from the Biology Department of SUSTech and Prof. Junyu Xiao from Peking University published their joint research paper entitled “Pyrazinamide and derivatives block ethylene biosynthesis by inhibiting ACC oxidase” on Nature Communications Online.
The plant hormone ethylene gas plays important roles in plant growth and development, defense response, as well as adaption to stress. Ethylene is also involved in the regulation of fruit ripening and senescence, which has unique value in the management of postharvest fruits, vegetables and flowers. A high level of ethylene bioproduction will reduce their shelf life, leading to huge postharvest losses and problems of food safety. In China, the annual loss of postharvest fruits and vegetables has reached several hundred million yuan. Therefore, specific and safe ethylene action inhibitors will have great economic and social benefits.
For this purpose, prof. Hongwei Guo’s Group developed a plant chemical genetics approach, using Arabidopsis ethylene overproduction mutant eto1-2 and constitutive ethylene response mutant ctr1-1 to screen a small chemical library with 2000 compounds, and identified 3 small chemicals: kynurenine (KYN), ponalrestat (PRT) and pyrazinamide (PZA), which inhibit ethylene biosynthesis or signaling. Their early research has reported that KYN inhibits TAA1/TARs, a key enzyme of auxin biosynthesis downstream of ethylene signaling (He et al., 2011 Plant Cell), and recently they found that PRT also targets another key enzyme of auxin biosynthesis downstream of ethylene signaling, and the related works is prepared for pubilcation.
Unlike KYN and PRT, PZA specifically inhibits the “triple responses” of ethylene overproduction mutant eto1-2 (fig. A). PZA treatment inhibits the ethylene responses induced by ethylene precursor ACC, suggesting that PZA may function through inhibiting ACC oxidase (ACO). In vitro biochemical analysis shows that PZA dosen’t inhibit ACO activity directly, and needs to be transformed into pyrazinoic acid (POA) by Arabidopsis nicotinamidase (fig. B), and then competitively inhibits the catalytic activity of ACO in the form of POA.
Cooperating with Junyu Xiao’s group, Hongwei Guo’s group further analyzes the crystal structure of the complex of Arabidopsis ACO2 and POA (2.1 A), and reveals the inhibition mechanism at the atomic level (fig. C and D). The crystal structure shows that POA interacts with ACO2 through the formation of coordination bonds with Zn2+ or Fe2+ in the active site of ACO2. In addition, hydrogen bonds, hydrophobic interactions, and Fan Dehua forces between POA and its surrounding amino acids also reinforce its binding to ACO2. Through the mutation of the key amino acids of ACO2 protein involving in interacting with POA, they further prove that POA or its analogue 2-PA can mimic ACC, the endogenous substrate of ACO, thus competitively inhibit ACO activity. These results not only illustrate the inhibitory mechanism of POA at the atomic level, but also provide a theoretical basis for further structural optimization of POA to enhance its potency.
A. PZA specifically inhibits the ethylene response of eto1-2.
B. PZA can be transformed into POA by Arabidopsis NICs.
C. The crystal structure of the complex of Arabidopsis ACO2 and POA.
D. Molecular details of the interaction between POA and ACO2.
Interestingly, PZA is a widely used anti-TB first-line drug, and in M. tuberculosis, PZA also needs to be converted into its active form, POA, to play a bacteriostatic role. Although the possible target proteins have been reported, it is still controversial about the action mechanism of PZA/POA in anti-TB. This study reports that in plant, POA inhibits ACO activity by binding Fe2+ and specific amino acid sites in the active site of ACO protein. Similarly, in M. tuberculosis, it is reported that Fe and anaerobic environment can promote the antibacterial activity of PZA, implying that there may be a oxidoreductase similar to ACO protein being the target of PZA in the genome of M. tuberculosis. Altogether, the idetification of new target of PZA/POA in other species other than M. tuberculosis for the first time probably shed new light on the study of the action mechanism of PZA/POA in anti-TB.
Xiangzhong Sun (PhD student) from Guo’s group and Yaxin Li (PhD student) from Xiao’s group are co-first authors. Prof. Hongwei Guo and Prof. Junyu Xiao are co-corresponding authors of the paper. This research was funded by Southern University of Science and Technology, National Natural Ncience Foundation of China and Peking University-Tsinghua University Center for Life Sciences.
The paper links: https://www.nature.com/articles/ncomms15758