L-Asparaginases of Extremophilic Microorganisms in Biomedicine
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Asparaginases of Extremophilic Microorganisms in Biomedicine M. V. Duminaa, M. A. Eldarova, D. D. Zdanovb, and N. N. Sokolovb, * a
Federal Research Center “Fundamentals of Biotechnology” of the Russian Academy of Sciences, ul. 60-Letiya Oktyabrya 7/1, Moscow, 117312 Russia b Institute of Biomedical Chemistry, ul. Pogodinskaya 10, Moscow, 119121 Russia *e-mail: [email protected] Received November 29, 2019; revised February 11, 2020; accepted March 3, 2020
Abstract—L-asparaginase is widely used in the treatment of acute lymphoblastic leukemia and several other lymphoproliferative diseases. In addition to its biomedical application, L-asparaginase is used in food industry to reduce the level of acrylamide, which is considered as neurotoxic and carcinogenic agent to humans, and in biosensors for determination of the L-asparagine level in biochemistry and food chemistry. In view of great significance of L-asparaginases in different fields, disadvantages of commercial enzymes, and the wide distribution of the enzyme in nature there is a need for novel L-asparaginases from new sources. In this context, extremophilic microorganisms exhibiting unique physiological properties such as thermal stability, adaptation to extreme cold conditions, salt, and pH tolerance attract much interest as one of the most valuable sources for novel L-asparaginases. The results of of structural, functional studies, physico-chemical properties, kinetic characteristics, and stability of L-asparaginases from extremophilic microorganisms suggest the prospect of using these enzymes in biology and medicine. Keywords: L-asparaginase, antitumor drug, extremophilic microorganisms, stability, structural and functional properties DOI: 10.1134/S1990750820040046
INTRODUCTION L-asparaginase (L-asparagine amidohydrolase (L-ASPase), EC 3.5.1.1) is the first bacterial enzyme used in clinical oncohematology that selectively targets the metabolism of cancer cells. Despite the fact that it is studied and used for more than 40 years, L-ASPase still remains one of the main drugs for the combination chemotherapy of acute lymphoblastic leukemia (ALL) [1, 2]. This enzyme is effective in the treatment of lymphosarcoma, lymphogranulomatosis (Hodgkin’s disease), acute myeloid leukemia, reticulosarcoma, solid and several other types of tumors [3–11]. L-ASPase from Escherichia coli (EcA) causes complete remission in 40–60% of children with ALL [12], and remission reaches 90% when L-ASPase based therapy is combined with other cytostatics [13]. Based on the enzyme, ALL treatment protocols have been developed [14, 15]. L-ASPase catalyzes hydrolysis of the amide group of the side chain of L-asparagine with formation of L-aspartic acid and ammonia. L-ASPase also cleaves L-glutamine, but at a lower rate than L-asparagine; the efficiency of hydrolysis of these substrates depends on the source of enzymes [16]. Based on affinity for L-asparagine, localization in the cell, and L-glutaminase activity, bacterial L-ASPases have been classified into two types [17].
Type I includes
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