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A human-like glutaminase-free asparaginase is highly efficacious in ASNS leukemia and solid cancer mouse xenograft models.
Cancer Lett
December 2024
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, USA; Enzyme By Design Inc., Chicago, USA; Research Biologist, Biological Science Research and Development, Department of Veterans Affairs Medical Center, Chicago, IL, USA. Electronic address:
L-asparaginase (L-ASNase) is crucial in treating pediatric acute lymphoblastic leukemia (ALL), but its use is hampered by side effects from the immunogenicity and L-glutaminase (L-GLNase) co-activity of FDA-approved bacterial L-ASNases, often leading to treatment discontinuation and poor outcomes. The toxicity of these L-ASNases makes them especially challenging to use in adult cancer patients. To overcome these issues, we developed EBD-200, a humanized guinea pig L-ASNase with low Km and no L-GLNase activity, eliminating glutamine-related toxicity.
View Article and Find Full Text PDFElucidation of the Reaction Mechanism of l-Asparaginase: A QM/MM Study.
J Chem Inf Model
January 2023
Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Autopista Concepción-Talcahuano 7100, Talcahuano 4260000, Chile.
The l-asparaginase (l-ASNase) enzyme catalyzes the conversion of the non-essential amino acid l-asparagine into l-aspartic acid and ammonia. Importantly, the l-ASNases are used as a key part of the treatment of acute lymphoblastic leukemia (ALL); however, despite their benefits, they trigger severe side effects because they have their origin in bacterial species ( and ). Therefore, one way to solve these side effects is the use of l-ASNases with characteristics similar to those of bacterial types, but from different sources.
View Article and Find Full Text PDFMolecular dynamics simulations of human L-asparaginase1: Insights into structural determinants of enzymatic activity.
J Mol Graph Model
December 2021
Fundação Oswaldo Cruz - Ceará, Fiocruz - CE, Protein Engineering and Health Solutions Group - GEPeSS, zip-code: 60175-047, Fortaleza, CE, Brazil. Electronic address:
The l-asparaginase enzyme is used in cancer therapy, mainly acute lymphoid leukemia (ALL). Commercial enzymes (EcASNase2) cause adverse reactions during treatment, such as immunogenicity. A human enzyme could be a non-immunogenic substitute.
View Article and Find Full Text PDFAspartate is an endogenous metabolic limitation for tumour growth.
Nat Cell Biol
July 2018
The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Defining the metabolic limitations of tumour growth will help to develop cancer therapies. Cancer cells proliferate slower in tumours than in standard culture conditions, indicating that a metabolic limitation may restrict cell proliferation in vivo. Aspartate synthesis can limit cancer cell proliferation when respiration is impaired; however, whether acquiring aspartate is endogenously limiting for tumour growth is unknown.
View Article and Find Full Text PDFDiscovery of human-like L-asparaginases with potential clinical use by directed evolution.
Sci Rep
August 2017
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
L-asparaginase is a chemotherapy drug used to treat acute lymphoblastic leukemia (ALL). The main prerequisite for clinical efficacy of L-asparaginases is micromolar K for asparagine to allow for complete depletion of this amino acid in the blood. Since currently approved L-asparaginases are of bacterial origin, immunogenicity is a challenge, which would be mitigated by a human enzyme.
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