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Signal Transduct Target Ther. 2019 May 24;4:17. doi: 10.1038/s41392-019-0052-y. eCollection 2019.

Deciphering the regulatory and catalytic mechanisms of an unusual SAM-dependent enzyme.

Author information

1
1Division of Respiratory and Critical Care Medicine, Center of Infectious Diseases, National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 China.
2
2Shanghai Synchrotron Radiation Facility, Zhangjiang Lab, Zhangheng Road 239, Pudong District, Shanghai, 201203 China.
3
3Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041 China.
4
4West China School of Public Health, Sichuan University, Chengdu, 610041 China.
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Contributed equally

Abstract

S-adenosyl-1-methionine (SAM)-dependent enzymes regulate various disease-related behaviors in all organisms. Recently, the leporin biosynthesis enzyme LepI, a SAM-dependent enzyme, was reported to catalyze pericyclic reactions in leporin biosynthesis; however, the mechanisms underlying LepI activation and catalysis remain unclear. This study aimed to investigate the molecular mechanisms of LepI. Here, we reported crystal structures of LepI bound to SAM/5'-deoxy-5'-(methylthio) adenosine (MTA), S-adenosyl-homocysteine (SAH), and SAM/substrate states. Structural and biochemical analysis revealed that MTA or SAH inhibited the enzyme activities, whereas SAM activated the enzyme. The analysis of the substrate-bound structure of LepI demonstrated that this enzymatic retro-Claisen rearrangement was primarily driven by three critical polar residues His133, Arg197, Arg295 around the active site and assisted by SAM with unclear mechanism. The present studies indicate that the unique mechanisms underlying regulatory and catalysis of the unusual SAM-dependent enzyme LepI, not only strengthening current understanding of the fundamentally biochemical catalysis, but also providing novel insights into the design of SAM-dependent enzyme-specific small molecules.

KEYWORDS:

Structural biology

Conflict of interest statement

Competing interestsThe authors declare no competing interests.

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