Structure and Enzymology of ADP-ribosyl Cyclases: Conserved Enzymes that Produce Multiple Calcium Mobilizing Metabolites
Cyclic ADP-ribose is an important calcium mobilizing metabolite produced by the ADP-ribosyl cyclase (cyclases) family of enzymes. Three evolutionarily conserved ADP-ribosyl cyclase superfamily members have been identified, one from the invertebrate Aplysia californica and two from mammalian tissues, CD38 and CD157. CD38 regulates calcium signaling in a number of cell types, and it was recently shown that cyclic ADP-ribose produced by CD38 modulates calcium mobilization induced upon chemokine receptor engagement. Excitingly, because immunocytes deficient in CD38 are unable to migrate to inflammatory sites in vivo, this enzyme has now become an attractive target for drug development. To rationally design inhibitors it is critical to understand the mechanism(s) by which CD38 catalyzes the transformation of its substrate NAD+ into cyclic ADP-ribose. Likewise, it is necessary to identify the CD38 substrate-binding site. Importantly, significant progress has been made in these two areas and much is now known about the structure and enzymology of CD38 and the other ADP-ribosyl cyclase superfamily members. In this review, we will outline the critical data demonstrating a role for CD38 in regulating calcium mobilization in mammalian cells. We will also describe the crystallographic data and site-directed mutagenesis studies that have helped to elucidate the CD38 structure and the identification of its active site and key catalytic residues. Finally, we will address the important advances in our understanding of the kinetic and molecular mechanisms that control cyclic ADP-ribose production by CD38.
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Document Type: Review Article
Affiliations: Laboratoire de Chimie Bioorganique, UMR 7514 CNRS / ULP, Faculte de Pharmacie, 67400 Strasbourg - Illkrich, France.
Publication date: 2004-05-01
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- Current Molecular Medicine is an interdisciplinary journal focused on providing the readership with current and comprehensive reviews on fundamental molecular mechanisms of disease pathogenesis, the development of molecular-diagnosis and/or novel approaches to rational treatment. The reviews should be of significant interest to basic researchers and clinical investigators in molecular medicine. Periodically the journal will invite guest editors to devote an issue on a basic research area that shows promise to advance our understanding of the molecular mechanism(s) of a disease or has potential for clinical applications.