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      Proteomic Characterization of Two Medically Important Malaysian Snake Venoms, Calloselasma rhodostoma (Malayan Pit Viper) and Ophiophagus hannah (King Cobra)

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          Abstract

          Calloselasma rhodostoma (CR) and Ophiophagus hannah (OH) are two medically important snakes found in Malaysia. While some studies have described the biological properties of these venoms, feeding and environmental conditions also influence the concentration and distribution of snake venom toxins, resulting in variations in venom composition. Therefore, a combined proteomic approach using shotgun and gel filtration chromatography, analyzed by tandem mass spectrometry, was used to examine the composition of venoms from these Malaysian snakes. The analysis revealed 114 proteins (15 toxin families) and 176 proteins (20 toxin families) in Malaysian Calloselasma rhodostoma and Ophiophagus hannah species, respectively. Flavin monoamine oxidase, phospholipase A 2, phosphodiesterase, snake venom metalloproteinase, and serine protease toxin families were identified in both venoms. Aminopeptidase, glutaminyl-peptide cyclotransferase along with ankyrin repeats were identified for the first time in CR venom, and insulin, c-type lectins/snaclecs, hepatocyte growth factor, and macrophage colony-stimulating factor together with tumor necrosis factor were identified in OH venom for the first time. Our combined proteomic approach has identified a comprehensive arsenal of toxins in CR and OH venoms. These data may be utilized for improved antivenom production, understanding pathological effects of envenoming, and the discovery of biologically active peptides with medical and/or biotechnological value.

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          Most cited references104

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          Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.

          Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse. We have previously described a women with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. Gly-->Arg483 prevents processing of proPC1 and leads to its retention in the endoplasmic reticulum (ER). A-->C+4 of the intro-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
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            Venoms as a platform for human drugs: translating toxins into therapeutics.

            Glenn King (2011)
            An extraordinarily diverse range of animals have evolved venoms for predation, defence, or competitor deterrence. The major components of most venoms are peptides and proteins that are often protease-resistant due to their disulfide-rich architectures. Some of these toxins have become valuable as pharmacological tools and/or therapeutics due to their extremely high specificity and potency for particular molecular targets. There are currently six FDA-approved drugs derived from venom peptides or proteins. This article surveys the current pipeline of venom-derived therapeutics and critically examines the potential of peptide and protein drugs derived from venoms. Emerging trends are identified, including an increasing industry focus on disulfide-rich venom peptides and the use of a broader array of molecular targets in order to develop venom-based therapeutics for treating a wider range of clinical conditions. Key technical advances in combination with a renewed industry-wide focus on biologics have converged to provide a larger than ever pipeline of venom-derived therapeutics. Disulfide-rich venom peptides obviate some of the traditional disadvantages of therapeutic peptides and some may be suitable for oral administration. Moreover, some venom peptides can breach the blood brain barrier and translocate across cell membranes, which opens up the possibility of exploiting molecular targets not previously accessible to peptide drugs.
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              Structural considerations of the snake venom metalloproteinases, key members of the M12 reprolysin family of metalloproteinases.

              The importance of proteinases in the pathologies associated with Viperid envenoming has long been appreciated. Over the past 40 years substantial research has clearly implicated metalloproteinases in the venom (snake venom metalloproteinases; SVMPs) as playing key roles in the development of such symptoms as hemorrhage, edema, hypotension, hypovolemia, inflammation and necrosis. In spite of this wealth of information there are still many unresolved questions pertaining to the structural basis for the various SVMPS giving rise to the diversity of activities. In this short review we will not attempt to provide an exhaustive collation of structural studies on the SVMPs; however, we will give a brief outline of the structural classification of the SVMPs; as well as relate them to the other members of the reprolysin family of metalloproteinases, the ADAMs. The information put forth in the text does not allow specific conclusions to be drawn on the structural basis for SVMP functional diversity, but it is our goal that it will allow for the development of testable hypotheses that can be experimentally pursued. What the reader will observe is that there are very interesting structural features displayed by the various SVMP classes and subclasses that provide insight into their functional characteristics.
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                Author and article information

                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                26 October 2018
                November 2018
                : 10
                : 11
                : 434
                Affiliations
                [1 ]Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; sugitakunalan@ 123456hotmail.com (S.K.); iekhsan.othman@ 123456monash.edu (I.O.); sharifah.syedhassan@ 123456monash.edu (S.S.H.)
                [2 ]Monash Venom Group, Department of Pharmacology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria 3800, Australia
                Author notes
                [* ]Correspondence: wayne.hodgson@ 123456monash.edu ; Tel.: +61-399-054-861
                Author information
                https://orcid.org/0000-0002-6670-1622
                https://orcid.org/0000-0001-6347-4455
                Article
                toxins-10-00434
                10.3390/toxins10110434
                6266455
                30373186
                4e48737e-5f5a-436a-86b3-a85a3f27d33a
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 October 2018
                : 23 October 2018
                Categories
                Article

                Molecular medicine
                calloselasma rhodostoma,ophiophagus hannah,toxin,proteomics,venomics,venom proteome
                Molecular medicine
                calloselasma rhodostoma, ophiophagus hannah, toxin, proteomics, venomics, venom proteome

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