Mechanistic Issues in Asparagine Synthetase Catalysis

Richards, Nigel G. J.; Schuster, Sheldon M.

doi:10.1002/9780470123188.ch5

Cited by 67 publications

(63 citation statements)

References 159 publications

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“…ASNS encodes an enzyme that catalyzes the glutamine-and ATP-dependent conversion of aspartic acid to asparagine (19). The expression of ASNS is enhanced by amino acid deprivation, and this regulation is transcriptional in nature (20).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it has been reported that its expression is enhanced by amino acid deprivation and glucose deprivation and that it is related to drug resistance of leukemia and oncogenesis triggered by mutated p53 (17,18). ASNS encodes an enzyme that catalyzes the biosynthesis of L-asparagine from L-aspartate in an ATP-dependent reaction for which L-glutamine is the nitrogen source (19). ASNS expression in mammalian tissues is highly regulated by the nutritional status of the cells (20) and is enhanced by glucose deprivation as well as amino acid deprivation (21).…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Expression of Asparagine Synthetase under Glucose-Deprived Conditions Protects Pancreatic Cancer Cells from Apoptosis Induced by Glucose Deprivation and Cisplatin

Cui

Darmanin²,

Natsuisaka

et al. 2007

Cancer Research

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Although hypovasculature is an outstanding characteristic of pancreatic cancers, the tumor cells survive and proliferate under severe hypoxic, glucose-deprived conditions caused by low blood supply. It is well known that the hypoxia-inducible factor-1 pathway is essential for the survival of pancreatic cancer cells under hypoxic conditions. To discover how pancreatic cancer cells adapt to glucose deprivation as well as hypoxia, we sought glucose deprivation-inducible genes by means of a DNA microarray system. We identified 63 genes whose expression was enhanced under glucose-deprived conditions at >2-fold higher levels than under normal glucose conditions. Among these genes, asparagine synthetase (ASNS) was studied in detail. Although it is known to be associated with drug resistance in leukemia and oncogenesis triggered by mutated p53, its function is yet to be determined. In this study, we found that glucose deprivation induced the overexpression of ASNS through an AMP-activated protein kinaseindependent and activating transcription factor-4-dependent manner and that ASNS protects pancreatic cancer cells from apoptosis induced by glucose deprivation itself. ASNS overexpression also induced resistance to apoptosis triggered by cisplatin [cis-diammine-dichloroplatinum (CDDP)] and carboplatin, but not by 5-fluorouracil, paclitaxel, etoposide, or gemcitabine. We show that glucose deprivation induces the activation of c-jun NH 2 -terminal kinase (JNK)/stress-activated protein kinase (SAPK) in a mock transfectant but not in an ASNS transfectant. Consequently, an inhibitor of JNK/SAPK decreased the sensitivity of pancreatic cancer cells to apoptosis by glucose deprivation and CDDP. These results strongly suggest that ASNS is induced by glucose deprivation and may play a pivotal role in the survival of pancreatic cancer cells under glucose-deprived conditions. [Cancer Res 2007;67(7):3345-55]

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced Expression of Asparagine Synthetase under Glucose-Deprived Conditions Protects Pancreatic Cancer Cells from Apoptosis Induced by Glucose Deprivation and Cisplatin

Cui

Darmanin²,

Natsuisaka

et al. 2007

Cancer Research

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“…This reaction proceeds in an ATP-dependent manner with glutamine serving as the nitrogen source (9). Most tissues contain sufficient ASNS activity to maintain asparagine or the enzyme is upregulated in response to asparagine depletion (10,11).…”

Section: Introductionmentioning

confidence: 99%

Asparagine synthetase expression and its potential prognostic value in patients with NK/T cell lymphoma

Zhang

et al. 2014

Oncology Reports

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“…Human asparagine synthetase (ASNS) catalyzes the biosynthesis of L-asparagine from Laspartate in an ATP-dependent reaction for which L-glutamine is the nitrogen source under physiological conditions (Scheme 1) (19). Recent work has demonstrated the importance of ASNS overexpression in conferring ASNase resistance in cell lines (20), and several lines of evidence suggest that inhibiting ASNS activity represents a viable strategy for treating ASNase-resistant leukemias in the clinic (1,8,21).…”

Section: Introductionmentioning

confidence: 99%

Asparagine Synthetase Chemotherapy

Richards

Kilberg

2006

Annu. Rev. Biochem.

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196

218

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Modern clinical treatments of childhood acute lymphoblastic leukemia (ALL) employ enzymebased methods for depletion of blood asparagine in combination with standard chemotherapeutic agents. Significant side effects can arise in these protocols and, in many cases, patients develop drug-resistant forms of the disease that may be correlated with up-regulation of the enzyme glutamine-dependent asparagine synthetase (ASNS). Though the precise molecular mechanisms that result in the appearance of drug resistance are the subject of active study, potent ASNS inhibitors may have clinical utility in treating asparaginase-resistant forms of childhood ALL. This review provides an overview of recent developments in our understanding of (a) the structure and catalytic mechanism of ASNS, and (b) the role that ASNS may play in the onset of drug-resistant childhood ALL. In addition, the first successful, mechanism-based efforts to prepare and characterize nanomolar ASNS inhibitors are discussed, together with the implications of these studies for future efforts to develop useful drugs.

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Mechanistic Issues in Asparagine Synthetase Catalysis

Cited by 67 publications

References 159 publications

Enhanced Expression of Asparagine Synthetase under Glucose-Deprived Conditions Protects Pancreatic Cancer Cells from Apoptosis Induced by Glucose Deprivation and Cisplatin

Enhanced Expression of Asparagine Synthetase under Glucose-Deprived Conditions Protects Pancreatic Cancer Cells from Apoptosis Induced by Glucose Deprivation and Cisplatin

Asparagine synthetase expression and its potential prognostic value in patients with NK/T cell lymphoma

Asparagine Synthetase Chemotherapy

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