6OVG

L-Methionine Depletion with an Engineered Human Enzyme Disrupts Prostate Cancer Metabolism

Summary for 6OVG

• Entry DOI: 10.2210/pdb6ovg/pdb
• Descriptor: Cystathionine gamma-lyase, SULFATE ION (3 entities in total)
• Functional Keywords: engineering, lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 365920.44

Authors

Yan, W.,Irani, S.,Zhang, J. (deposition date: 2019-05-07, release date: 2020-04-22, Last modification date: 2023-11-15)

Primary citation

Lu, W.C.,Saha, A.,Yan, W.,Garrison, K.,Lamb, C.,Pandey, R.,Irani, S.,Lodi, A.,Lu, X.,Tiziani, S.,Zhang, Y.J.,Georgiou, G.,DiGiovanni, J.,Stone, E.
Enzyme-mediated depletion of serum l-Met abrogates prostate cancer growth via multiple mechanisms without evidence of systemic toxicity.
Proc.Natl.Acad.Sci.USA, 117:13000-13011, 2020

PubMed 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.

PubMed: 32434918
DOI: 10.1073/pnas.1917362117

Experimental method

X-RAY DIFFRACTION (2.719 Å)