ArticleACS chemical biology2012
De novo engineering of a human cystathionine-γ-lyase for systemic (L)-Methionine depletion cancer therapy.
Article in ACS chemical biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 46 citations in OpenAlex.
- Integrated production and protein-protein docking analysis of3 Biotech · 2025Article
- Article
- Methionine Dependency and Restriction in Cancer: Exploring the Pathogenic Function and Therapeutic Potential.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Elucidation of the stereochemical mechanism of cystathionine γ-lyase reveals how substrate specificity constrains catalysis.ACS catalysis · 2024Article
- Dietary Manipulation of Amino Acids for Cancer Therapy.Nutrients · 2023Review
- Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria.British journal of pharmacology · 2023Review
- MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation.International journal of molecular sciences · 2022Article
- Artificial Diets Based on Selective Amino Acid Restriction versus Capecitabine in Mice with Metastatic Colon Cancer.Nutrients · 2022Article
- Targeting the methionine addiction of cancer.American journal of cancer research · 2022Review
- YALI0C22088g from Yarrowia lipolytica catalyses the conversion of l-methionine into volatile organic sulfur-containing compounds.Microbial biotechnology · 2021Article
- Enzyme-mediated depletion of serum l-Met abrogates prostate cancer growth via multiple mechanisms without evidence of systemic toxicity.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Catalytic Roles of Coenzyme Pyridoxal-5'-phosphate (PLP) in PLP-dependent Enzymes: Reaction Pathway for Methionine-γ-lyase-catalyzed L-methionine Depletion.ACS catalysis · 2020Article
- Methionine tumor starvation by erythrocyte-encapsulated methionine gamma-lyase activity controlled with per os vitamin B6.Cancer medicine · 2017Article
- Structural Snapshots of an Engineered Cystathionine-γ-lyase Reveal the Critical Role of Electrostatic Interactions in the Active Site.Biochemistry · 2017Article
- Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.Nature medicine · 2017Article
- Glioblastoma multiforme: emerging treatments and stratification markers beyond new drugs.The British journal of radiology · 2015Review
- Targeted enzyme prodrug therapy for metastatic prostate cancer - a comparative study of L-methioninase, purine nucleoside phosphorylase, and cytosine deaminase.Journal of biomedical science · 2014Article
- L-methionase: a therapeutic enzyme to treat malignancies.BioMed research international · 2014Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
It has been known for nearly a half century that human tumors, including those derived from the nervous system such as glioblastomas, medulloblastoma, and neuroblastomas are much more sensitive than normal tissues to l-methionine (l-Met) starvation. More recently, systemic l-Met depletion by administration of Pseudomonas putida methionine-γ-lyase (MGL) could effectively inhibit human tumors xenografted in mice. However, bacterial-derived MGLs are unstable in serum (t(1/2) = 1.9 ± 0.2 h) and highly immunogenic in primates. Since the human genome does not encode a human MGL enzyme, we created de novo a methionine degrading enzyme by reengineering the structurally homologous pyridoxal phosphate-dependent human enzyme cystathionine-γ-lyase (hCGL). hCGL degrades l-cystathionine but displays no promiscuous activity toward l-Met. Rational design and scanning saturation mutagenesis led to the generation of a variant containing three amino acid substitutions (hCGL-NLV) that degraded l-Met with a k(cat)/K(M) of 5.6 × 10(2) M(-1) s(-1) and displayed a serum deactivation t(1/2) = 78 ± 5 h (non-PEGylated). In vitro, the cytotoxicity of hCGL-NLV toward 14 neuroblastoma cell lines was essentially indistinguishable from that of the P. putida MGL. Intravenous administration of PEGylated hCGL-NLV in mice reduced serum l-Met from 123 μM to <5 μM for over 30 h. Importantly, treatment of neuroblastoma mouse xenografts with PEGylated hCGL-NLV resulted in near complete cessation of tumor growth. Since the mode of action of hCGL-NLV does not require breaching the blood-brain barrier, this enzyme may have potential application for sensitive tumors that arise from or metastasize to the central nervous system.
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Registered trials
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