Asparagine synthetase (ASNS) catalyzes the conversion of
aspartate and
glutamine to
asparagine and
glutamate in an
ATP-dependent reaction. The
enzyme is ubiquitous in its organ distribution in mammals, but basal expression is relatively low in tissues other than the exocrine pancreas. Human ASNS activity is highly regulated in response to cell stress, primarily by increased transcription from a single gene located on chromosome 7. Among the genomic elements that control ASNS transcription is the C/EBP-ATF response element (CARE) within the promoter.
Protein limitation or an imbalanced dietary
amino acid composition activate the ASNS gene through the
amino acid response (AAR), a process that is replicated in cell culture through limitation for any single
essential amino acid. Endoplasmic reticulum stress also increases ASNS transcription through the PERK-eIF2-ATF4 arm of the unfolded protein response (UPR). Both the AAR and UPR lead to increased synthesis of ATF4, which binds to the CARE and induces ASNS transcription. Elevated expression of ASNS
protein is associated with resistance to
asparaginase therapy in childhood
acute lymphoblastic leukemia and may be a predictive factor in
drug sensitivity for certain solid
tumors as well. Activation of the GCN2-eIF2-ATF4 signaling pathway, leading to increased ASNS expression appears to be a component of solid
tumor adaptation to nutrient deprivation and/or
hypoxia. Identifying the roles of ASNS in fetal development, tissue differentiation, and
tumor growth may reveal that ASNS function extends beyond
asparagine biosynthesis.