{"doi":"10.1073/pnas.1917362117","title":"Enzyme-mediated depletion of serum <scp>l</scp> -Met abrogates prostate cancer growth via multiple mechanisms without evidence of systemic toxicity","abstract":"Extensive studies in prostate cancer and other malignancies have revealed that l-methionine (l-Met) and its metabolites play a critical role in tumorigenesis. Preclinical and clinical studies have demonstrated that systemic restriction of serum l-Met, either via partial dietary restriction or with bacterial l-Met-degrading enzymes exerts potent antitumor effects. However, administration of bacterial l-Met-degrading enzymes has not proven practical for human therapy because of problems with immunogenicity. As the human genome does not encode l-Met-degrading enzymes, we engineered the human cystathionine-γ-lyase (hMGL-4.0) to catalyze the selective degradation of l-Met. At therapeutically relevant dosing, hMGL-4.0 reduces serum l-Met levels to >75% for >72 h and significantly inhibits the growth of multiple prostate cancer allografts/xenografts without weight loss or toxicity. We demonstrate that in vitro, hMGL-4.0 causes tumor cell death, associated with increased reactive oxygen species, S-adenosyl-methionine depletion, global hypomethylation, induction of autophagy, and robust poly(ADP-ribose) polymerase (PARP) cleavage indicative of DNA damage and apoptosis.","journal":"Proceedings of the National Academy of Sciences","year":2020,"id":65931,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":54,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9459,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":348910,"name":"Achinto Saha","orcid":"0000-0002-4810-551X","position":1,"is_corresponding":false},{"id":348911,"name":"Wupeng Yan","orcid":"0000-0001-5387-6362","position":2,"is_corresponding":false},{"id":349745,"name":"Kendra Garrison","orcid":null,"position":3,"is_corresponding":false},{"id":106343,"name":"Candice Lamb","orcid":"0000-0002-6204-2156","position":4,"is_corresponding":false},{"id":348912,"name":"Renu Pandey","orcid":"0000-0003-1892-2495","position":5,"is_corresponding":false},{"id":348913,"name":"Seema Irani","orcid":"0000-0001-5159-3473","position":6,"is_corresponding":false},{"id":348914,"name":"Alessia Lodi","orcid":"0000-0002-2104-5713","position":7,"is_corresponding":false},{"id":348915,"name":"Xiyuan Lu","orcid":"0000-0002-8701-3458","position":8,"is_corresponding":false},{"id":348916,"name":"Stefano Tiziani","orcid":"0000-0002-7230-0307","position":9,"is_corresponding":false},{"id":348305,"name":"Yan Zhang","orcid":"0000-0002-9360-5388","position":10,"is_corresponding":false},{"id":106348,"name":"George Georgiou","orcid":"0000-0002-8823-3073","position":11,"is_corresponding":false},{"id":348917,"name":"John DiGiovanni","orcid":"0000-0003-4233-6728","position":12,"is_corresponding":false},{"id":106347,"name":"Everett Stone","orcid":"0000-0002-2459-9762","position":13,"is_corresponding":false},{"id":348909,"name":"Weicheng Lu","orcid":"0000-0001-6498-0931","position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":null,"created_at":"2026-07-18T21:13:43.728351Z","pmid":"32434918","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}