English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Simple Summary  Certain mutations causing extremely low abundance of asparagine synthetase (the enzyme responsible for producing asparagine, one of the amino acids required for normal growth and development) have been identified in humans with neurological problems and small head and brain size. Currently, yeast is becoming more popular in modeling many human diseases. In this study, we incorporate a mutation, associated with human asparagine synthetase deficiency, into the yeast asparagine synthetase gene to demonstrate that this mutation can also show similar effects as those observed in humans, leading to very low abundance of yeast asparagine synthetase and slower yeast growth rate. This suggests that our yeast system can be alternatively used to initially screen for any drugs that can help rescue the protein levels of asparagine synthetase before applying them to further studies in mammals and humans. Furthermore, this mutation might specifically be introduced into the asparagine synthetase gene of the target cancer cells in order to suppress the overproduction of asparagine synthetase within these abnormal cells, therefore inhibiting the growth of cancer, which might be helpful for patients with blood cancer to prevent them developing any resistance to the conventional asparaginase treatment.    Abstract  Asparagine synthetase deficiency (ASD) has been found to be caused by certain mutations in the gene encoding human asparagine synthetase (ASNS). Among reported mutations, A6E mutation showed the greatest reduction in ASNS abundance. However, the effect of A6E mutation has not yet been tested with yeast asparagine synthetase (Asn1/2p). Here, we constructed a yeast strain by deleting  ASN2  from its genome, introducing the A6E mutation codon to  ASN1 , along with  GFP  downstream of  ASN1 . Our mutant yeast construct showed a noticeable decrease of Asn1p(A6E)-GFP levels as compared to the control yeast expressing Asn1p(WT)-GFP. At the stationary phase, the A6E mutation also markedly lowered the assembly frequency of the enzyme. In contrast to Asn1p(WT)-GFP, Asn1p(A6E)-GFP was insensitive to changes in the intracellular energy levels upon treatment with sodium azide during the log phase or fresh glucose at the stationary phase. Our study has confirmed that the effect of A6E mutation on protein expression levels of asparagine synthetase is common in both unicellular and multicellular eukaryotes, suggesting that yeast could be a model of ASD. Furthermore, A6E mutation could be introduced to the  ASNS  gene of acute lymphoblastic leukemia patients to inhibit the upregulation of ASNS by cancer cells, reducing the risk of developing resistance to the asparaginase treatment.

Effects of A6E Mutation on Protein Expression and Supramolecular Assembly of Yeast Asparagine Synthetase