title: Porcine CD38 exhibits prominent secondary NAD(+) cyclase activity.
abstract: Cyclic ADP-ribose (cADPR) mobilizes intracellular Ca(2+) stores and activates Ca(2+) influx to regulate a wide range of physiological processes. It is one of the products produced from the catalysis of NAD(+) by the multifunctional CD38/ADP-ribosyl cyclase superfamily. After elimination of the nicotinamide ring by the enzyme, the reaction intermediate of NAD(+) can either be hydrolyzed to form linear ADPR or cyclized to form cADPR. We have previously shown that human CD38 exhibits a higher preference towards the hydrolysis of NAD(+) to form linear ADPR while Aplysia ADP-ribosyl cyclase prefers cyclizing NAD(+) to form cADPR. In this study, we characterized the enzymatic properties of porcine CD38 and revealed that it has a prominent secondary NAD(+) cyclase activity producing cADPR. We also determined the X-ray crystallographic structures of porcine CD38 and were able to observe conformational flexibility at the base of the active site of the enzyme which allow the NAD(+) reaction intermediate to adopt conformations resulting in both hydrolysis and cyclization forming linear ADPR and cADPR respectively.
authors.affiliation: School of Life Sciences, the Chinese University of Hong Kong, Hong Kong.|The Centre of Novel Biomaterials, the Chinese University of Hong Kong, Hong Kong.
authors.forename: Kai Yiu
authors.initials: KY
authors.lastname: Ting
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong.
authors.forename: Christina F P
authors.initials: CF
authors.lastname: Leung
authors.affiliation: Department of Physiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Graeff
authors.affiliation: School of Chemical Biology & Biotechnology, Peking University Campus, Shenzhen, China.
authors.forename: Hon Cheung
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department of Physiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong.
authors.forename: Quan
authors.initials: Q
authors.lastname: Hao
authors.affiliation: School of Life Sciences, the Chinese University of Hong Kong, Hong Kong.|The Centre of Novel Biomaterials, the Chinese University of Hong Kong, Hong Kong.|Department of Physiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong.
authors.forename: Masayo
authors.initials: M
authors.lastname: Kotaka
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000737:chemistry / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism*; D000072417:Protein Domains; D013552:Swine
chemical_list: D009243:NAD; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1
keywords: CD38; NAD+ cyclization; X-ray crystallography; cyclic ADP-ribose; secondary enzyme activity