Low expression of asparagine synthetase in lymphoid blasts precludes its role in sensitivity to L-asparaginase

Heřmanová, Ivana; Žaliová, Markéta; Trka, Jan; Starková, Júlia

doi:10.1016/j.exphem.2012.04.005

Cited by 42 publications

(40 citation statements)

References 32 publications

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“…The cytotoxic potential of ScASNase1 was analysed in vitro in three different cell types: HUVEC, as healthy cells that cover the blood vessel wall and are therefore in contact with circulating drugs; REH, considered resistant to treatment with L-ASNase because it has high ASNS levels of expression23; and MOLT-4, described as a sensitive L-ASNase lineage. Nevertheless, MOLT-4 evolves resistance six weeks after L-ASNase treatment, through the augmented expression of ASNS 24.…”

Section: Resultsmentioning

confidence: 99%

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Recombinant L-asparaginase 1 from Saccharomyces cerevisiae: an allosteric enzyme with antineoplastic activity

Costa

Schultz

Pedra

et al. 2016

Sci Rep

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L-asparaginase (L-ASNase) (EC 3.5.1.1) is an important enzyme for the treatment of acute lymphoblastic leukaemia. Currently, the enzyme is obtained from bacteria, Escherichia coli and Erwinia chrysanthemi. The bacterial enzymes family is subdivided in type I and type II; nevertheless, only type II have been employed in therapeutic proceedings. However, bacterial enzymes are susceptible to induce immune responses, leading to a high incidence of adverse effects compromising the effectiveness of the treatment. Therefore, alternative sources of L-ASNase may be useful to reduce toxicity and enhance efficacy. The yeast Saccharomyces cerevisiae has the ASP1 gene responsible for encoding L-asparaginase 1 (ScASNase1), an enzyme predicted as type II, like bacterial therapeutic isoforms, but it has been poorly studied. Here we characterised ScASNase1 using a recombinant enzyme purified by affinity chromatography. ScASNase1 has specific activity of 196.2 U/mg and allosteric behaviour, like type I enzymes, but with a low K0.5 = 75 μM like therapeutic type II. We showed through site-directed mutagenesis that the T64-Y78-T141-K215 residues are involved in catalysis. Furthermore, ScASNase1 showed cytotoxicity for the MOLT-4 leukemic cell lineage. Our data show that ScASNase1 has characteristics described for the two subfamilies of l-asparaginase, types I and II, and may have promising antineoplastic properties.

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Section: Resultsmentioning

confidence: 99%

“…Using the same concentration of EcASNase2, the mortality of MOLT-4 cells was 95%43. The REH cell line uses L-Gln pathway asparagine synthetase for the synthesis of L-Asn23. The low glutaminase activity of ScASNase1 prevents the mortality of this lineage.…”

Section: Discussionmentioning

confidence: 99%

Recombinant L-asparaginase 1 from Saccharomyces cerevisiae: an allosteric enzyme with antineoplastic activity

Costa

Schultz

Pedra

et al. 2016

Sci Rep

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“…Furthermore, single gene analysis points to a suppression of amino acid metabolism after six weeks of exposure to 4.1 mGy/h by the downregulation of phosphoglycerate dehydrogenase (PHGDH) (FC Ϫ 2.41) and phosphoserine aminotransferase 1 (PSAT1) (FC Ϫ 1.87), which are key enzymes in the biosynthesis of serine (Baek et al 2003, Furuya et al 2008. Another downregulated gene after six weeks of exposure to 4.1 mGy/h, is asparagine synthetase (ASNS) (FC Ϫ 1.68), which is involved in asparagine biosynthesis (Hermanova et al 2012). …”

Section: Discussionmentioning

confidence: 98%

Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation

Rombouts

Aerts

Quintens

et al. 2014

International Journal of Radiation Biology

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“…It was shown that nearly 15-20% of patients treated with L-asparaginase of E. coli develop hypersensitivity and toxicity to the drug. [31], [32], [33], [1]. …”

Section: Purification Of L-asparaginasementioning

confidence: 99%

Purification and Cytotoxicity of L-asparaginase from Streptomyces griseoluteus GDJ1

2017

IJSR

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L-asparaginase (L-asparagine amidohydrolase E.C.3.5.1.1) is an effective antineoplastic enzyme, used in acute lymphoblastic leukemia (ALL) chemotherapy. L-asparaginase activity of marine actinomycetes in soil samples of Agnitheertham (Rameswaram) and Periyar lake, Kumily were investigated. Totally fifty one actinomycetes were isolated from both the soil samples in different selective media. Out of fifty one isolates, four were found to produce L-asparaginase. Among them, the strain AT-R-S1 produced high amount of L-asparaginase. Hence it was selected for the further identification and based on molecular identification the strain AT-R-S1 was identified as Streptomyces griseoluteus GDJ1. Purification of the enzyme from the strain S.griseoluteus GDJ1 (AT-R-S1) was carried out. The final purification of the enzyme in CM-Sephadex C-50 column chromatography yielded 1.27 U/ml of enzyme in 0.09 mg of protein with a specific activity of 14.11 U/mg with approximately 119 folds purity. Cytotoxicity of different concentration of purified L-asparaginase was determined on VERO cells. The anti proliferative activity of L-asparaginase in MCF-7 and HeLa cells was determined and the EC 50 value was found to be 31.37 and 38.99 µg respectively. The above results were encouraging and worth pursuing for further development of Streptomyces griseoluteus GDJ1 (AT-R-S1) as an alternative resource for therapeutic L-asparaginase.

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Low expression of asparagine synthetase in lymphoid blasts precludes its role in sensitivity to L-asparaginase

Cited by 42 publications

References 32 publications

Recombinant L-asparaginase 1 from Saccharomyces cerevisiae: an allosteric enzyme with antineoplastic activity

Recombinant L-asparaginase 1 from Saccharomyces cerevisiae: an allosteric enzyme with antineoplastic activity

Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation

Purification and Cytotoxicity of L-asparaginase from Streptomyces griseoluteus GDJ1

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