An inhibitory factor for cell-free protein synthesis from Salmonella enteritidis exhibits cytopathic activity against Chinese hamster ovary cells

Iwamaru, Yoshifumi; Miyake, Masami; Arii, Junko; Tanabe, Yuzo; Noda, Masatoshi

doi:10.1006/mpat.2001.0471

Cited by 6 publications

(8 citation statements)

References 39 publications

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“…19 This study also suggests that the sum total of salmonella cytotoxicity may be the combined actions of multiple toxic substances, one of which is L-asparaginase. 19 This study also suggests that the sum total of salmonella cytotoxicity may be the combined actions of multiple toxic substances, one of which is L-asparaginase.…”

Section: Discussionmentioning

confidence: 74%

Clinical and pathologic characteristics of nontyphoidal salmonella encephalopathy

et al. 2002

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Section: Discussionmentioning

confidence: 74%

Clinical and pathologic characteristics of nontyphoidal salmonella encephalopathy

et al. 2002

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“…Typhimurium uses L-Asparaginase II to inhibit the response of T cells may be similar to the mechanism by which clinically administered L-asparaginases help eliminate human cancers. The mechanistic details of how inhibition occurs are supported by recent studies demonstrating that purified L-Asparaginase II from S. enteritidis and H. pylori can inhibit protein synthesis, block cell-cycle progression, and suppress replication of cultured cell lines (Iwamaru et al, 2001; Scotti et al, 2010; Shibayama et al, 2011). Additional support comes from our own work indicating that S .…”

Section: Discussionmentioning

confidence: 97%

L-Asparaginase II Produced by Salmonella Typhimurium Inhibits T Cell Responses and Mediates Virulence

Kullas

McClelland

Yang

et al. 2012

Cell Host & Microbe

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SUMMARY Salmonella enterica serovar Typhimurium avoids clearance by the host immune system by suppressing T cell responses; however, the mechanisms that mediate this immunosuppression remain unknown. We show that S. Typhimurium inhibit T cell responses by producing L-Asparaginase II, which catalyzes the hydrolysis of L-asparagine to aspartic acid and ammonia. L-Asparaginase II is necessary and sufficient to suppress T cell blastogenesis, cytokine production, and proliferation and to downmodulate expression of the T cell receptor. Furthermore, S. Typhimurium-induced inhibition of T cells in vitro is prevented upon addition of L-asparagine. S. Typhimurium lacking the L-Asparaginase II gene (STM3106) are unable to inhibit T cell responses and exhibit attenuated virulence in vivo. L-Asparaginases are used to treat acute lymphoblastic leukemia through mechanisms that likely involve amino acid starvation of leukemic cells, and these findings indicate that pathogens similarly use L-asparagine deprivation to limit T cell responses.

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“…The observation that asparaginase II inhibits protein synthesis in cell free extracts indicates that intracellular expression of the type II activity is toxic. 43,44 The active site…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure and Allosteric Regulation of the Cytoplasmic Escherichia coli l-Asparaginase I

Yun

Nourse

White

et al. 2007

Journal of Molecular Biology

110

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AnsA is the cytoplasmic asparaginase from Escherichia coli involved in intracellular asparagine utilization. Analytical ultracentifugation and X-ray crystallography reveal that AnsA forms a tetrameric structure as a dimer of two intimate dimers. Kinetic analysis of the enzyme reveals that AnsA is positively cooperative, displaying a sigmoidal substrate dependence curve with an [S](0.5) of 1 mM L-asparagine and a Hill coefficient (n(H)) of 2.6. Binding of L-asparagine to an allosteric site was observed in the crystal structure concomitant with a reorganization of the quarternary structure, relative to the apo enzyme. The carboxyl group of the bound asparagine makes salt bridges and hydrogen bonds to Arg240, while the N(delta2) nitrogen interacts with Thr162. Mutation of Arg240 to Ala increases the [S](0.5) value to 5.9 mM, presumably by reducing the affinity of the site for L-asparagine, although the enzyme retains cooperativity. Mutation of Thr162 to Ala results in an active enzyme with no cooperativity. Transmission of the signal from the allosteric site to the active site appears to involve subtle interactions at the dimer-dimer interface and relocation of Gln118 into the vicinity of the active site to position the probable catalytic water molecule. These data define the structural basis for the cooperative regulation of the intracellular asparaginase that is required for proper functioning within the cell.

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An inhibitory factor for cell-free protein synthesis from Salmonella enteritidis exhibits cytopathic activity against Chinese hamster ovary cells

Cited by 6 publications

References 39 publications

Clinical and pathologic characteristics of nontyphoidal salmonella encephalopathy

Clinical and pathologic characteristics of nontyphoidal salmonella encephalopathy

L-Asparaginase II Produced by Salmonella Typhimurium Inhibits T Cell Responses and Mediates Virulence

Crystal Structure and Allosteric Regulation of the Cytoplasmic Escherichia coli l-Asparaginase I

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