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Snake

Publications

Book chapter

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​Zabidi NZ, Misuan N, Farouk IA, Lal SK, Yap MKK (2024). Therapeutic applications of snake venom proteins as anti-cancer agents. In R.C. Sobti et al. (Eds), Molecular Biomarkers for Cancer Diagnosis and Therapy. Springer, Singapore. https://doi.org/10.1007/978-981-99-3746-2_32


Yong Y, Hiu JJ, Yap MKK (2022). The secretory phenotypes of envenomed cells: Insights into venom cytotoxicity. Advances in Protein Chemistry and Structural Biology – Secretory Proteins. Donev, R. (ed). Academic Press, In Press.

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Yap MKK, Misuan N (2021). Exendin-4 and its related proteins. In S. Mackessy (Ed.), Handbook of Venoms and Toxins of Reptiles(Second ed., pp. 251-269). Florida, United States: CRC Press.

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Journal articles​

  • Yap MKK, Modahl CM, Hall SR (2024). Editorial: Experimental and computational aspects of bioactive proteins from animal venoms: an insight into pharmacological properties and drug discovery. Frontiers in Pharmacology. 15, 3, 1380193. https://doi.org/10.3389/fphar.2024.1380193

  • Lim EQ, Ahemad N, Yap MKK (2023). High-throughput virtual screening, pharmacophore modelling and antagonist effects of small molecule inhibitors against cytotoxin-induced cytotoxicity. Journal of Biomolecular Structures and Dynamics. https://doi.org/10.1080/07391102.2023.2293275  

  • Hiu JJ, Fung JKY, Tan HS, Yap MKK (2023). Unveiling the functional epitopes of cobra venom cytotoxin by
    immu    noinformatics and epitope-omic analyses. Scientific Reports 13, 12271. https://doi.org/10.1038/s41598-023-39222-2

  • Misuan N, Mohamad S, Tubiana T, Yap MKK (2023). Ensemble-based molecular docking and spectrofluorometric analysis of interaction between cytotoxin and tumor necrosis factor receptor 1. Journal of Biomolecular Structure and Dynamics. 6, 1-15. https://doi.org/10.1080/07391102.2023.2188945

  • Selvam R, Lim IHY, Lewis JC, Lim CH, Yap MKK, Tan HS (2023).  Selecting antibacterial aptamers against the BamA protein in Pseudomonas aeruginosa by incorporating genetic algorithm to optimise computational screening method. Scientific Reports. 13, 7582. https://doi.org/10.1038/s41598-023-34643-5

  • Quek WP, Ong YH, Yap MKK, Lee YY, Karim NAA, Chan ES (2023). A comparative study of the oxidative
    stability and the formation of monochloropropanediol esters (MCPDE) and glycidyl esters (GE) between
    physically and chemically refined palm olein during repeated deep-frying. Food Control. 150, 109737.

  • Quek WP, Ong YH, Yap MKK, Lee YY, Ab Karim NA, Chew CL, Chan ES (2023). The effects of quality changes in vegetable oils on the formation and absorption of monochloropropanediol esters (MCPDE) and glycidyl esters (GE) during deep-frying of potato chips. Food Control. 149, 109699.

  • Foo SC, Lee ZS, Yap MKK, Tan JW (2023). The antioxidant, wound healing properties and proteomic analysis
    of water extracts from the tropical cyanobacteria, Nostoc NIES-2111_MUM004. 3 Biotech 13, 71 (2023). https://doi.org/10.1007/s13205-022-03448-0

  • Quek WP, Yap MKK, Lee YY, Hock Ong AS, Chan ES (2022). Systematic comparison on the deep-frying performance of different vegetable oils from literature data using the rate of parameter change approach. Food Control. 137, 8, 108922.

  • Hiu JJ, Yap MKK (2022). The myth of cobra venom cytotoxin: More than just direct cytolytic actions. Toxicon: X. 14, 10 100123.

  • Yap MKK. (2022). A digital module-based experiential learning in protein biochemistry during the COVID-19pandemic paradigm. Biochemistry and Molecular Biology Education. 51(1), 77-80.https://doi.org/10.1002/bmb.21680

  • Wong JF, Hong HJ, Foo SC, Yap MKK, Tan JW (2022). A review on current and future advancements for commercialized microalgae species. Food Science and Human Wellness. 11: 1156-1170. 

  • Hiu JJ, Yap MKK (2021). The effects of Naja sumatrana venom cytotoxin, sumaCTX on alteration of the secretome in MCF-7 breast cancer cells following membrane permeabilization. International Journal of Biological Macromolecules. 184: 776-786. 

  • Teoh SQ, Yap MKK (2020). Naja sumatrana venom cytotoxin, sumaCTX exhibits concentration-dependent cytotoxicity via caspase-activated mitochondrial-mediated apoptosis without transitioning to necrosis. Toxin Reviews. DOI: 10.1080/15569543.2020.1799408. 

  • Hiu JJ, Yap MKK (2020). Cytotoxicity of snake venom enzymatic toxins: phospholipase A2 and l-amino acid oxidase. Biochemical Society Transactions. 48:719-731. DOI: 1042/BST20200110.

  • Gurunanselage Don RAS, Yap MKK (2019). Arctium lappa L. root extract induces cell death via mitochondrial-mediated caspase-dependent apoptosis in Jurkat human leukemic T cells. Biomedicine & Pharmacotherapy. 110:918-929. 

  • Yap MKK, Misuan M (2019). Exendin-4 from Heloderma suspectum venom: From discovery to its latest application as Type II diabetes combatant. Basic & Clinical Pharmacology & Toxicology. 124:513–527. DOI: 10.1111/bcpt.13169. 

  • Tan CH, Tan KY, Yap MKK, Tan NH (2017). Venomics of Tropidolaemus wagleri, the sexually dimorphic temple pit viper: Unveiling a deeply conserved atypical toxin arsenal. Scientific Reports. DOI: 10.1038/srep43237.

  • Fung SY, Tan CH, Yap MKK, Leong PK, Liew JL, Tan NH (2016). Unveiling the elusive and exotic: Venomics of the Malayan blue coral snake (Calliophis bivirgata flaviceps). Journal of Proteomics, 132:1-12.

  • Tan NH, Fung SY, Tan KY, Yap MKK, Ariaranee C, Tan CH (2015). Functional venomics of the Sri Lankan Russell’s viper (Daboia russelii) and its toxinological correlations. Journal of Proteomics, 128:403-423.

  • Yap MKK, Tan NH, Sim SM, Fung SY and Tan CH (2015). The effect of a polyvalent antivenom on the serum venom antigen levels of Naja sputatrix (Javan spitting cobra) venom in experimentally envenomed rabbits. Basic & Clinical Pharmacology & Toxicology, 117(4):274-279.

  • Yap MKK, Tan NH, Sim SM, Fung SY and Tan CH (2014). Pharmacokinetics of Naja sumatrana (Equatorial spitting cobra) venom and its major toxins in experimentally envenomed rabbits. PloS Neglected Tropical Diseases. DOI:10.1371/journal.pntd.0002890.

  • Yap MKK, Fung SY, Tan KY and Tan NH (2014). Proteomic characterization of venom of the medically important Southeast Asian Naja sumatrana (Equatorial spitting cobra). Acta Tropica. 13: 15-25.

  • Yap MKK, Tan NH, Sim SM and Fung SY (2013). Toxicokinetics of Naja sputatrix (Javan spitting cobra) venom following intramuscular and intravenous administrations of the venom into rabbits. Toxicon. 68:18-23.

  • Yap MKK, Sim SM, Tan NH and Fung SY (2011). Pharmacokinetics of Naja sputatrix (spitting cobra) venom in rabbits. Journal of Pharmacological Sciences. 115: Supp1,183P.

  • Yap MKK, Tan NH and Fung SY (2011). Biochemical and toxinological characterization of Naja sumatrana (Equatorial spitting cobra) venom. Journal of Venomous Animal Toxins including Tropical Diseases. 17(4): 451-459.

Conference/Proceedings 

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  • Hiu JJ, Tan HS, Yap MKK (2022). In silico selection of aptamers to cobra venom cytotoxin. BMC Proceedings.
    16(Suppl 7), 46 – 47, P-54. https://doi.org/10.1186/s12919-022-00237-8

  • Selvam R, Yap MKK, Tan HS (2022). Selecting antibacterial aptamers against an essential outer membrane
    protein in Pseudomonas aeruginosa via aptamer repurposing. BMC Proceedings. 16 (Suppl 7), 38-39, P-33.
    https://doi.org/10.1186/s12919-022-00237-8 

  • Hiu JJ, Yap MKK.  Experimental and computational investigation of membrane perturbing effects of snake cytotoxin (SCT) family. 5th Prato Conference on Pore Forming Protein. 22 - 24 June 2021. 

  • Misuan N, Yap MKK. Structural characteristics, physicochemical properties, and domain architectures of cobra venom cytotoxin. 2021 ASBMB Protein Data Bank Symposium - 50th-year celebration. 4 - 5 May 2021.

  • Teoh SQ, Hiu JJ, Yap MKK. The myth of venom cytotoxin – more than just cytolytic actions. Oxford Venoms & Toxins 2020. 16 - 17 Sep 2020.

  • Misuan N, Mohammad S, Yap MKK. Molecular docking of cobra venom cytotoxin with death receptors. The 19th International Conference on Bioinformatics. 25 - 29 Nov 2021. 

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Featured publications

Unveiling the functional epitopes of cobra venom cytotoxin byimmunoinformatics and epitope-omic analyses

Approximate 70% of cobra venom is composed of cytotoxin (CTX), which is responsible for the dermonecrotic symptoms of cobra envenomation. However, CTX is generally low in immunogenicity, and the antivenom is ineffective in attenuating its in vivo toxicity. Furthermore, little is known about its epitope properties for empirical antivenom therapy. This study aimed to determine the epitope sequences of CTX using the immunoinformatic analyses and epitope-omics profiling. A conserved CTX was used in this study to determine its T-cell and B-cell epitope sequences using immunoinformatic tools and molecular docking simulation with different Human Leukocyte Antigens (HLAs). The potential T-cell and B-cell epitopes were 'KLVPLFY,' 'CPAGKNLCY,' 'MFMVSTPTK,' and 'DVCPKNSLL.' Molecular docking simulations disclosed that the HLA-B62 supertype exhibited the greatest binding affinity towards cobra venom cytotoxin. The namely L7, G18, K19, N20, M25, K33, V43, C44, K46, N47, and S48 of CTX exhibited prominent intermolecular interactions with HLA-B62. The multi-enzymatic-limited-digestion/liquid chromatography-mass spectrometry (MELD/LC–MS) also revealed three potential epitope sequences as 'LVPLFYK,' 'MFMVS,' and ‘TVPVKR’. From different epitope mapping approaches, we concluded four potential epitope sites of CTX as ‘KLVPLFYK’, ‘AGKNL’, ‘MFMVSTPKVPV’ and ‘DVCPKNSLL’. Site-directed mutagenesis of these epitopes confirmed their locations at the functional loops of CTX. These epitope sequences are crucial to CTX’s structural folding and cytotoxicity. The results concluded the epitopes that resided within the functional loops constituted potential targets to fabricate synthetic epitopes for CTX-targeted antivenom production.

Ensemble-based molecular docking and spectrofluorometric analysis of interaction between cytotoxin and tumor necrosis factor receptor 1

Cytotoxin (CTX) is a three-finger toxin presents predominantly in cobra venom. The functional site of the toxin is located at its three hydrophobic loop tips. Its actual mechanism of cytotoxicity remains inconclusive as few conflicting hypotheses have been proposed in addition to direct cytolytic effects. The present work investigated the interaction between CTX and death receptor families via ensemble-based molecular docking and fluorescence titration analysis. Multiple sequence alignments of different CTX isoforms obtained a conserved CTX sequence. The three-dimensional structure of the conserved CTX was later determined using homology modelling, and its quality was validated. Ensemble-based molecular docking of CTX was performed with different death receptors, such as Fas-ligand and tumor necrosis factor receptor families. Our results showed that tumor necrosis factor receptor 1 (TNFR1) was the best receptor interacting with CTX attributed to the interaction of all three functional loops and evinced with low HADDOCK, Z-score and RMSD value. The interaction between CTX and TNFR1 was also supported by a concentration-dependent reduction of fluorescence intensity with increasing binding affinity. The possible intermolecular interactions between CTX and TNFR1 were Van der Waals forces and hydrogen bonding. Our findings suggest a possibility that CTX triggers apoptosis cell death through non-covalent interactions with TNFR1.

The secretory phenotypes of envenomed cells: Insights into venom cytotoxicity.

Snake envenomation is listed as Category A Neglected Tropical Diseases (NTD) by World Health Organization, indicates a severe public health problem. The global figures for envenomation cases are estimated to be more than 1.8 million annually. Even if the affected victims survive the envenomation, they might suffer from permanent morbidity due to local envenomation. One of the most prominent local envenomation is dermonecrosis. Dermonecrosis is a pathophysiological outcome of envenomation that often causes disability in the victims due to surgical amputations, deformities, contracture, and chronic ulceration. The key venom toxins associated with this local symptom are mainly attributed to substantial levels of enzymatic and non-enzymatic toxins as well as their possible synergistic actions. Despite so, the severity of the local tissue damage is based on macroscopic observation of the bite areas. Furthermore, limited knowledge is known about the key biomarkers involved in the pathogenesis of dermonecrosis. The current immunotherapy with antivenom is also ineffective against dermonecrosis. These local effects eventually end up as sequelae. There is also a global shortage of toxins-targeted therapeutics attributed to inadequate knowledge of the actual molecular mechanisms of cytotoxicity. This chapter discusses the characterization of secretory phenotypes of dermonecrosis as an advanced tool to indicate its severity and pathogenesis in envenomation. Altogether, the secretory phenotypes of envenomed cells and tissues represent the precise characteristics of dermonecrosis caused by venom toxins.

The effects of Naja sumatrana venom cytotoxin, sumaCTX on alteration of the secretome in MCF-7 breast cancer cells following membrane permeabilization

Naja sumatrana venom cytotoxin (sumaCTX) is a basic protein which belongs to three-finger toxin family. It has been shown to induce caspase-dependent, mitochondrial-mediated apoptosis in MCF-7 cells at lower concentrations. This study aimed to investigate the alteration of secretome in MCF-7 cells following membrane permeabilization by high concentrations of sumaCTX, using label-free quantitative (LFQ) approach. The degree of membrane permeabilization of sumaCTX was determined by lactate dehydrogenase (LDH) assay and calcein-propidium iodide (PI) assays. LDH and calcein-PI assays revealed time-dependent membrane permeabilization within a narrow concentration range. However, as toxin concentrations increased, prolonged exposure of MCF-7 cells to sumaCTX did not promote the progression of membrane permeabilization. The secretome analyses showed that membrane permeabilization was an event preceding the release of intracellular proteins. Bioinformatics analyses of the LFQ secretome revealed the presence of 105 significantly distinguished proteins involved in metabolism, structural supports, inflammatory responses, and necroptosis in MCF-7 cells treated with 29.8 μg/mL of sumaCTX. Necroptosis was presumably an initial stress response in MCF-7 cells when exposed to high sumaCTX concentration. Collectively, sumaCTX-induced the loss of membrane integrity in a concentration-dependent manner, whereby the cell death pattern of MCF-7 cells transformed from apoptosis to necroptosis with increasing toxin concentrations.

Naja sumatrana venom cytotoxin, sumaCTX exhibits concentration-dependent cytotoxicity via caspase-activated mitochondrial-mediated apoptosis without transitioning to necrosis

The mechanism of suma-cytotoxin (sumaCTX)-induced cytotoxicity is poorly understood, especially in the transition of cell death pattern. This study examines its cytotoxicity, caspase-3/7 activity, mitochondrial functions, and occurrence of apoptosis. The sumaCTX triggered cytotoxicity in MCF-7 cells before 24 h, with activation of caspase-3/7 and mitochondrial depolarization, followed by a substantial percentage of AV+ apoptotic cells. The absence of HMGB1 suggested apoptosis was the profound cell death independent of its membrane perturbing effect, without transitioning into necrosis. Its cytotoxicity was a concentration-dependent but not time-dependent process. The findings provide valuable insight into mechanisms of sumaCTX-induced cytotoxicity in breast cancer cells.

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