ArticleBiochemistry2018
Biochemical Characterization and Structure-Based Mutational Analysis Provide Insight into the Binding and Mechanism of Action of Novel Aspartate Aminotransferase Inhibitors.
Article in Biochemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 26 citations in OpenAlex.
- A pH-Responsive fluorescence lifetime probe reveals GOT1 phase separation in cellular anti-senescence.Smart molecules : open access · 2026Article
- Glioblastoma cells utilize evolutionarily adapted cell metabolism to promote their malignant proliferation.Acta neuropathologica communications · 2026Article
- Metabolic reprogramming in cancer: signaling pathways and therapeutic targets.Molecular cancer · 2026Review
- Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development.Nature communications · 2024Article
- Article
- The role of GOT1 in cancer metabolism.Frontiers in oncology · 2024Review
- Rod photoreceptor-specific deletion of cytosolic aspartate aminotransferase, GOT1, causes retinal degeneration.Frontiers in ophthalmology · 2023Article
- Ziprasidone suppresses pancreatic adenocarcinoma cell proliferation by targeting GOT1 to trigger glutamine metabolism reprogramming.Journal of molecular medicine (Berlin, Germany) · 2022Article
- Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain.Advances in cancer research · 2022Review
- Discovery of GOT1 Inhibitors from a Marine-DerivedMarine drugs · 2021Article
- GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis.Nature communications · 2021Article
- Molecular docking of two cytotoxic compounds fromNarra J · 2021Article
- Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias.Frontiers in oncology · 2021Review
- Aspartate aminotransferase Rv3722c governs aspartate-dependent nitrogen metabolism in Mycobacterium tuberculosis.Nature communications · 2020Article
- Natural Products and Derivatives Targeting at Cancer Energy Metabolism: A Potential Treatment Strategy.Current medical science · 2020Review
- A covalent small molecule inhibitor of glutamate-oxaloacetate transaminase 1 impairs pancreatic cancer growth.Biochemical and biophysical research communications · 2020Article
- Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy.Cancer & metabolism · 2020Article
- Review
- Molecular docking investigation of calotropone as a potential natural therapeutic agent against pancreatic cancer.Journal of advanced pharmaceutical technology & researchArticle
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Pancreatic cancer cells are characterized by deregulated metabolic programs that facilitate growth and resistance to oxidative stress. Among these programs, pancreatic cancers preferentially utilize a metabolic pathway through the enzyme aspartate aminotransferase 1 [also known as glutamate oxaloacetate transaminase 1 (GOT1)] to support cellular redox homeostasis. As such, small molecule inhibitors that target GOT1 could serve as starting points for the development of new therapies for pancreatic cancer. We ran a high-throughput screen for inhibitors of GOT1 and identified a small molecule, iGOT1-01, with in vitro GOT1 inhibitor activity. Application in pancreatic cancer cells revealed metabolic and growth inhibitory activity reflecting a promiscuous inhibitory profile. We then performed an in silico docking analysis to study inhibitor-GOT1 interactions with iGOT1-01 analogues that possess improved solubility and potency properties. These results suggested that the GOT1 inhibitor competed for binding to the pyridoxal 5-phosphate (PLP) cofactor site of GOT1. To analyze how the GOT1 inhibitor bound to GOT1, a series of GOT1 mutant enzymes that abolished PLP binding were generated. Application of the mutants in X-ray crystallography and thermal shift assays again suggested but were unable to formally conclude that the GOT1 inhibitor bound to the PLP site. Mutational studies revealed the relationship between PLP binding and the thermal stability of GOT1 while highlighting the essential nature of several residues for GOT1 catalytic activity. Insight into the mode of action of GOT1 inhibitors may provide leads to the development of drugs that target redox balance in pancreatic cancer.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.