The distribution of <scp>l</scp>-asparagine synthetase in the principal organs of several mammalian and avian species

Milman, Harry A.; Cooney, David A.

doi:10.1042/bj1420027

Cited by 62 publications

(28 citation statements)

References 16 publications

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“…This was not true of added Asp under similar conditions (55) because of its impermeability into periportal hepatocytes (57). A survey of various mammalian and avian species has shown that human and mouse liver have comparable asparagine synthetase activities but that mouse liver has a thousandfold increased activity of asparaginase compared with that of human (58). An increased Asn synthesis through the increased expression of the Asns gene in the Ctrn-KO and the double knock-out mice therefore could supply Asn as a diffusible source of cytosolic Asp within the mouse liver.…”

Section: Discussionmentioning

confidence: 99%

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Saheki

Iijima

et al. 2007

Journal of Biological Chemistry

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Citrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol.Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. An increased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD ؉ ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice.

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Section: Discussionmentioning

confidence: 99%

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Saheki

Iijima

et al. 2007

Journal of Biological Chemistry

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“…ASNS is expressed to varying degrees within human organs (http://www.proteinatlas.org/ENSG00000070669-ASNS/tissue), 5 but is particularly high in pancreas (32). However, when considering the requirement for asparagine at the level of individual cells, ASNS deficiency leads to extracellular asparagine dependence, as discussed above for ALL cells.…”

Section: Asparagine Synthetase Deficiencymentioning

confidence: 98%

Asparagine synthetase: Function, structure, and role in disease

Lomelino¹,

Andring²,

McKenna³

et al. 2017

Journal of Biological Chemistry

238

203

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Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. Elevated ASNS protein expression is associated with resistance to asparaginase therapy in childhood acute lymphoblastic leukemia. There is evidence that ASNS expression levels may also be inversely correlated with asparaginase efficacy in certain solid tumors as well. Children with mutations in the ASNS gene exhibit developmental delays, intellectual disability, microcephaly, intractable seizures, and progressive brain atrophy. Thus far, 15 unique mutations in the ASNS gene have been clinically associated with asparagine synthetase deficiency (ASD). Molecular modeling using the Escherichia coli ASNS-B structure has revealed that most of the reported ASD substitutions are located near catalytic sites or within highly conserved regions of the protein. For some ASD patients, fibroblast cell culture studies have eliminated protein and mRNA synthesis or stability as the basis for decreased proliferation.

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“…Unfortunately, mice, unlike humans, express endogenous L-ASP (at high levels; ref. 48), so they are questionable as models for assessment of ASNS as a biomarker for asparagine depletion therapy.…”

Section: Discussionmentioning

confidence: 99%

Asparagine synthetase as a causal, predictive biomarker for l-asparaginase activity in ovarian cancer cells

Lorenzi

Reinhold

Rudelius³

et al. 2006

Molecular Cancer Therapeutics

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L-Asparaginase (L-ASP), a bacterial enzyme used since the 1970s to treat acute lymphoblastic leukemia, selectively starves cells that cannot synthesize sufficient asparagine for their own needs. Molecular profiling of the NCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase (ASNS) expression and DNA copy number with sensitivity to L-ASP in the leukemia and ovarian cancer cell subsets. To assess whether the ovarian relationship is causal, we used RNA interference to silence ASNS in three ovarian lines and observed 4-to 5-fold potentiation of sensitivity to L-ASP with two of the lines. For OVCAR-8, the line that expresses the least ASNS, the potentiation was >500-fold. Significantly, that potentiation was >700-fold in the multidrug-resistant derivative OVCAR-8/ADR, showing that the causal relationship between ASNS expression and L-ASP activity survives development of classical multidrug resistance. Tissue microarrays confirmed low ASNS expression in a subset of clinical ovarian cancers as well as other tumor types. Overall, this pharmacogenomic/pharmacoproteomic study suggests the use of L-ASP for treatment of a subset of ovarian cancers (and perhaps other tumor types), with ASNS as a biomarker for patient selection.

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The distribution of l-asparagine synthetase in the principal organs of several mammalian and avian species

Cited by 62 publications

References 16 publications

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Asparagine synthetase: Function, structure, and role in disease

Asparagine synthetase as a causal, predictive biomarker for l-asparaginase activity in ovarian cancer cells

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