vestichИзвестия Национальной академии наук Беларуси. Серия химических наукProceedings of the National Academy of Sciences of Belarus, Chemical Series1561-83312524-2342The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1561-8331-2020-56-4-494-512vestich-621Research ArticleОБЗОРЫМногоцелевые биореакторы на основе фосфолиполизаMulti-purpose bioreactors based on phospholipolysisЛитвинкоН. М.LitvinkoN. M.

Литвинко Наталья Михайловна - доктор химических наук, доцент, заведующий лабораторией.

Ул. Акад. В. Ф. Купревича, 5/2, 220141, Минск

, Республика Беларусь). E-mail: al_h@mail.ru

Natalia M. Litvinko - D. Sc. (Chemistry), Associate Professor, Head of the laboratory.

5/2, Acad. V. F. Kuprevich Str., 220141, Minsk

al_h@mail.ruИнститут биоорганической химии, Национальная академия наук БеларусиInstitute of Bioorganic Chemistry, National Academy of Sciences of Belarus202005122020564494512Copyright © Литвинко Н.М., 20202020Литвинко Н.М.Litvinko N.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestichem.belnauka.by/jour/article/view/621

Представлен обзор основных экспериментальных результатов в области новых направлений (энзимо-терапия и энзимодиагностика) практического использования ферментативного гидролиза фосфолипидов (фосфолиполиза), нарушение которого приводит к развитию ряда социально опасных заболеваний: онкологических, сердечнососудистых, инфекционных, воспалительных и т. д. Разработан ряд многоцелевых биореакторов на основе использования ферментов фосфолипаз А2 (ФЛА2), принимающих участие в фосфолиполизе: одноферментные нанореакторы ФЛА2-лиганд и сопряженные биферментные нанореакторы; ФЛА2-гемоглобин; ФЛА2-миоглобин; ФЛА2-цитохром Р-450 (CYP2B4) и ФЛА2- цитохром Р-450 (CYP3A4).

Overview of the main experimental results in the field of new directions of phospholipolysis practical applications - enzyme therapy and diagnostics are presented. Phospholipases, which are enzymes that hydrolyze phospholipids, are known as markers of socially dangerous diseases: oncological, cardiovascular, infectious, inflammatory, etc. We proposed a number of diagnostic biosystems based on phosphatideacylhydrolases and hemoproteins: Phospholipase A2-ligand, Phospholipase A2-cytochrome P450, Phospholipase A2-myoglobin, Phospholipase A2-hemoglobin. The latter system was used to produce and implement for the first time in the clinical practice the diagnostic kit PLA2-PHOA for identifying patients with necrotic pancreatitis. The results of preclinical and clinical testing of the PLA2-PHOA kit for the detection of pancreatitis based on the determination of the activity of phospholipase A2 of blood are presented and discussed.

фосфолипаза А2фосфолиполиздиагностические биосистемыphospholipase A2phospholipolysisdiagnostic biosystemsАвтор выносит благодарность всем коллегам, участвовавшим в выполнении перечисленных выше исследований. Значительный вклад в эту работу внесли старший научный сотрудник Скоростецкая Л. А., магистры А. Н. Мартынюк, Ю. Ш. Ермакович и Е. А. Ремеева, канд. биол. наук С. В. Кучуро, кандидат химических наук Г. Н. Антончик, кандидат химических наук Д. О. ГерловскийAuthor expresses her gratitude to all colleagues who participated in the implementation of the above studies. A significant contribution to this work was made by Senior Researcher L. A. Skorostetskaya, Masters A. N. Martynyuk, Yu. Sh. Ermakovich and E. A. Remeeva, Ph. D. (Biology) S. V. Kuchuro, Ph. D. (Chemistry) G. N. Antonchik, Ph. D. (Chemistry) D. O. GerlovskyReferencesMouchlis, V. D. Phospholipase A2 catalysis and lipid mediator lipidomics / V. D. Mouchlis, E. A. Dennis // BBA - Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 766-771 https://https://doi.org/10.1016/j.bbalip.2018.08.010Mouchlis V. D., Dennis E. A. Phospholipase A2 catalysis and lipid mediator lipidomics. BBA - Molecular and Cell Biology of Lipids, 2019, vol. 1864, no 6, pp. 766-771. https://doi.org/10.1016/j.bbalip.2018.08.010Kita, Y. Cytosolic phospholipase A2 and lysophospholipid acyltransferases / Y. Kita, H. Shindou, T. Shimizu // BBA -Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 838-845. https://doi.org/10.1016Zj.bbalip.2018.08.006.Kita Y., Shindou H., Shimizu T. Cytosolic phospholipase A2 and lysophospholipid acyltransferases. BBA - Molecular and Cell Biology of Lipids, 2019, vol. 1864, no. 6, pp. 838-845. https://doi.org/10.1016/j.bbalip.2018.08.006Kono, N. Platelet-activating factor acetylhydrolases: An overview and update / N. Kono, H. Arai // BBA - Molecular and Cell Biology of Lipid. - 2019. - Vol. 1864, N 6. - P. 922-931. https://doi.org/10.1016/j.bbalip.2018.07.006Kono N., Arai, H. Platelet-activating factor acetylhydrolases: An overview and update. BBA - Molecular and Cell Biology of Lipids, 2019, vol. 1864, no. 6, pp. 922-931. https://doi.org/10.1016/j.bbalip.2018.07.006Murakami, M. Group IID, IIE, IIF and III secreted phospholipase A2s / M. Murakami, Y. Taketomi, K. Yamamoto // BBA - Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 803-818. https://https://doi.org/10.1016/j.bbalip.2018.08.014Murakami M., Miki Y., Sato H., Murase R., Taketomi Y., Yamamoto K. Group IID, IIE, IIF and III secreted phospholipase A2s. BBA - Molecularand Cell Biology of Lipids, 2019, vol. 1864, no. 6, pp. 803-818. https://doi.org/10.1016/j.bbalip.2018.08.014Murakami, M. Novel functions of phospholipase A2s: Overview / M. Murakami // BBA - Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 763-765. https://doi.org/10.1016/j.bbalip.2019.02.005Murakami M. Novel functions of phospholipase A2s: Overview. BBA - Molecular and Cell Biology of Lipids, 2019, 2019, vol. 1864, no. 6, pp. 763-765. https://doi.org/10.1016/j.bbalip.2019.02.005Hirabayashi, T. The role of PNPLA1 in ro-O-acylceramide synthesis and skin barrier function Z T. Hirabayashi, M. Murakami, A. Kihara // BBA - Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 869-879. https://doi:10.1016/j.bbalip.2018.09.010Hirabayashi T., Murakami M. Kihara A. The role of PNPLA1 in ro-O-acylceramide synthesis and skin barrier function. BBA - Molecular and Cell Biology of Lipids, 2019, vol. 1864, no. 6, pp. 869-879. https://doi.org/10.1016/j.bbalip.2018.09.010Hui, D. Y. Group 1B phospholipase A2 in metabolic and inflammatory disease modulation / D. Y. Hui // BBA - Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 784-788. https://doi.org/10.1016/j.bbalip.2018.07.001Hui D. Y. Group 1B phospholipase A2 in metabolic and inflammatory disease modulation. BBA - Molecular and Cell Biology of Lipids, 2019, vol. 1864, no. 6, pp. 784-788. https://doi.org/10.1016/j.bbalip.2018.07.001Function of secreted phospholipase A2 group-X in asthma and allergic / J. D. Nolina [et al.] // BBA - Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 827-837. https://doi.org/10.1016/j.bbalip.2018.11.009Nolina J. D., Murphya R. C., Gelbb M. H., Altemeiera W.A., Henderson W. R. Jr., Hallstrand T. S. Function of secreted phospholipase A2 group-X in asthma and allergic. BBA - Molecular and Cell Biology of Lipids, 2019, vol. 1864, no. 6, pp. 827-837. https://doi.org/10.1016/j.bbalip.2018.11.009]Tappia, P. S. Phospholipases in Health and Disease / P. S. Tappia, N. S. Dhalla. - New York: Springer, 2014. - 410 p. https://doi.org/10.1007/978-1-4939-0464-8Tappia P. S., Dhalla N. S. Phospholipases in Health and Disease. New York: Springer, 2014, 410 p. https://doi.org/10.1007/978-1-4939-0464-8Samuchiwal, S. K. Harmful and protective roles of group V phospholipase A2: Current perspectives and future directions / S. K. Samuchiwal, B. Balestrieri // BBA - Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 819-826. https://doi:10.1016/j.bbalip.2018.10.001Samuchiwal S. K., Balestrieri B. Harmful and protective roles of group V phospholipase A2: Current perspectives and future directions. BBA - Molecular and Cell Biology of Lipids, 2019, vol. 1864, no. 6, pp. 819-826. https://doi:10.1016/j.bbalip. 2018.10.001Kaiser, E. Phospholipase A2: its usefulness in laboratory diagnostics / E. Kaiser // Crit. Rev. Clin. Lab. Sci. - 1999. -Vol. 36, N 2. - P. 65-163. https://doi.org/10.1080/10408369991239187Kaiser E. Phospholipase A2: its usefulness in laboratory diagnostics // Critical Reviews in Clinical Laboratory Sciences, 1999, vol. 36, no. 2, pp. 65-163. https://doi.org/10.1080/10408369991239187Камышников, В. С. Липопротеин-ассоциированная и секреторная фосфолипазы А2: особенности метаболического влияния и клиническая значимость / В. С. Камышников [и др.] // Лабораторией диагностика. Восточная Европа. - 2017. -Т. 6, № 2. - С. 44-55.Kamyshnikov V., Litvinko N., Pekhtereva N., Yakovlev-Malykh N., Yuraga T. Lipoprotein-associated and secretory phospholipase А2: features of metabolic influence and clinical significance of research. Laboratornaya diagnostika. Vosto-chnaya Evropa=Laboratory diagnostics. Eastern Europe, 2017, vol. 6, no. 2, pp. 44-55 (in Russian).Serum phospholipase A and prognosis in intensive care patients / R. Schaefer [et al.] // J. Clin. Chem. Clin. Biochem. -1990. - Vol. 28, N 4. - P. 253-254.Schaefer R., Teschner M., Penzel W., Habscheid W., Heidland A., Hoffmann G. E. Serum phospholipase A and prognosis in intensive care patients. Journal of Clinical Chemistry and Clinical biochemistry, 1990. vol. 28, no. 4, pp. 253-254.Dore, E. Roles of secreted phospholipase A2 group IIA in inflammation and hostdefense / E. Dore, E. Boilard // BBA -Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 789-802. https://doi.org/10.1016/j.bbalip.2018.08.017Dore E., Boilard E. Roles of secreted phospholipase A2 group IIA in inflammation and host defense. BBA - Molecular and Cell Biology of Lipids, 2019, vol. 1864, no. 6, pp. 789-802. https://doi.org/10.1016/j.bbalip.2018.08.017Способ дифференциальной диагностики вирусного гепатита и подпеченочной желтухи: а. с. 1296936 СССР / В. Н. Никифоров, М. В. Шмавонян, П. А. Казарян, А. Л. Мхитарян, Д. С. Вопян.- Опубл. 15.03.87.Nikiforov V. N., Shmavonyan M. V., Kazaryan P. A., Mkhitaryan A. L., Vopyan D. S. Method of differential diagnosis of viral hepatitis and subhepatic jaundice. Author’s certificate 1296936 USSR. Publ. date 15.03.1987 (in Russian).Light-generating methods using dioxyethanes activated by anchimeric cleavage: Patent no. 5248618 USA / A. Haces. -Publ. date 28.09.1993.Haces A. Light-generating methods using dioxyethanes activated by anchimeric cleavage. Patent no. 5248618 USA. Publ. date 28.09.1993.Degradation of annexin I in bronchoalveolar lavage fluid in patients with cystic fibrosis / F. H. C. Tsao [et al.] // Am. J Respir. Cell. Mol. Biol. - 1998. - Vol.18, N 1. - P. 120-128. https://doi.org/10.1165/ajrcmb.18.1.2808Tsao F. H. C., Meyer K. C., Chen X., Rosenthal N. S., Hu J. Degradation of annexin I in bronchoalveolar lavage fluid in patients with cystic fibrosis. American Journal of Respiratory Cell and Molecular Biology, 1998, vol. 18, no. 1, pp. 120-128. https://doi.org/10.1165/ajrcmb.18.1.2808Diagnostic test for the detection of type IV cytosolic phospholipase A2 (cPLA2): UK Patent GB19990005417 / A. C. A. Glen, D. J. McDonald. - Publ. date: 27.02.2004.Glen A. C. A., McDonald D. J. Diagnostic test for the detection of type IV cytosolic phospholipase A2 (cPLA2). UK Patent GB19990005417. Publ. date 27.02.2004.Nevalainen, T. J. Serum phospholipases A2 in inflammatory diseases / T. J. Nevalainen // Clin. Chem. - 1993. - Vol. 39, no. 12. - P. 2453-2459. https://doi.org/10.1093/clinchem/39.12.2453Nevalainen T. J. Serum phospholipases A2 in inflammatory diseases. Clinical Chemistry, 1993, vol. 39, no. 12, pp. 2453-2459. https://doi.org/10.1093/clinchem/39.12.2453Nevalainen, T. The role of phospholipase A2 in acute pancreatitis / T. Nevalainen // Z. Med. Lab. Diagn. - 1989. - Vol. 30, N 6. - P. 299-303.Nevalainen T. The role of phospholipase A2 in acute pancreatitis. Zeitschrift fur medizinische Laboratoriums diag-nostik, 1989, vol. 30, no. 6, pp. 299-303.Application of a new monoclonal antibody for time-resolved fluoroimmunoassay of human pancreatic phospholipase A2 / S. A. Santavuori [et al.] // Clin. Chem. Lab. Med. - 1991. - Vol. 29, N 12. - P. 819-826. https://doi.org/10.1515/cclm.1991.29.12.819Santavuori S. A., Kortesuo P. T., Eskola J. U., Nevalainen T. J. Application of a new monoclonal antibody for time-resolved fluoroimmunoassay of human pancreatic phospholipase A2 Clinical Chemistry and Laboratory Medicine, 1991, vol. 29, no. 12, pp. 819-826. https://doi.org/10.1515/cclm.1991.29.12.819 .Фосфолипазы плазмы крови при ожоговом шоке / Т. Л. Заец [и др.] // Бюлл. эксп. биол. мед. - 1987. - Т. 103. -С. 403-404.Zayets T.L., Lavrov V.A., Marchuk A.I., Nosova I. M. Phospholipases of blood plasma in burn shock.Byulleten’ eks-perimental noi biologii i meditsiny = Bulletin of Experimental Biology and Medicine, 1987, vol. 103, pp. 403-404 (in Russian).Makela, A. Serum phospholipase A2, amylase, lipase, and urinary amylase activities in relation to the severity of acute pancreatitis / A. Makela, T. Kuusi, T. Schroder // Eur. J. Surg. - 1997. - Vol. 163, N 12. - P. 915-922.Makela A. Kuusi T., Schroder T. Serum phospholipase A2, amylase, lipase, and urinary amylase activities in relation to the severity of acute pancreatitis. European journal of surgery, 1997, vol. 163, no. 12, pp. 915-922.Photometric test to measure the enzymatic activity of pancreatic phospholipase A2 to distinguish between mild and severe (necrotizing) forms of acute pancreatitis in serum or plasma: DE Patent № DE19530410.1 / U. Helfrich. - Publ. date 20.02.1997.Helfrich U. Photometric test to measure the enzymatic activity of pancreatic phospholipase A2 to distinguish between mild and severe (necrotizing) forms of acute pancreatitis in serum or plasma. DE Patent № DE19530410.1. Publ. date 20.02.1997.Measurement of Phospholipase A2 Polypeptide in Tissue Cells: Patent 5747264 USA / C. J. Schmidt, F. Tobin, F. E. Wilkinson. - Publ. date 05.05.1998.Schmidt C. J., Tobin F., Wilkinson F. E. Measurement of Phospholipase A2 Polypeptide in Tissue Cells. US Patent no. 5747264. Publ. date 05.05.1998.Human phospholipase activating protein and methods for diagnosis of rheumatoid arthritis: Patent № US 626589 / J. Bomalaski, S. Clark, M. A. Shorr, Robert G. L.; applicant and patent holder J. Bomalaski, S. Clark, M. A. Shorr, G. L. Robert. - Publ. date 25.06.92.Bomalaski J., Clark S., Shorr M. A., Robert G. L.; applicant and patent holder Bomalaski J., Clark S., Shorr M. A., Robert G. L. Human phospholipase activating protein and methods for diagnosis of rheumatoid arthritis. Patent № US 626589. Publ. date 25.06.92.PLA2 activity as a marker for ovarian and other gynecologic cancers: Patent USA №US20130045947 / Yan Xu. -Publ. date 21.02.2013.Yan Xu.PLA-2 activity as a markerfor ovarian and other gynecologic cancers. Patent no. US20130045947. Publ. date 21.02.2013.Method for evaluating blood-neural barrier permeability: US Patent no. 8349577 / Kh. Iqbal, S. Chalbot, I.Grund-ke-Iqbal. - Publ. date 08.01.2013.Iqbal Kh., Chalbot S., Grundke-Iqbal I. Method for evaluating blood-neural barrier permeability. US Patent no. 8349577. Publ. date 08.01.2013.Methods for detecting Lp-PLA2 activity and inhibition of Lp-PLA2 activity / Yaping Shou, Yin-Fai Siu, George T. Walker. - Publ. date 01.11. 2012.Yaping Shou, Yin-Fai Siu, George T. Walker. Methods for detecting Lp-PLA2 activity and inhibition of Lp-PLA2 activity. US Patentno. US20120276569. Publ. date 01.11. 2012.Methods for detecting Lp-PLA2 activity and inhibition of Lp-PLA2 activity: US Patent no. US8846309B2 / Yaping Shou, Yin-Fai Siu, George T. Walker. - Publ. date 30.09. 2014.Yaping Shou, Yin-Fai Siu, George T. Walker. Methods for detecting Lp-PLA2 activity and inhibition of Lp-PLA2 activity. US Patent no. US8846309B2. Publ. date 30.09. 2014.Methods for detecting Lp-PLA2 activity and inhibition of Lp-PLA2 activity: US Patent no. US20150017671 / Yaping Shou, Yin-Fai Siu, George T. Walker. - Publ. date 15.01. 2015.Yaping Shou, Yin-Fai Siu, George T. Walker. Methods for detecting Lp-PLA2 activity and inhibition of Lp-PLA2 activity. US Patent no. US20150017671. Publ. date 15.01. 2015.Methods for detecting Lp-PLA2 activity and inhibition of Lp-PLA2 activity: US Patent no. US20150247858 / Yaping Shou, Yin-Fai Siu, George T. Walker. - Publ. date 03.09. 2015.Yaping Shou, Yin-Fai Siu, George T. Walker. Methods for detecting Lp-PLA2 activity and inhibition of Lp-PLA2 activity. US Patent no US20150247858. Publ. date 03.09. 2015.Methods of detecting Lp-PLA2 activity: Patent no. WO2005074604A2 / Xiaozhu Duan, Nam Kim, Robert L. Wolfert. - Publ. date 18.08.2005.Xiaozhu Duan, Nam Kim, Robert L Wolfert. Methods of detecting Lp-PLA2 activity.Patentno. WO2005074604 A2. Publ. date. 18.08.2005.Phospholipid oxidation and Lp-PLA2 as predictors of coronary artery disease. Patent US20090317819/ SotiriosTsimi-kas, JosephWitztum. - Publ. date 24.12.2009.Sotirios Tsimikas, Joseph Witztum. Phospholipid oxidation and LP-PLA2 as predictors of coronary artery disease. Patent no. US20090317819. Publ. date 24.12.2009.Compositions and methods for inhibition of phospholipase A2 mediated inflammation. Patent no. WO2003076389A1/ E. Dennis, T. Yaksh, K. Killermann Lucas, C. Svensson, D. A. Six, G. Kokotos, V. Constantinou-Kokotou. - Publ. date 18.09.2003.Dennis E., Yaksh T., Killermann Lucas K., Svensson C., Six D. A., Kokotos G., Constantinou-Kokotou V. Compositions and methods for inhibition ofphospholipase A2 mediated inflammation. Patent no. WO2003076389A1. Publ. date 18.09.2003.Single-photon emission computed tomography Positron Emission Tomography (PET): Patentno. 2019063634 USA / O. Melina, E. Jestin, F. Guibbal, S. Benard. - Publ. date 4.04.2019.Melina O., Jestin E., Guibbal F., Benard S. Single-photon emission computed tomography Positron Emission Tomography (PET).US Patent no. 2019063634. Publ. date 04.04.2019.Литвинко, Н. М. Прикладная энзимология фосфатидацилгидролаз в изучении взаимосвязи структура-функция в ряду биополимеров и низкомолекулярных биорегуляторов / Н. М. Литвинко // Вес. Нац. акад. навук Беларусь Сер. xiM. навук. - 2017. - № 3. - С. 115-128.Litvinko N. M.Applied enzymology of phosphatidacylhydrolases in a study of the structure-function relationship in the series of biopolymers and low-molecular bioregulators. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seryya khi-michnykh navuk = Proceedings of the National Academy of Sciences of Belarus. Chemical series, 2017, no. 3, pp. 115-128 (in Russian).Литвинко, Н. М. Активность фосфолипаз А2 и С при биохимческом моделировании / Н. М. Литвинко. -Минск: Технопринт, 2003. - 350 с.Litvinko N. М. Activity of phospholipases А2 and Cin biochemical modeling. Minsk, Technoprint Publ., 2003. 350 p. (in Russian).Литвинко, Н. М. Межфазный катализ липолитических реакций в биоорганической химии: особенности и практическое применение / Н. М. Литвинко // Вес. Нац. акад. навук Беларусь Сер. xiM. навук. - 2015. - № 4. -С. 109-121.Litvinko N. M. Interphase catalysis of lipolytic reactions in bioorganic chemistry: features and practical application. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seryya khimichnykh navuk = Proceedings of the National Academy of Sciences of Belarus. Chemical series, 2015, no. 4, pp. 109-121 (in Russian).Герловский, Д. О. Активность панкреатической фосфолипазы А2 в присутствии ряда производных 1,3-циклогександиона и некоторых органофосфатов: дис кандидат химических наук: 03.01.04 /Д. О. Герловский. - Минск, 2012. - 194 с.Gerlovsky D. O. Activity ofpancreatic phospholipase A2 in the presence of a number of 1,3-cyclohexanedione derivatives and some organophosphates. Minsk, 2012. 194 p. (in Russian).Брокерхофф, X. Липолитические ферменты / X. Брокерхофф, Р. Дженсен. - М.: Мир, 19 78. - 330 cBrockerhoff H., Jensen R. Lipolytic enzymes. Academic Press, Inc. 1974.Litvinko, N. M. Hydrolysis of glycerophospholipids ву the phosphatidylinosite-specific phospholipase // Biophosphates and Their Analogous - Synthesis, Structure, Metabolism and Activity / N. M. Litvinko. - Amsterdam: Elsevier Science Publishers, 1987. - P. 315-320.Litvinko N. M. Hydrolysis of glycerophospholipids ву the phosphatidylinosite-specific phospholipase. Biophosphates and Their Analogous - Synthesis, Structure, Metabolism and Activity. Amsterdam, Elsevier Science Publishers, 1987, pp. 315-320.Litvinko, N. M. Phospholipolysis: research and new approaches to practical use / N. M. Litvinko // Abstr. of International Conf. Innovations in Food Science and Human Nutrition (IFHN-2018), 13-15 September 2018. - Rome, Italy, 2018. - P. 59.Litvinko N. M. Phospholipolysis: research and new approaches to practical use. Abstr. of International Conf. Innovations in Food Science and Human Nutrition (IFHN-2018), 13-15 September 2018, Rome, Italy, pp. 59.Litvinko, N. M. Diagnostic biosystems based on phosphatideacylhydrolases and hemoproteins / N. M. Litvinko, L. A. Skorostetskaya, D. O. Gerlovsky // Frontiers in Life Sciences. Signaliing and Metabolism, 1st Belarussian-Polish-Lithuanian Conf., 8-9 November 2018. - Grodno, 2018. - P. 209-210.Litvinko N. M., Skorostetskaya L. A., Gerlovsky D. O. Diagnostic biosystems based on phosphatideacylhydrolases and hemoproteins Frontiers in Life Sciences. Signaliing and Metabolism. 1st Belarussian-Polish-Lithuanian. Conf., 8-9 November 2018. Grodno, 2018, pp. 209-210.Новые инновационные технологии клинико-биохимического исследования как фундаментальная основа лабораторной медицины и дальнейшего становления экономики знаний / В. С. Камышников [и др.] // Инновационные технологии в медицине. - 2018. - Т. 6, № 1. - С. 72-82.Kamyshnikov V. S., Kiselev P. A., Litvinko N. M., Vorobey А. V., Skorostetskaya L. А., Juraha Т. М. New innovative technologies of clinical and biochemical research as a fundamental basis of translational laboratory medicine and further development of the “knowledge-based economy”. Innovatsionnye tekhnologii v meditsine = Innovative Technologies in Medicine, 2018, vol. 6, no. 1, pp. 72-82 (in Russian).Litvinko, N. M. The interaction of phospholipase A2 with oxidized phospholipids at the lipid-water surface with different structural organization / N. M Litvinko, L. A. Skorostetskaya, D. O. Gerlovsky // Chemistry and Physics of Lipids. -2018. - Vol. 211. - P. 44-51. https://doi.org/10.1016/j.chemphyslip.2017.10.010Litvinko N. M., Skorostetskaya L. A., Gerlovsky D. O. The in teraction of phospholipase A2with oxidized phospholipids at the lipid-water surface with different structural organization. Chemistry and Physics of Lipids, 2018, vol. 211, pp. 44-51. https://doi.org/10.1016/j.chemphyslip.2017.10.010Litvinko, N. M. A new approach toward the application of biochemical systems based on phospholipolysis / N. M Litvinko, L. A. Skorostetskaya, D. O. Gerlovsky // Current Research in Bioorganic and Organic Chemistry. - 2019. -Vol. 3. - P.19.Litvinko N. M., Skorostetskaya L. A., Gerlovsky D. O. A new approach toward the application of biochemical systems based on phospholipolysis. Current Research in Bioorganic and Organic Chemistry, 2019, vol. 3, pp. 19.Differential Spectroscopy in Studying of the Phospholipolysis: Results and New Approaches to Practical Use as Enzyme Therapy and Diagnostics / N. M. Litvinko [et al.] // Proceedings of BIT’s 7th Annual Conference of AnalytiX-2019, Singapore, 12-15 April 2019. - P. 59.Litvinko N. M., Yermakovich Yu. Sh., Skorostetskaya L. A., Gerlovsky D. O. Differential Spectroscopy in Studying of the Phospholipolysis: Results and New Approaches to Practical Use as Enzyme Therapy and Diagnostics. Proceedings of BIT’s 7th Annual Conference of AnalytiX-2019, Singapore, 12-15 April 2019,рр. 59.Phosphatideacylhydrolases: priority role in digestion and a new application for the detection of pancreatitis / N. M. Lit-vinko [et al.] // Abstr. 2 nd conference on innovations in food science& human nutrition. 12-14 Sep, 2019. - London, 2019. - P. 55.Litvinko N. M., Skorostetskaya L. A., Gerlovsky D. O., Kamyshnikov V. S. Phosphatideacylhydrolases: priority role in digestion and a new application for the detection of pancreatitis. Abstr. 2nd conference on innovations in food science& human nutrition, Sep. 12-14, 2019, London, 2019, pp. 55.Диагностические биосистемы на основе фосфатидацилгидролаз и гемопротеинов // Н. М. Литвинко [и др.] // Биохимия и молекулярная биология: сб. науч. тр. - Минск: ИВЦ Минфина, 2019. - Вып. 3. Механизмы регуляции процессов жизнедеятельности в норме и патологии. - С. 34-39.Litvinko N. M., Skorostetskaya L.A., Ermakovich Yu. Sh., Gerlovsky D. O. Diagnostic biosystems based on phos-phatidacylhydrolases and hemoproteins. Biokhimiya i molekulyarnaya biologiya: sb. nauch. tr. [Biochemistry and Molecular Biology.Collection of proceedings]. Minsk, DCCof the Ministry of Finance, 2019, vol. 3. Mechanisms of regulation of vital processes in health and disease, pp. 34-39 (in Russian).Эффект УФ-облученных жирных кислот на спектральные свойства миоглобина / Н. М. Литвинко [и др.] // Докл. Нац. акад. наук Беларуси. - 2019. - Т. 63. № 1. - С. 44-54.Litvinko N. M., Skorostetskaya L.A., Gerlovsky D. O., Ermakovich Yu. Sh., Evdokimova G. S. Effect of UV-irra-diated fatty acids on the spectral properties of myoglobin. Doklady Natsional'noi akademii nauk Belarusi = Doklady of the National Academy of Sciences of Belarus, 2019, vol. 63, no. 1, pp. 44-54 (in Russian).Computer-aided drug design guided by hydrogen/deuterium exchange mass spectrometry: A powerful combination for the development of potent and selective inhibitors of Group VIA calcium-independent phospholipase A2 / V. D. Mouchlis [et al.] // Bioorg. Med. Chem. - 2016. - Vol. 24. - P. 4801-4811. https://doi.org/10.1016/j.bmc.2016.05.009Mouchlis V. D., Morisseau C., Hammock B. D., Li S., McCammon J. A., Dennis E. A. Computer-aided drug design guided by hydrogen/deuterium exchange mass spectrometry: A powerful combination for the development of potent and selective inhibitors of Group VIA calcium-independent phospholipase A2. Bioorganic & Medicinal Chemistry, 2016, vol. 24, no. 20, pp. 4801-4811. https://doi.org/10.1016/j.bmc.2016.05.009Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention / J. Cao [et al.] // Chem. Rev. - 2011. - Vol. 111, no. 10. - P. 6130-6185. https://doi.org/10.1021/cr200085wDennis E., Cao J., Hsu Y.-H., Magrioti V., Kokotos G. Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chemical Reviews, 2011, vol. 111, no. 10, pp. 6130-6185. https://doi.org/10.1021/cr200085wSmall-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2 / A. Nikolaou [et al.] // BBA - Molecular and Cell Biology of Lipids. - 2019. - Vol. 1864, N 6. - P. 941-956. http//:doi:10.1016/j. bbalip.2018.08.009Nikolaou A., Kokotou M. G., Vasilakaki S., Kokotos G. Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2. BBA - Molecular and Cell Biology of Lipids, 2019, vol. 1864, no. 6, pp. 941-956. http//doi:10.1016/j.bbalip.2018.08.009Mouchlis, V. D. Design of new secreted phospholipase A2 inhibitors based on docking calculations by modifying the pharmacophore segments of the FPL67047XX inhibitor / V. D. Mouchlis, T. M. Mavromoustakos, G. Kokotos // J. Com-put.-Aided Mol. Des. - 2010. - Vol. 24, N 2. - P. 107-115. https://doi.org/10.1007/s10822-010-9319-7Mouchlis V. D., Mavromoustakos T. M., Kokotos G. Design of new secreted phospholipase A2 inhibitors based on docking calculations by modifying the pharmacophore segments of the FPL67047XX inhibitor. Journal of Computer-Aided Molecular Design, 2010, vol. 24, no. 2, pp. 107-115. https://doi.org/10.1007/s10822-010-9319-7Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2 / G. Kokotos [et al.] // J. Med. Chem. - 2010. - Vol. 53, N 9. - P. 3602-3610. https://doi.org/10.1021/jm901872vKokotos G., Hsu Y.-H., Burke J., Baskakis C., Kokotos C., Magrioti V., Dennis E. Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2. Journal of Medicinal Chemistry, 2010, vol. 53, no. 9, pp. 3602-3610. https://doi.org/10.1021/jm901872vDevelopment of potent and selective inhibitors for group VIA calcium-independent phospholipase A2 guided by molecular dynamics and structure-activity relationships / D. Mouchlis [et al.] // J. Med. Chem. - 2016. - Vol. 59, no. 9. -P. 4403-4414. https://doi.org/10.1021/acs.jmedchem.6b00377Mouchlis D., Limnios M. G., Kokotou E., Barbayianni G., Kokotos J. A., McCammon E. A., Dennis. Development of potent and selective inhibitors for group VIA calcium-independent phospholipase A2 guided by molecular dynamics and structure-activity relationships. Journal of Medicinal Chemistry, 2016, vol. 59, no. 9, pp. 4403-4414. https://doi.org/10.1021/ acs.jmedchem.6b00377Phospholipase inhibitors: US Patent no. 2003153751 USA / J. S. Seehra, N. Kaila, J. S. Mckew, F. Lovering, J. E. Bemis, Y. Xiang. - Publ. date 14.08.2003.Seehra J. S., Kaila N., Mckew J. S., Lovering F., Bemis J. E., Xiang Y. Phospholipase inhibitors. US Patent no. 2003153751 USA. Publ. date 14.08.2003.Inhibition of secretory phospholipase A2. 1-Design, synthesis and structure-activity relationship studies starting from 4-tetradecyloxybenzamidine to obtain specific inhibitors of group II sPLA2s/ L. Assogbaa [et al.] // European Journal of Medicinal Chemistry. - 2005. - Vol. 40, N 9. - P. 850-861. https://doi.org/10.1016/j.ejmech.2005.03.027Assogbaa L., Ahamada-Himidia A., Meddad-Bel Habicha N., D. Aouna D., Bouklia L., Massicota, F., Mouni-erc C. M., Hueta J., Lamouri A., Ombetta J.-E., Godfroid J.-J., Donga, C.-Z., Heymans F. Inhibition of secretory phospholipase A2. 1-Design, synthesis and structure-activity relationship studies starting from 4-tetradecyloxybenzamidine to obtain specific inhibitors of group II sPLA2s. European Journal of Medicinal Chemistry, 2005, vol. 40, no. 9, pp. 850-861. https://doi.org/10.1016/j.ejmech.2005.03.027Способ определения эффекторных свойств физиологически активных соединений: патент BY №5752 / Н. М. Литвинко, С. В. Кучуро, Т. А. Желдакова, Е. Р. Филич. - Опубл. 30.12.2003Litvinko N. М., Kuchuro S. V., Zheldakova Т. А., Filich Е. R. Method for determining the effector properties ofphys-iologically active compounds. Patent BY no. 5752. Publ. date 30.12.2003 (in Russian).Способ определения антигемолитической активности химического соединения: патент BY №10604 / Н. М. Литвинко, С. В. Кучуро, Г. Н. Рахуба, Д. Б. Рубинов, Т. А. Желдакова. - Опубл. 30.06.2008Litvinko N. M., Kuchuro S. V., Rakhuba G. N., Rubinov D. B., Zheldakova Т. А. Method for determining the anti-hemolytic activity of a chemical compound. Patent BY no. 10604. Publ. date 30.06.2008 (in Russian).3,5-дизамещенные производные тиотетроновой кислоты, проявляющие антифосфолипазную активность антипанкреатического профиля действия, и способ их получения: патент BY №10191 / Д. Б. Рубинов, Т. А. Желдакова, Н. М. Литвинко, С. В. Кучуро, Г. Н. Рахуба. - Опубл. 28.02.2008.Rubinov D. B., Zheldakova Т. А., Litvinko N. M., Kuchuro S. V., Rakhuba G. N. 3,5-isubstituted thiotetronic acid derivatives exhibiting antiphospholipase activity with an antipancreatic profile of action, and a methodfor their preparation. Patent BY no. 10191. Publ. date 28.02.2008 (in Russian).Производные в—трикетонов тиофенового ряда, проявляющие антифосфолипазную активность антигемоли-тического профиля действия: патент BY №10192 / Д. Б. Рубинов, Т. А. Желдакова, Н. М. Литвинко, С. В. Кучуро, Г. Н. Рахуба. - Опубл. 28.02.2008.Rubinov D. B., Zheldakova Т. А., Litvinko N. M., Kuchuro S. V., Rakhuba G. N. Derivatives of в—triketones of the thiophene series, exhibiting antiphospholipase activity of the antihemolytic action profile. Patent BY №10192. Publ. date 28.02.2008 (in Russian).Кучуро, С. В. Механизмы взаимодействия фосфолипазы А2, простагландинов и этанола в регуляции липолиза в биологических мембранах: дис канд. биол. наук: 03.00.04 / С. В. Кучуро. - Минск, 2001. - 130 c.Kuchuro S. V. Mechanisms of interaction ofphospholipase A2, prostaglandins and ethanol in the regulation of lipolysis in biological membranes. Minsk, 2001. 130 p. (in Russian).Рахуба, Г. Н. Липолитические реакции с участием фосфолипаз А2 и механизмы их регуляции по принципу обратной связи: дис кандидат химических наук: 03.00.04 / Г. Н. Рахуба. - Минск, 2007. - 143 c.Rakhuba G. N. Lipolytic reactions involving phospholipases A2 and mechanisms of their regulation according to the principle of feedback. Minsk, 2007. 143 p. (in Russian).Фосфодиэфирные производные ацикловира - новые ингибиторы панкреатической фосфолипазы А2 / Д. О. Герловский [и др.] // Докл. Нац. акад. наук Беларуси. - 2010. - Т. 54, № 1. - С. 75-82.Gerlovsky D. O., Litvinko N. M., Skorostetskaya L. А., Kuchuro S. V., Kalinichenko Е. N., Farina А. V. Phosphodiesters of acyclovir - new inhibitors of pancreatic phospholipase А2. Doklady Natsional 'noi akademii nauk Belarusi = Doklady of the National Academy of Sciences of Belarus, 2010, vol. 54, no. 1, pp. 75-82 (in Russian).Deems, R. A. Kinetic analysis of phospholipase A2 activity toward mixed micelles and its implications for the study of lipolytic enzymes / R. A. Deems, B. R. Eaton, E. A. Dennis // J. Biol. Chem. - 1975. - Vol. 250, N 23. - P. 9013-9020.Deems R. A., Eaton B. R., Dennis E. A. Kinetic analysis of phospholipase A2 activity toward mixed micelles and its implications for the study of lipolytic enzymes. Journal of Biological Chemistry, 1975, vol. 250, no. 23, pp. 9013-9020.Hendrickson, H. S. Analysis of the kinetics of phospholipid activation of cobra venom phospholipase A2 / H. S. Hendrickson, E. A. Dennis // J. Biol. Chem. - 1984. - Vol. 259, N 9. - P. 5740-5744.Hendrickson H. S., Dennis E. A. Analysis of the kinetics of phospholipid activation of cobra venom phospholipase A2. Journal of Biological Chemistry, 1984, vol. 259, no. 9, pp. 5740-5744.Конъюгат фосфолипида с модифицированным нуклеозидом, фармацевтическая композиция и средство, повышающее устойчивость к действию панкреатической фосфолипазы А2: Патент BY №11905 / Н. М. Литвинко, Е. Н. Калиниченко, Е. В. Жерносек, С. В. Кучуро. - Опубл. 28.02.2008.Litvinko N. M., Kalinichenko Е. N., Zhernosek Е. V., Kuchuro S. V. Konjugate of phospholipid with modified nucleoside, pharmaceutical composition and agent that increases resistance to the action of pancreatic phospholipase А2. Patent BY № 11905. Publ. date 28.02.2008 (in Russian). .The enzymatic synthesis of Phospholipide-Nucleoside conjugates and study of their substrate activity for the digestive phospholipase A2 / N. M. Litvinko [et al.] // Journal of Nanotechnoligy: Nanomedicine & Nanobiotechnology. - 2020. -Vol. 7. - P. 55-56.Litvinko N. M., Remeeva E. A., Artsemyeva J. N., Zinchenko A. I., Gerlovsky D. O., Birichevskaya L. L., Pavluchen-ko N. I., Mikhailopulo I. A. The enzymatic synthesis of Phospholipide-Nucleoside conjugates and study of their substrate activity for the digestive phospholipase A2. Journal of Nanotechnoligy: Nanomedicine & Nanobiotechnology, 2020, vol. 7, pp. 55-56.Type-IIA secreted phospholipase A2 is an endogenous antibiotic-like protein of the host / Y. Wu [et al.] // Biochimie. -2010. - Vol. 92. - P. 583-587. https://doi.org/10.1016/j.biochi.2010.01Wu Y., Raymond B., Goossens P. L., Njamkepo E., Guiso N., Paya M., Touqui L. Type-IIA secreted phospholipase A2 is an endogenous antibiotic-like protein of the host. Biochimie, 2010, vol. 92, pp. 583-587. https://doi.org/10.1016/j.biochi.2010.01Activation of Notch-1 in oral epithelial cells by P. gingivalis triggers the expression of the antimicrobial protein PLA2-IIA / A. Al-Attar [et al.] // Mucosal Immunol. - 2018. - Vol. 11, N 4. - P. 1-13. https://doi.org/10.1038/s41385-018-0014-7Al-Attar A., Alimova Y., Kirakodu S., Kozal A., Novak M. J., Stromberg A. J., Orraca L., Gonzalez-Martinez J., Martinez M., Ebersole J. L., Gonzalez O. A. Activation of Notch-1 in oral epithelial cells by P. gingivalis triggers the expression of the antimicrobial protein PLA2-IIA. Mucosal Immunology, 2018, vol. 11, no. 4, pp. 1-13. https://doi.org/10.1038/s41385-018-0014-7Jimenez, M. A continuous spectrophotometric assay for phospholipase A(2) activity / M. Jimenez // Anal. Biochem. -2003. - Vol. 319. - P. 131-137.Jimenez M. A continuous spectrophotometric assay for phospholipase A2 activity. Analytical Biochemistry, 2003, vol. 319, no. 1, pp. 131-137. https://doi.org/10.1016/s0003-2697(03)00331-2Особенности взаимодействия цитохрома Р450 и фосфолипаз А2 разной специфичности, обнаруживаемые КД-спектроскопией / Н. М. Литвинко [и др.] // Докл. Нац. акад. наук Беларуси. - 2016. - Т. 60, № 6. - С. 64-71.Litvinko N. M., Antonchik G. N., Glushakova Т. G., Gerlovsky D. O. Features of the protein-protein interaction of cytochrome P450 and PLA2 of different nature revealed using circular dichroism spectroscopy. Doklady Natsional'noi aka-demii nauk Belarusi = Doklady of the National Academy of Sciences of Belarus, 2016, vol. 60, no. 6, pp. 64-71 (in Russian).Супрамолекулярный комплекс жирной кислоты с гемоглобином как индикатор фосфолиполиза для выявления экспериментального панкреатита / Н. М. Литвинко [и др.] // Докл. Нац. акад. наук Беларуси. - 2016. -Т. 60, № 4. - С. 82-88.Litvinko N. M., Skorostetskaya L. А., Gudko Т. G., TsimokhovaM. M., Kamyshnikov V. S., Vizhinis Е. I., Vorobey V. А. Supramolecular complex of fatty acid with hemoglobin as an indicator of phospholipolysis to identify experimental pancreatitis. Doklady Natsional 'noi akademii nauk Belarusi = Doklady of the National Academy of Sciences of Belarus, 2016, vol. 60, no. 4, pp. 82-88 (in Russian).Способ определения активности фосфолипазы А2 в сыворотке крови: патент BY № 12552 / Н. М. Литвинко, Л. А. Скоростецкая, С. В. Кучуро, Г. Н. Рахуба. - Опубл. 30.06.2009.Litvinko N. M., Skorostetskaya L. А., Kuchuro S. V., Rakhuba G. N. Method for determining the activity ofphospho-lipase A2 in blood serum. Patent BY № 12552. Publ. date 30.06.2009 (in Russian).Способ диагностики панкреатита по уровню А2 фосфолипазной активности сыворотки крови: патент BY №13143 / Н. М. Литвинко, Л. А. Скоростецкая. - Опубл. 30.04.2010.Litvinko N. M., Skorostetskaya L. А. Method for diagnosing pancreatitis by A2 level of serum phospholipase activity. Patent BY № 13143. Publ. date 30.04.2010 (in Russian).Бурлакова, Е. Б. Биоантиоксиданты / Е. Б. Бурлакова // Рос. хим. журн. - 2007. - Т. LI, № 1. - С. 3-12.Burlakova E. B. Bioantioxidants. Russian Journal of General Chemistry, 2007, vol. 77, no. 11, pp. 1983-1993. https:// doi.org/10.1134/s107036320711028x

The authors declare that there are no conflicts of interest present.