Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis

Kexin Hu; Qing Zhang; Yang Chen; Jintong Yang; Ying Xia; Bing Rao; Shaobai Li; Yafeng Shen; Mi Cao; Hongliang Lu; An Qin; Xian-Cheng Jiang; Deqiang Yao; Jie Zhao; Lu Zhou; Yu Cao

doi:10.1038/s41594-024-01237-2

Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis

Nat Struct Mol Biol. 2024 Feb 22. doi: 10.1038/s41594-024-01237-2. Online ahead of print.

Authors

Kexin Hu^#¹, Qing Zhang^#^{2

3

4}, Yang Chen^#¹, Jintong Yang^#⁵, Ying Xia¹, Bing Rao^{1

2}, Shaobai Li¹, Yafeng Shen¹, Mi Cao¹, Hongliang Lu⁶, An Qin^{2

3}, Xian-Cheng Jiang⁷, Deqiang Yao^{8

9}, Jie Zhao^{10

11}, Lu Zhou¹², Yu Cao^{13

14}

Affiliations

¹ Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁵ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
⁶ College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Department of Cell Biology, State University of New York Downstate Health Sciences University, Brooklyn, NY, USA.
⁸ Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yaodeqiang@renji.com.
⁹ Institute of Aging & Tissue Regeneration, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yaodeqiang@renji.com.
¹⁰ Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. profzhaojie@126.com.
¹¹ Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. profzhaojie@126.com.
¹² Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China. zhoulu@fudan.edu.cn.
¹³ Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yu.cao@shsmu.edu.cn.
¹⁴ Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yu.cao@shsmu.edu.cn.

^# Contributed equally.

PMID: 38388831
DOI: 10.1038/s41594-024-01237-2

Abstract

Sphingomyelin (SM) has key roles in modulating mammalian membrane properties and serves as an important pool for bioactive molecules. SM biosynthesis is mediated by the sphingomyelin synthase (SMS) family, comprising SMS1, SMS2 and SMS-related (SMSr) members. Although SMS1 and SMS2 exhibit SMS activity, SMSr possesses ceramide phosphoethanolamine synthase activity. Here we determined the cryo-electron microscopic structures of human SMSr in complexes with ceramide, diacylglycerol/phosphoethanolamine and ceramide/phosphoethanolamine (CPE). The structures revealed a hexameric arrangement with a reaction chamber located between the transmembrane helices. Within this structure, a catalytic pentad E-H/D-H-D was identified, situated at the interface between the lipophilic and hydrophilic segments of the reaction chamber. Additionally, the study unveiled the two-step synthesis process catalyzed by SMSr, involving PE-PLC (phosphatidylethanolamine-phospholipase C) hydrolysis and the subsequent transfer of the phosphoethanolamine moiety to ceramide. This research provides insights into the catalytic mechanism of SMSr and expands our understanding of sphingolipid metabolism.