For more than 40 years L-asparaginases are used in combined therapy of acute lymphoblastic leukemia in children and the range of tumors sensitive to these enzymes constantly extends. This review summarizes results of studies aimed at creation of new systems for heterological expression of bacterial L-asparaginases as Erwinia carotovora (EwA), Helicobacter pylori (HpA), Yersinia pseudotuberculosis (YpA) and Rhodospirillum rubrum (RrA); special attention is paid to isolation of purified enzymes and their crystallization, modification by chitosan/polyethylene, physicochemical, kinetic and structural properties characterization, and the study of the cytotoxic or anti-proliferative activity of new recombinant L-asparaginases on cell cultures in vitro. The resultant recombinant L-asparaginases (EwA, YpA, HpA и RrA) exhibit reasonable cytotoxic action on the human leukemia cells comparable to the pharmacologically available L-asparaginase EcA and represent practical interest in respect to creation, on their basis, new effective antineoplastic remedies. Further prospects of researches on bacterial L-asparaginases are associated with development of analogs of Rhodospirillum rubrum L-asparaginase (RrA) by means of directed changes of the protein structure using genetic engineering, development of chito-PEGylation for receiving L-asparaginase preparations with improved pharmacokinetic characteristics.
L-Asparaginazy na protiazhenii bolee 40 let uspeshno primeniaiutsia v kombinirovannoĭ khimioterapii ostrykh limfoblastnykh leĭkozov u deteĭ, i spektr opukholeĭ, chuvstvitel'nykh k deĭstviiu dannykh fermentov, postoianno rasshiriaetsia. V dannom obzore obobshcheny rezul'taty rabot po sozdaniiu novykh sistem geterologicheskoĭ ékspressii bakterial'nykh L-asparaginaz Erwinia carotovora (EwA), Nelicobacter pylori (HpA), Yersinia pseudotuberculosis (YpA) i Rhodospirillum rubrum (RrA), vydeleniiu vysokoochishchennykh i kristallicheskikh preparatov fermenta, kharakteristike ikh fiziko-khimicheskikh, kineticheskikh i strukturnykh svoĭstv. Poluchennye rekombinantnye L-asparaginazy EwA, YpA, HpA i RrA sopostavimy s primeniaiushchimsia v klinike lekarstvennym preparatom L-asparaginazy Escherichia coli (EcA) po éffektivnosti tsitotoksicheskogo deĭstviia na kletki leĭkozov cheloveka. Oni predstavliaiut prakticheskiĭ interes v plane sozdaniia na ikh osnove novykh éffektivnykh protivoopukholevykh lekarstvennykh preparatov. Dal'neĭshie perspektivy issledovaniĭ po bakterial'nym L-asparaginazam sviazany s polucheniem analogov L-asparaginazy RrA posredstvom napravlennogo izmeneniia struktury belka metodami geneticheskoĭ inzhenerii, a takzhe s razrabotkoĭ preparatov L-asparaginaz, modifitsirovannykh poliétilenglikolem i khitozanom dlia uluchsheniia farmakokineticheskikh kharakteristik.
Keywords: L-asparaginase; L-glutaminase; PEGylated L-asparaginase; chito-PEGylation; leukemia; recombinant proteins.