Redox switching mechanism of the adenosine 5'-phosphosulfate kinase domain (APSK2) of human PAPS synthase 2

Lin Zhang; Wenyan Song; Tingting Li; Yajuan Mu; Pan Zhang; Jingyan Hu; Houwen Lin; Jian Zhang; Hai Gao; Liang Zhang

doi:10.1016/j.str.2023.04.012

Redox switching mechanism of the adenosine 5'-phosphosulfate kinase domain (APSK2) of human PAPS synthase 2

Structure. 2023 Jul 6;31(7):826-835.e3. doi: 10.1016/j.str.2023.04.012. Epub 2023 May 18.

Authors

Lin Zhang¹, Wenyan Song¹, Tingting Li¹, Yajuan Mu¹, Pan Zhang¹, Jingyan Hu¹, Houwen Lin², Jian Zhang³, Hai Gao⁴, Liang Zhang⁵

Affiliations

¹ Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Research Centre for Marine Drugs, State Key Laboratory of Oncogene and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Institute of Marine Biomedicine, Shenzhen Polytechnic, Shenzhen 518055, China.
³ Medicinal Bioinformatics Center, Shanghai JiaoTong University School of Medicine, Shanghai China.
⁴ Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: gaohai@fudan.edu.cn.
⁵ Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: liangzhang2014@sjtu.edu.cn.

PMID: 37207644
DOI: 10.1016/j.str.2023.04.012

Abstract

Adenosine 5'-phosphosulfate kinase (APSK) catalyzes the rate-limiting biosynthetic step of the universal sulfuryl donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In higher eukaryotes, the APSK and ATP sulfurylase (ATPS) domains are fused in a single chain. Humans have two bifunctional PAPS synthetase isoforms: PAPSS1 with the APSK1 domain and PAPSS2 containing the APSK2 domain. APSK2 displays a distinct higher activity for PAPSS2-mediated PAPS biosynthesis during tumorigenesis. How APSK2 achieves excess PAPS production has remained unclear. APSK1 and APSK2 lack the conventional redox-regulatory element present in plant PAPSS homologs. Here we elucidate the dynamic substrate recognition mechanism of APSK2. We discover that APSK1 contains a species-specific Cys-Cys redox-regulatory element that APSK2 lacks. The absence of this element in APSK2 enhances its enzymatic activity for excess PAPS production and promotes cancer development. Our results help to understand the roles of human PAPSSs during cell development and may facilitate PAPSS2-specific drug discovery.

Keywords: 3'-phosphoadenosine-5'-phosphosulfate (PAPS); adenosine 5'-phosphosulfate kinase (APSK); human PAPS synthase; redox switching; redox-regulatory element; sulfation.

MeSH terms

Humans
Oxidation-Reduction
Phosphotransferases (Alcohol Group Acceptor)* / chemistry
Phosphotransferases (Alcohol Group Acceptor)* / genetics

Substances

adenylylsulfate kinase
Phosphotransferases (Alcohol Group Acceptor)
PAPS synthetase