Structural basis for substrate recognition by a S-adenosylhomocysteine hydrolase Lpg2021 from Legionella pneumophila

Yongshan Gao; Rao Xie; Yanan Chen; Beibei Yang; Min Wang; Lan Hua; Xu Wang; Weiqiang Wang; Na Wang; Honghua Ge; Jinming Ma

doi:10.1016/j.ijbiomac.2024.132289

Structural basis for substrate recognition by a S-adenosylhomocysteine hydrolase Lpg2021 from Legionella pneumophila

Int J Biol Macromol. 2024 May 10;270(Pt 1):132289. doi: 10.1016/j.ijbiomac.2024.132289. Online ahead of print.

Authors

Yongshan Gao¹, Rao Xie², Yanan Chen², Beibei Yang², Min Wang², Lan Hua², Xu Wang², Weiqiang Wang², Na Wang³, Honghua Ge⁴, Jinming Ma⁵

Affiliations

¹ Institute of Health Sciences and Technology, Institutes of Material Science and Information Technology, Anhui University, Hefei 230601, China; School of Resources and Environmental Engineering, Anhui University, Hefei 230601, China.
² Institute of Health Sciences and Technology, Institutes of Material Science and Information Technology, Anhui University, Hefei 230601, China.
³ Institute of Health Sciences and Technology, Institutes of Material Science and Information Technology, Anhui University, Hefei 230601, China. Electronic address: wangn6@ahu.edu.cn.
⁴ Institute of Health Sciences and Technology, Institutes of Material Science and Information Technology, Anhui University, Hefei 230601, China. Electronic address: hhge@ahu.edu.cn.
⁵ Institute of Health Sciences and Technology, Institutes of Material Science and Information Technology, Anhui University, Hefei 230601, China. Electronic address: jmma@ahu.edu.cn.

PMID: 38735607
DOI: 10.1016/j.ijbiomac.2024.132289

Abstract

S-Adenosyl-l-homocysteine hydrolase (SAHH) is a crucial enzyme that governs S-adenosyl methionine (SAM)-dependent methylation reactions within cells and regulates the intracellular concentration of SAH. Legionella pneumophila, the causative pathogen of Legionnaires' disease, encodes Lpg2021, which is the first identified dimeric SAHH in bacteria and is a promising target for drug development. Here, we report the structure of Lpg2021 in its ligand-free state and in complexes with adenine (ADE), adenosine (ADO), and 3-Deazaneplanocin A (DZNep). X-ray crystallography, isothermal titration calorimetry (ITC), and molecular docking were used to elucidate the binding mechanisms of Lpg2021 to its substrates and inhibitors. Virtual screening was performed to identify potential Lpg2021 inhibitors. This study contributes a novel perspective to the understanding of SAHH evolution and establishes a structural framework for designing specific inhibitors targeting pathogenic Legionella pneumophila SAHH.

Keywords: Crystal structure; Inhibitors; SAH hydrolase.