title: Activation of zinc-requiring ectoenzymes by ZnT transporters during the secretory process: Biochemical and molecular aspects.
abstract: In humans, about 1000 enzymes are estimated to bind zinc. In most of these enzymes, zinc is present at the active site; thus, these enzymes are functional as "zinc-requiring enzymes". Of these zinc-requiring enzymes, zinc-requiring ectoenzymes (defined as secretory, membrane-bound, and organelle-resident enzymes) have received much attention because of their important physiological functions, involvement in a number of diseases, and potential applications as therapeutic targets for diseases. Zinc-requiring ectoenzymes may become active by coordinating zinc at their active site during the secretory process, which requires elaborate control of zinc mobilization from the extracellular milieu to the cytosol and then lumen in the early secretory pathway. Therefore, zinc transporters should properly maintain the process at systemic, cellular, and subcellular levels by mobilizing zinc across biological membranes. However, few studies have examined the mechanisms underlying this process. In this review, current knowledge of the activation process of zinc-requiring ectoenzymes by ZnT zinc transporters in the early secretory pathway is briefly reviewed at the molecular level, with a focus on tissue-nonspecific alkaline phosphatase. Moreover, we also discuss whether zinc-chaperone proteins function during the activation of these enzymes.
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan. Electronic address: kambe1@kais.kyoto-u.ac.jp.
authors.forename: Taiho
authors.initials: T
authors.lastname: Kambe
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Taka-Aki
authors.initials: TA
authors.lastname: Takeda
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Yukina
authors.initials: Y
authors.lastname: Nishito
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D020134:Catalytic Domain; D027682:Cation Transport Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D011485:Protein Binding; D055571:Secretory Pathway; D015032:Zinc / Q000737:chemistry*
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D004798:Enzymes; D018832:Molecular Chaperones; C017800:zinc-binding protein; D015032:Zinc
keywords: Chaperone; Early secretory pathway; Tissue-nonspecific alkaline phosphatase; Zinc-requiring ectoenzymes; ZnT/SLC30A