人PAPS合酶2的腺苷5'-磷酸硫酸激酶结构域（APSK2）的氧化还原转换机制。

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

作者信息

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

机构信息

Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

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.

出版信息

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

DOI:10.1016/j.str.2023.04.012

PMID:37207644

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.

摘要

腺苷5'-磷酸硫酸激酶（APSK）催化通用硫酰基供体3'-磷酸腺苷-5'-磷酸硫酸（PAPS）的限速生物合成步骤。在高等真核生物中，APSK和ATP硫酸化酶（ATPS）结构域融合在一条单链中。人类有两种双功能PAPS合成酶异构体：具有APSK1结构域的PAPSS1和含有APSK2结构域的PAPSS2。在肿瘤发生过程中，APSK2对PAPSS2介导的PAPS生物合成表现出明显更高的活性。APSK2如何实现过量的PAPS产生尚不清楚。APSK1和APSK2缺乏植物PAPSS同源物中存在的传统氧化还原调节元件。在这里，我们阐明了APSK2的动态底物识别机制。我们发现APSK1含有一个APSK2所缺乏的物种特异性半胱氨酸-半胱氨酸氧化还原调节元件。APSK2中该元件的缺失增强了其产生过量PAPS的酶活性，并促进癌症发展。我们的结果有助于理解人类PAPSS在细胞发育过程中的作用，并可能促进PAPSS2特异性药物的发现。