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      Snake venom NAD glycohydrolases: primary structures, genomic location, and gene structure

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          Abstract

          NAD glycohydrolase (EC 3.2.2.5) (NADase) sequences have been identified in 10 elapid and crotalid venom gland transcriptomes, eight of which are complete. These sequences show very high homology, but elapid and crotalid sequences also display consistent differences. As in Aplysia kurodai ADP-ribosyl cyclase and vertebrate CD38 genes, snake venom NADase genes comprise eight exons; however, in the Protobothrops mucrosquamatus genome, the sixth exon is sometimes not transcribed, yielding a shortened NADase mRNA that encodes all six disulfide bonds, but an active site that lacks the catalytic glutamate residue. The function of this shortened protein, if expressed, is unknown. While many vertebrate CD38s are multifunctional, liberating both ADP-ribose and small quantities of cyclic ADP-ribose (cADPR), snake venom CD38 homologs are dedicated NADases. They possess the invariant TLEDTL sequence (residues 144–149) that bounds the active site and the catalytic residue, Glu228. In addition, they possess a disulfide bond (Cys121–Cys202) that specifically prevents ADP-ribosyl cyclase activity in combination with Ile224, in lieu of phenylalanine, which is requisite for ADPR cyclases. In concert with venom phosphodiesterase and 5′-nucleotidase and their ecto-enzyme homologs in prey tissues, snake venom NADases comprise part of an envenomation strategy to liberate purine nucleosides, and particularly adenosine, in the prey, promoting prey immobilization via hypotension and paralysis.

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          Most cited references35

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          GalaxyWEB server for protein structure prediction and refinement

          Three-dimensional protein structures provide invaluable information for understanding and regulating biological functions of proteins. The GalaxyWEB server predicts protein structure from sequence by template-based modeling and refines loop or terminus regions by ab initio modeling. This web server is based on the method tested in CASP9 (9th Critical Assessment of techniques for protein Structure Prediction) as ‘Seok-server’, which was assessed to be among top performing template-based modeling servers. The method generates reliable core structures from multiple templates and re-builds unreliable loops or termini by using an optimization-based refinement method. In addition to structure prediction, a user can also submit a refinement only job by providing a starting model structure and locations of loops or termini to refine. The web server can be freely accessed at http://galaxy.seoklab.org/.
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            Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38.

            CD38 is a 42-kilodalton glycoprotein expressed extensively on B and T lymphocytes. CD38 exhibits a structural homology to Aplysia adenosine diphosphate (ADP)-ribosyl cyclase. This enzyme catalyzes the synthesis of cyclic ADP-ribose (cADPR), a metabolite of nicotinamide adenine dinucleotide (NAD+) with calcium-mobilizing activity. A complementary DNA encoding the extracellular domain of murine CD38 was constructed and expressed, and the resultant recombinant soluble CD38 was purified to homogeneity. Soluble CD38 catalyzed the formation and hydrolysis of cADPR when added to NAD+. Purified cADPR augmented the proliferative response of activated murine B cells, potentially implicating the enzymatic activity of CD38 in lymphocyte function.
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              The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging.

              Recent reports indicate that intracellular NAD levels decline in tissues during chronological aging, and that therapies aimed at increasing cellular NAD levels could have beneficial effects in many age-related diseases. The protein CD38 (cluster of differentiation 38) is a multifunctional enzyme that degrades NAD and modulates cellular NAD homeostasis. At the physiological level, CD38 has been implicated in the regulation of metabolism and in the pathogenesis of multiple conditions including aging, obesity, diabetes, heart disease, asthma, and inflammation. Interestingly, many of these functions are mediated by CD38 enzymatic activity. In addition, CD38 has also been identified as a cell-surface marker in hematologic cancers such as multiple myeloma, and a cytotoxic anti-CD38 antibody has been approved by the FDA for use in this disease. Although this is a remarkable development, killing CD38-positive tumor cells with cytotoxic anti-CD38 antibodies is only one of the potential pharmacological uses of targeting CD38. The present review discusses the biology of the CD38 enzyme and the current state of development of pharmacological tools aimed at CD38, and explores how these agents may represent a novel approach for treating human conditions including cancer, metabolic disease, and diseases of aging.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                peerj
                peerj
                PeerJ
                PeerJ Inc. (San Diego, USA )
                2167-8359
                6 February 2019
                2019
                : 7
                : e6154
                Affiliations
                [1 ]Ecology and Evolution Unit, Okinawa Institute of Science and Technology , Onna, Kunigami-gun, Okinawa, Japan
                [2 ]Ecology and Evolution Unit and Division of Faculty Affairs, Okinawa Institute of Science and Technology , Onna, Kunigami-gun, Okinawa, Japan
                Article
                6154
                10.7717/peerj.6154
                6368836
                757b2865-26f9-473c-bf8e-33b2f66e6f13
                ©2019 Koludarov and Aird

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 26 September 2018
                : 25 November 2018
                Funding
                Funded by: Okinawa Institute of Science and Technology
                This work was supported by the Okinawa Institute of Science and Technology to the Ecology and Evolution Unit. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Biochemistry
                Genomics
                Toxicology
                Zoology

                snake venom,nad glycohydrolase,nadase,cd38,adp-ribosyl cyclase,protobothrops mucrosquamatus genome,exons,adenosine,phosphodiesterase,5′-nucleotidase

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