ТОКСИНЫ ЯДА АФРИКАНСКИХ МАМБ (DENDROASPIS SP.) КАК АЛЛЕЛОХИМИЧЕСКИЕ АГЕНТЫ

Д.Б. Гелашвили, Е.Б. Романова

Аннотация


В обзоре рассмотрено современное состояние исследований уникального набора полипептидов яда африканских мамб. Приведена новейшая структурная классификация выделенных из яда мамб полипептидов: пептиды, стабилизированные тремя дисульфидными связями, , дендротоксины (dendrotoxins), ингибиторы трипсина (trypsin inhibitors), кальциклудин (calcicludine); пептиды, стабилизированные четырьмя дисульфидными связями, гомологичные «трехпальцевым» α-нейротоксинам из яда других змей α-нейротоксины (α-neurotoxins), мускариновые токсины (muscarinic toxins), фасцикулины (fasciculins), токсины ангустицепсинового типа (angusticeps type toxins), кальцисептины (calciseptines), мамбалгины (mambalgins). Отдельный класс объединяет полипептиды разных размеров и структур: натрийуретический пептид дендроасписа (Dendroaspis Natriuretic Peptide, DNP), мамбин (mambin: син. dendroaspin), кишечный токсин MIT1 (mamba intestinal toxin1). Обсуждены механизмы действия, разнообразие функций и области применения конкретных полипептидов. Уникальные белки и пептиды яда мамб воздействуют на клеточную мембрану и ассоциированные с ней белки/рецепторы, влияя тем самым на ключевые процессы жизнедеятельности клетки: передачу сигналов, клеточную адгезию, миграцию, пролиферацию и жизнеспособность клеток. Физиологическое действие на органы и ткани делает токсины яда мамб перспективными для использования в качестве лекарственных препаратов, действующих на клеточном и субклеточном уровнях. Успехи в изучении структуры и механизмов действия токсинов на специфические рецепторы в организме приближают к созданию лекарств нового поколения для обезболивания и лечения сердечно-сосудистых заболеваний и других терапевтических средств.

Ключевые слова


африканские мамбы, токсины яда, токсические полипептиды, аллелохимические агенты.

Полный текст:

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Литература


Гелашвили ДБ. Природные токсины в меж- и внутривидовых взаимодействиях человека. Журнал общей биологии. 2002;63(3):258-69.

Гелашвили ДБ, Крылов ВН, Романова ЕБ. Зоотоксинология: биоэкологические и биомедицинские аспекты. Нижний Новгород: Изд-во ННГУ; 2015.

Gelashvili DB. [Natural toxins in inter- and intraspecific interaction of human beings (Elements of Ethnotoxinology)]. Zhurnal Obshey Biologii. 2002;63(3):258-69. (In Russ.)

Gelashvili DB, Krylov VN, Romanova YeB. Zootoksinologiya: Bioekologicheskiye i Biomedicinskiye Aspekty. [Zootoxinology: Bioecological and Biomedical Aspects]. Nizhniy Novgorod: Izdatelstvo Nizhegorodskogo Gosudarstvennogo Universiteta; 2015. (In Russ.)

Adem A, Аsblom A, Johansson G, Mbugua PM, Karlsson E. Affiliations expand toxins from the venom of the green mamba Dendroaspis angusticeps that inhibit the binding of quinuclidinyl benzilate to muscarinic acetylcholine receptors. Biochim Biophys Acta (BBA) Mol Cell Res. 1988;968(3):340-5. doi: 10.1016/0167-4889(88)90025-0.

Adem A, Karlsson E. Muscarinic receptor subtype selective toxins. Life Sci. 1997;60:1069-76. doi: 10.1016/s0024-3205(97)00049-0.

Albrand JP, Blackledge MJ, Pascaud F. NMR and restrained molecular dynamics study of the three-dimensional solution structure of toxin FS2, a specific blocker of the L-type calcium channel, isolated from black mamba venom. Biochemistry. 1995;34:5923-37. doi: 10.1021/bi00017a022.

Anadon A, Martinez-Larranaga MR, Valerio LG. Onchidal and fasciculins. In: R. Gupta (Ed.). Handbook of Toxicology of Chemical Warfare Agents. Academic Press; 2015. P. 411-20. doi: 10.1016/b978-0-12-800159-2.00030-0.

Anderson AJ, Harvey AL, Mbugua PM. Effects of fasciculin 2, an anticholinesterase polypeptide from green mamba venom, on neuromuscular transmission in mouse diaphgragm preparations. Neurosci Lett. 1985;54:123-8. doi: 10.1016/s0304-3940(85)80066-5.

Barber CM, Isbister GK, Hodgson WC. Alpha neurotoxins. Toxicon. 2013;66:47-58. https://doi.org/10.1016/j.toxicon.2013.01.019.

Baron A, Diochot S, Salinas M, Deval E, Noël J, Lingueglia E. Venom toxins in the exploration of molecular, physiological and pathophysiological functions of acid-sensing ion channels. Toxicon. 2013;75:187-204. doi: 10.1016/j.toxicon.2013.04.008.

Bechis G, Granier C, Rietschoten J, Jover E, Rochat H, Miranda F. Purification of six neurotoxins from the venom of Dendroaspis viridis. Primary structure of two long toxins. Eur J Biochem. 1976;68:445-56. doi: 10.1111/j.1432-1033.1976.tb10832.x.

Benishin CG, Sorensen RG, Brown WE, Krueger BK, Blaustein MP. Four polypeptide components of green mamba venom selectively block certain potassium channels in rat brain synaptosomes. Mol Pharmacol. 1988;34:152-9. PMID: 2457792.

Blanchet G, Collet G, Mourier G, Gilles N, Fruchart-Gaillard C, Marcon E, Servent D. Polypharmacology profiles and phylogenetic analysis of three-finger toxins from mamba venom: Case of aminergic toxins. Biochimie. 2014;103:109-17. doi: 10.1016/j.biochi.2014.04.009.

Blanchet G, Upert G, Mourier G, Gilquin B, Gilles N, Servent D. New α-adrenergic property for synthetic MTβ and CM-3 three-finger fold toxins from black mamba. Toxicon. 2013;75:160-7. doi: 10.1016/j.toxicon.2013.04.017.

Boisbouvier J, Albrand J.-P, Blackledge M, Jaquinod M, Schweitz H, Lazdunski M, Marion D. A structural homologue of colipase in black mamba venom revealed by NMR floating disulphide bridge analysis. J Mol Biol. 1998;283:205-19. doi: 10.1006/jmbi.1998.2057.

Bourne Y, Taylor P, Marchot P. Acetylcholinesterase inhibition by fasciculin: Crystal structure of the complex. Cell. 1995;83:503-12. doi: 10.1016/0092-8674(95)90128-0.

Bradley KN. Muscarinic toxins from the green mamba. Pharmac Therap. 2000;85:87-109. doi: 10.1016/s0163-7258(99)00064-9.

De Weille JR, Schweitz H, Maes P, Tartar A, Lazdunski M. Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L-type calcium channel. Proc Natl Acad Sci. 1991;88:2437-40. doi: 10.1073/pnas.88.6.2437.

Dickey DM, Potter LR. Dendroaspis natriuretic peptide and the designer natriuretic peptide, CD-NP, are resistant to proteolytic inactivation. J Mol Cell Card. 2011;51:67-71. doi: 10.1016/j.yjmcc.2011.03.013.

Diochot S, Baron A, Salinas M, Douguet D, Scarzello S, Dabert-Gay A-S, Debayle D, Friend V, Alloui A, Lazdunski M, Lingueglia E. Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature. 2012;490:552-5. doi: 10.1038/nature11494.

Dufton MJ, Harvey AL. Dendrotoxins: How does structure determine function? J Toxicol Tox Rev. 1998;17:161-82. doi: 10.3109/15569549809009248.

Engmark M, Andersen MR, Laustsen AH, Patel J, Sullivan E, De Masi F, Hansen CS, Kringelum JV, Lomonte B, Gutierrez JM, Lund O. High-throughput immuno-profiling of mamba (Dendroaspis) venom toxin epitopes using high-density peptide microarrays. Sci Rep. 2016;6(1):36629. doi: 10.1038/srep36629.

Harel M, Kleywegt GJ, Ravelli RB, Silman I, Sussman JL. Crystal structure of an acetylcholinesterase-fasciculin complex: interaction of a three-fingered toxin from snake venom with its target. Structure. 1995;3:1355-66. doi: 10.1016/s0969-2126(01)00273-8.

Harvey A, Robertson B. Dendrotoxins: structure-activity relationships and effects on potassium ion channels. Curr Med Chem. 2004;11:3065-72. doi: 10.2174/0929867043363820.

Harvey AL. Recent studies on dendrotoxins and potassium ion channels. Gen Pharmacol Vasc Syst. 1997;28:7-12. doi: 10.1016/s0306-3623(96)00173-5.

Harvey AL. Twenty years of dendrotoxins. Toxicon. 2001;39:15-26. doi: 10.1016/s0041-0101(00)00162-8.

Harvey AL, Anderson AJ. Dendrotoxins: snake toxins that block potassium channels and facilitate neurotransmitter release. Pharmacol Ther. 1985;31:33-55. doi: 10.1016/0163-7258(85)90036-1.

Harvey AL, Karlsson E. Protease inhibitor homologues from mamba venoms: facilitation of acetylcholine release and interactions with prejunctional blocking oxins. Br J Pharmacol 1982;77:153-61. doi: 10.1111/j.1476-5381.1982.tb09281.x.

Imredy JP, MacKinnon R. Energetic and structural interactions between δ-dendrotoxin and a voltage-gated potassium channel. J Molec Biol. 2000;296:1283-94. doi: 10.1006/jmbi.2000.3522.

Jolkkonen M, Giersbergen PLM, Hellman U, Wernstedt C, Oras A, Satyapan N, Adem A, Karlsson E. Muscarinic toxins from the black mamba Dendroaspis polylepis. Eur J Biochem. 1995;234:579-85. doi: 10.1111/j.1432-1033.1995.579_b.x.

Joubert FJ, Strydom DJ. Snake venoms. The amino-acid sequence of trypsin inhibitor E of Dendroaspis polylepis polylepis (black mamba) venom. Eur J Biochem. 1978;87:191-8. doi: 10.1111/j.1432-1033.1978.tb12366.x.

Joubert FJ, Taljaard N. Some properties and the complete primary structures of two reduced and S-carboxymethylated polypeptides (S5C1 and S5C10) from Dendroaspis jamesoni kaimosae (Jameson’s mamba) venom. Biochim Biophys Acta. 1979;579:228-33. doi: 10.1016/0005-2795(79)90101-6.

Joubert FJ, Taljaard N. The complete primary structures of two reduced and S-carboxymethylated angusticeps-type toxins from Dendroaspis angusticeps (green mamba) venom. Biochim Biophys Acta. 1980;623:449-56. doi: 10.1016/0005-2795(80)90274-3.

Joubert FJ, Taljaard N. Snake Venoms. The amino acid sequences of two proteinase inhibitor homologues from Dendroaspis angusticeps venom. Hoppe Seylers Z Physiol Chem. 1980;361(1):661-74. doi: 10.1515/bchm2.1980в. 361.1.661.

Karlsson E. Snake toxins with high selectivity for subtypesof muscarinic acetylcholine receptors. Biochimie. 2000;82:793-806. doi: 10.1016/s0300-9084(00)01176-7.

Karlsson E, Mbugua PM, Rodriguez-Ithurralde D. Fasciculins, anticholinesterase toxins from the venom of the green mamba Dendroaspis angusticeps. J Physiol (Paris). 1984;79:232-40. PMID: 6530667.

Karlsson E, Mbugua PM, Rodriguez-Ithurralde D. Anticholinesterase toxins. Pharmacol Ther. 1985;30:259-76. doi: 10.1016/0163-7258(85)90051-8.

Kasturiratne A, Wickremasinghe AR, de Silva N, Gunawardena NK, Pathmeswaran A, Premaratna R, Savioli L, Lalloo DG, de Silva HJ. The global burden of snakebite: A literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Med. 2008;5(11):e218. doi: 10.1371/journal.pmed.0050218.

Kodama RT, Kuniyoshi AK, da Silva CCF, Cajado-Carvalho D, Duzzi B, Mariano DC, Pimenta DC, Borges R, da Silva WD, Portaro FCV. A Kunitz-type peptide from Dendroaspis polylepis venom as a simultaneous inhibitor of serine and cysteine proteases. J Venom Anim Toxins Incl Trop Dis. 2020;26:e20200037. https://doi.org/10.1590/1678-9199-JVATITD-2020-0037.

Kuroda H, Chen YN, Watanabe TX, Chen YN, Watanabe TX, Kimura T, Sakakibara S. Solution synthesis of calciseptine, an L-type specific calcium channel blocker. Pept Res. 1992;5:265-8. PMID: 1450521.

Lee CY, Tsai MC, Tsaur ML, Lin WW, Carlsson FH, Joubert FJ. Pharmacological study on angusticeps-type toxins from mamba snake venoms. J Pharmacol Exp Ther. 1985;233:491-8. PMID: 3158733.

Lu X, Sun Y, Shang D, Wattam B, Egglezou S, Hughes T, Hyde E, Scully M, Kakkar V. Evaluation of the role of proline residues flanking the RGD motif of dendroaspin, an inhibitor of platelet aggregation and cell adhesion. Biochemical J. 2001;355(3):633-8. doi: 10.1042/bj3550633.

Lu X, Davies J, Lu D, Xia M, Wattam B, Shang D, Sun Y, Scully M, Kakkar V. The effect of the single substitution of arginine within the RGD tripeptide motif of a modified neurotoxin dendroaspin on its activity of platelet aggregation and cell adhesion. Cell Commun Adhes. 2006;13(3):171-83. doi: 10.1080/15419060600726183.

Marchot P, Khelif A, Ji Y-H, Mansuelle P, Bougis PE. Binding of 1251-fasciculin to rat brain acetylcholinesterase. The complex still binds diisopropyl fluorophosphates. J Biol Chem. 1993;268(17):12458-67. https://doi.org/10.1016/S0021-9258(18)31411-X.

Marchot P, Bougis PE. Elapidae Toxins: The fasciculins, and their interaction with acetylcholinesterase. Animal Toxins. 2000:246-75. doi: 10.1007/978-3-0348-8466-2_16.

McDiarmid RW, Campbell JA, Toure TA. Snake Species of the World. A Taxonomic and Geographic Reference. (Vol. 1). Herpetologists League, Washington, D.C., 1999.

McDowell RS, Dennis MS, Louie A, Shuster M, Mulkerrin MG, Lazarus RA. Mambin, a potent glycoprotein IIb-IIIa antagonist and platelet aggregation inhibitor structurally related to the short neurotoxins. Biochemistry. 1992;31:4766-72. doi: 10.1021/bi00135a004.

Menez A, Stöcklin R, Mebs D. «Venomics» or: The venomous systems genome project. Toxicon. 2006;7(3): 255-9. doi: 10.1016/j.toxicon.2005.12.010.

Mourier G, Salinas M, Kessler P, Stura EA, Leblanc M, Tepshi L, Besson T, Diochot S, Baron A, Douguet D, Lingueglia E, Servent D. Mambalgin-1 pain-relieving peptide, stepwise solid-phase synthesis, crystal structure, and functional domain for acid-sensing ion channel 1a inhibition. J Biol Chem. 2016;291:2616-29. doi: 10.1074/jbc.m115.702373.

Nagai-Okatani C, Kangawa K, Minamino N. Three molecular forms of atrial natriuretic peptides: quantitative analysis and biological characterization. J Pept Sci. 2016;23:486-95. doi: 10.1002/psc.2969.

Näreoja K, Kukkonen J, Rondinelli S, Toivola DM, Meriluoto J, Näsman J. Adrenoceptor activity of muscarinic toxins identified from mamba venoms. Br J Pharmacol. 2011;164:538-50. doi: 10.1111/j.1476-5381.2011.01468.x.

Nishio H, Katoh E, Yamazaki T, Inui T, Nishiuchi Y, Kimura T. Structure-activity relationships of calcicludine and dendrotoxin-I, homologous peptides acting on different targets, calcium and potassium channels. Biochem Biophys Res Commun. 1999;262:319-21. doi: 10.1006/bbrc.1999.1198.

Park S-A, Kim T-G, Han M-K, Ha K-C, Kim S-Z, Kwak Y-G. Dendroaspis natriuretic peptide regulates the cardiac L-type Ca2+channel activity by the phosphorylation of α1cproteins. Exp Mol Med. 2012;44:363-8. doi: 10.3858/emm.2012.44.6.041.

Rodriguez-Ithurralde D, Silveira R, Barbeito L, Dajas F. Fasciculin, a powerful anticholinesterase polypeptide from Dendroaspis angusticeps venom. Neurochem Int. 1983;5:267-74. doi: 10.1016/0197-0186(83)90028-1.

Salinas M, Besson T, Delettre Q, Diochot S, Boulakirba S, Douguet D, Lingueglia E. Binding Site and Inhibitory Mechanism of the Mambalgin-2 Pain-relieving Peptide on Acid-sensing Ion Channel 1a. J Biol Chem. 2014;289:13363-73. doi: 10.1074/jbc.m114.561076.

Schweitz H, Heurteaux C, Bois P, Moinier D, Romey G, Lazdunski M. Calcicludine, a venom peptide of the Kunitz-type protease inhibitor family, is a potent blocker of high-threshold Ca2+ channels with a high affinity for L-type channels in cerebellar granule neurons. Proc Natl Acad Sci USA. 1994;91:878-82. doi: 10.1073/pnas.91.3.878.

Schweitz H, Moinier D. Mamba toxins. Persp Drug Discov Design. 1999;15:83-110. doi.org/10.1023/A:1017043518954.

Schweitz H, Pacaud P, Diochot S, Moinier D, Lazdunski M. MIT1, a black mamba toxin with a new and highly potent activity on intestinal contraction. FEBS Lett. 1999;461:183-8. doi: 10.1016/s0014-5793(99)01459-3.

Schweitz H, Vigne P, Moinier D, Frelin C, Lazdunski M. A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis angusticeps). J Biol Chem. 1992;267:13928-32. doi: 10.1016/s0021-9258(19)49658-0.

Servent D, Blanchet G, Mourier G, Marquer C, Marcon E, Fruchart-Gaillard C. Muscarinic toxins. Toxicon. 2011;58:455-63. doi: 10.1016/j.toxicon.2011.08.004.

Servent D, Fruchart-Gaillard C. Muscarinic toxins: tools for the study of the pharmacological and functional properties of muscarinic receptors. J Neurochem. 2009;109:1193-202. doi: 10.1111/j.1471-4159.2009.06092.x.

Sigle R, Hackett M, Aird SD. Primary structures of four trypsin inhibitor E homologs from venom of Dendroaspis angusticeps: structure-function comparisons with other dendrotoxin homologs. Toxicon. 2002;40:297-308. doi: 10.1016/s0041-0101(01)00227-6.

Skarżynski T. Crystal structure of α-dendrotoxin from the green mamba venom and its comparison with the structure of bovine pancreatic trypsin inhibitor. J Mol Biol. 1992;224:671-83. doi: 10.1016/0022-2836(92)90552-u.

Stotz SC, Spaetgens RL, Zamponi GW. Block of voltage-dependent calcium channel by the green mamba toxin calcicludine. J Membr Biol. 2000;74:157-65. doi: 10.1007/s002320001040.

Strydom DJ. Snake venom toxins. The amino acid sequences of two toxins from Dendroaspis polylepis polylepis (black mamba) venom. J Biol Chem. 1972;247:4029-42. https://doi.org/10.1016/S0021-9258(19)45135-1.

Strydom DJ. Snake venom toxins. The amino-acid sequence of a short-neurotoxin homologue from Dendroaspis polylepis polylepis (black mamba) venom. Eur J Biochem. 1977;76:99-106. doi: 10.1111/j.1432-1033.1977.tb11574.x.

Strydom DJ. Snake venom toxins. Purification and properties of low-molecular eight polypeptides of Dendroaspis polylepis polylepis (black mamba) venom. Eur J Biochem. 1976;69:169-76. doi: 10.1111/j.1432-1033.1976.tb10870.x.

Strydom DJ, Joubert FJ. The amino acid sequence of a weak trypsin inhibitor B from Dendroaspis polylepis polylepis (black mamba) venom. Hoppe Seylers Z Physiol Chem. 1981;362:1377-84. doi: 10.1515/bchm2.1981.362.2.1377.

Sun D, Yu Y, Xue X, Pan M, Wen M, Li S, Qu Q, Li X, Zhang L, Li X, Liu L, Yang M, Tian C. Cryo-EM structure of the ASIC1a-mambalgin-1 complex reveals that the peptide toxin mambalgin-1 inhibits acid-sensing ion channels through an unusual allosteric effect. Cell Discovery. 2018;4:27. doi: 10.1038/s41421-018-0026-1.

Sutcliffe MJ, Jaseja M, Hyde EI. Three-dimensional structure of the RGD-containing neurotoxin homologue dendroaspin. Nat Struct Biol. 1994;1:802-7. doi: 10.1038/nsb1194-802.

Tytgat J, Vandenberghe I, Ulens C, Beeumen JV. New polypeptide components purified from mamba venom. FEBS Lett. 2001;491:217-21. doi: 10.1016/s0014-5793(01)02201-3.

Wang C-IA, Reeks T, Vetter I, Vergara I, Kovtun O, Lewis RJ, Alewood PF, Durek T. Isolation and structural and pharmacological characterization of α-Elapitoxin-Dpp2d, an amidated three finger toxin from black mamba venom. Biochemistry. 2014; 53:3758-66. doi: 10.1021/bi5004475.

Watanabe TX, Itahara Y, Kuroda H, Chen YN, Kimura T, Sakakibara S. Smooth muscle relaxing and hypotensive activities of synthetic calciseptine and the homologous snake venom peptide FS2. Jpn J Pharmacol. 1995;68(3):305-13. doi: 10.1254/jjp.68.305.

Wattam B, Shang D, Rahman S, Egglezou S, Scully M, Kakkar V, Lu X. Arg-Tyr-Asp (RYD) and Arg-Cys-Asp (RCD) motifs in dendroaspin promote selective inhibition of β1 and β3 integrins. Biochem J. 2001;356:11-7. doi: 10.1042/bj3560011.

Whittaker RH, Feeny PP. Allelochemics: Chemical interactions between species. Science. 1971;17(3973):757-70. doi: 10.1126/science.171.3973.757

Williams JA, Lu X, Rahman S. Dendroaspin: A potent integrin receptor inhibitor from the venoms of Dendroaspis viridis and D. jamesonii. Biochem Soc Trans. 1992;21:73S. doi: 10.1042/bst021073s.




DOI: http://dx.doi.org/10.24855/biosfera.v15i3.824

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