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  • Title: [Suppression of telomerase activity leukemic cells by mutant forms of Rhodospirillum rubrum L-asparaginase].
    Author: Pokrovskaya MV, Zhdanov DD, Eldarov MA, Aleksandrova SS, Veselovskiy AV, Pokrovskiy VS, Grishin DV, Gladilina JA, Sokolov NN.
    Journal: Biomed Khim; 2017 Jan; 63(1):62-74. PubMed ID: 28251953.
    Abstract:
    The active and stable mutant forms of short chain cytoplasmic L-asparaginase type I of Rhodospirillum rubrum (RrA): RrA+N17, D60K, F61L, RrA+N17, A64V, E67K, RrA+N17, E149R, V150P, RrAE149R, V150P and RrAE149R, V150P, F151T were obtained by the method of site-directed mutagenesis. It is established that variants RrA-N17, E149R, V150P, F151T and RrАE149R, V150P are capable to reduce an expression hTERT subunit of telomerase and, hence, activity of telomeres in Jurkat cells, but not in cellular lysates. During too time, L-asparaginases of Escherichia coli, Erwinia carotovora and Wolinella succinogenes, mutant forms RrА+N17, D60K, F61L and RrА+N17, A64V, E67K do not suppress of telomerase activity. The assumption of existence in structure RrA of areas (amino acids residues in the position 146-164, 1-17, 60-67) which are responsible for suppression of telomerase activity is made. The received results show that antineoplastic activity of some variants RrA is connected both with reduction of concentration of free L-asparagine, and with expression suppression of hTERT telomerase subunit, that opens new prospects for antineoplastic therapy. Metodom saĭt-napravlennogo mutageneza polucheny v ochishchennom sostoianii aktivnye i stabil'nye mutantnye formy korotkotsepochechnoĭ tsitoplazmaticheskoĭ L-asparaginazy I tipa iz Rhodospirillum rubrum (RrA): RrA+N17, D60K, F61L, RrA+N17, A64V, E67K, RrA+N17, E149R, V150P, RrAE149R, V150P i RrAE149R, V150P, F151T. Ustanovleno, chto varianty RrAE149R, V150P, F151T i RrA+N17, E149R, V150P sposobny snizhat' ékspressiiu hTERT sub"edinitsy telomerazy i, sledovatel'no, aktivnost' telomerazy v kletkakh Jurkat, no ne v kletochnykh lizatakh. V to zhe vremia, L-asparaginazy Escherichia coli, Erwinia carotovora, Wolinella succinogenes, mutantnye formy RrA+N17, D60K, F61L i RrA+N17, A64V, E67K ne podavliali aktivnost' telomerazy. Sdelano predpolozhenie o sushchestvovanii v strukture RrA oblasteĭ (aminokislotnye ostatki 146-164, 1-17, 60-67), otvechaiushchikh za podavlenie telomeraznoĭ aktivnosti. Poluchennye rezul'taty pokazyvaiut, chto protivoopukholevaia aktivnost' nekotorykh variantov RrA sviazana kak s umen'sheniem kontsentratsii svobodnogo L-asparagina, tak i s ugneteniem ékspressii hTERT sub"edinitsy telomerazy, chto otkryvaet novye perspektivy dlia protivoopukholevoĭ terapii.
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