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The Cape cobra (Naja nivea) is one of the African cobras of highest medical importance, but much remains to be learned about its venom. Here, we used a shotgun proteomics approach to better understand the qualitative composition of N. nivea venom and tested its cytotoxicity and protease activity as well as its effect on intracellular Ca2+ release and NO synthesis. We identified 156 venom components representing 17 protein families, with the dominant ones being three-finger toxins, mostly of the short-chain type. Two-thirds of the three-finger toxin entries identified were assigned as cytotoxins, while the remainder were categorized as neurotoxins, including short-chain, long-chain, and ancestral three-finger toxins. We also identified snake venom metalloproteinases and members of CRISP, l-amino acid oxidase, and other families. Protease activity and its effect on intracellular Ca2+ release and NO synthesis were low. Phospholipase A2 activity was surprisingly high, despite this toxin family being marginally recovered in the analyzed venom. Cytotoxicity was relevant only at higher venom concentrations, with macrophage and neuroblastoma cell lines showing the lowest viability. These results are in line with the predominantly neurotoxic envenomation symptoms caused by Cape cobra bites. The present overview of the qualitatively complex and functionally intriguing venom of N. nivea may provide insights into the pathobiochemistry of this species\u2019 venom.<\/jats:p>","DOI":"10.3390\/toxins16100438","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T08:10:16Z","timestamp":1728634216000},"page":"438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Toxin Diversity, Cytotoxicity, and Enzymatic Activity of Cape Cobra (Naja nivea) Venom"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7234-8685","authenticated-orcid":false,"given":"Tim","family":"L\u00fcddecke","sequence":"first","affiliation":[{"name":"Animal Venomics Lab, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany"},{"name":"Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany"},{"name":"LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3576-8805","authenticated-orcid":false,"given":"Ignazio","family":"Avella","sequence":"additional","affiliation":[{"name":"Animal Venomics Lab, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany"},{"name":"LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany"},{"name":"Institute for Insect Biotechnology, Justus Liebig University Giessen, Heinrich-Buff-Ring 26\u201332, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0810-3699","authenticated-orcid":false,"given":"Maik","family":"Damm","sequence":"additional","affiliation":[{"name":"Animal Venomics Lab, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany"},{"name":"LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany"},{"name":"Institute for Insect Biotechnology, Justus Liebig University Giessen, Heinrich-Buff-Ring 26\u201332, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5260-9797","authenticated-orcid":false,"given":"Lennart","family":"Schulte","sequence":"additional","affiliation":[{"name":"Animal Venomics Lab, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany"},{"name":"Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany"},{"name":"LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany"},{"name":"Institute for Insect Biotechnology, Justus Liebig University Giessen, Heinrich-Buff-Ring 26\u201332, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3172-1036","authenticated-orcid":false,"given":"Johanna","family":"Eichberg","sequence":"additional","affiliation":[{"name":"Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany"},{"name":"BMBF Junior Research Group in Infection Research \u201cASCRIBE\u201d, Ohlebergsweg 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kornelia","family":"Hardes","sequence":"additional","affiliation":[{"name":"Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany"},{"name":"LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany"},{"name":"BMBF Junior Research Group in Infection Research \u201cASCRIBE\u201d, Ohlebergsweg 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5035-2504","authenticated-orcid":false,"given":"Susanne","family":"Schiffmann","sequence":"additional","affiliation":[{"name":"LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7661-5832","authenticated-orcid":false,"given":"Marina","family":"Henke","sequence":"additional","affiliation":[{"name":"LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8569-7537","authenticated-orcid":false,"given":"Thomas","family":"Timm","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Justus Liebig University Giessen, Friedrichstrasse 24, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0377-395X","authenticated-orcid":false,"given":"G\u00fcnter","family":"Lochnit","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Justus Liebig University Giessen, Friedrichstrasse 24, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8276-4968","authenticated-orcid":false,"given":"Andreas","family":"Vilcinskas","sequence":"additional","affiliation":[{"name":"Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany"},{"name":"LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany"},{"name":"Institute for Insect Biotechnology, Justus Liebig University Giessen, Heinrich-Buff-Ring 26\u201332, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kasturiratne, A., Wickremasinghe, A.R., De Silva, N., Gunawardena, N.K., Pathmeswaran, A., Premaratna, R., Savioli, L., Lalloo, D.G., and De Silva, H.J. 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