期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep40227
关键词
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资金
- MEXT [22000006, 24689003, 16H05099, 16H00823, 15K05529, 16J01710]
- SENTAN, JST
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Asahi Glass Foundation
- Takeda Science Foundation
- Naito Foundation
- JSPS KAKENHI [15K18994, 24229001]
- Program for the Strategic Research Foundation at Private Universities
- Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan
- JSPS TEI-SOKU Program [PU14008]
- Uehara Memorial Foundation
- Kobayashi International Scholarship Foundation
- Cooperative Research Program of the Institute for Protein Research, Osaka University [2014A6933, 2014B6933]
- [G15011]
- Grants-in-Aid for Scientific Research [17H06173, 15K18994, 26460115, 15H05371, 16K15123, 16H05099, 26111012, 26111008, 16J01710, 15K14937, 16H00823, 15K05529, 14F04908] Funding Source: KAKEN
Very recent studies indicate that sulfur atoms with oxidation state 0 or -1, called sulfane sulfurs, are the actual mediators of some physiological processes previously considered to be regulated by hydrogen sulfide (H2S). 3-Mercaptopyruvate sulfurtransferase (3MST), one of three H2S-producing enzymes, was also recently shown to produce sulfane sulfur (H2Sn). Here, we report the discovery of several potent 3MST inhibitors by means of high-throughput screening (HTS) of a large chemical library (174,118 compounds) with our H2S-selective fluorescent probe, HSip-1. Most of the identified inhibitors had similar aromatic ring-carbonyl-S-pyrimidone structures. Among them, compound 3 showed very high selectivity for 3MST over other H2S/sulfane sulfur-producing enzymes and rhodanese. The X-ray crystal structures of 3MST complexes with two of the inhibitors revealed that their target is a persulfurated cysteine residue located in the active site of 3MST. Precise theoretical calculations indicated the presence of a strong long-range electrostatic interaction between the persulfur anion of the persulfurated cysteine residue and the positively charged carbonyl carbon of the pyrimidone moiety of the inhibitor. Our results also provide the experimental support for the idea that the 3MST-catalyzed reaction with 3-mercaptopyruvate proceeds via a ping-pong mechanism.
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