Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey

Expert Opin Biol Ther. 2015 Jan;15(1):21-31. doi: 10.1517/14712598.2015.963050. Epub 2014 Dec 2.


Introduction: All tested cancer cell types are methionine dependent in that the cells arrest and eventually die when deprived of methionine, a condition that is generally nontoxic to normal cells. Methionine dependence is the only known general metabolic defect in cancer. Methionine-deprived cancer cells arrest at the S/G2 phase, an unusual position for cell cycle arrest. In order to exploit the cancer-specific metabolic defect of methionine dependence, methioninases were developed.

Areas covered: The present Expert Opinion describes the phenomena of methionine dependence and a methioninase cloned from Pseudomonas putida (chemical name: l-methionine α-deamino-γ-mercaptomethane lyase [EC]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer as well as in macaque monkeys and a pilot Phase I trial of human cancer patients. Efficacy of rMETase has been demonstrated against various cancer types in mouse models.

Expert opinion: The most promising application of rMETase therapy is in sequential combination therapy, whereby the cancer cells within a tumor are trapped in S/G2 by methioninase treatment and then treated with chemotherapeutic agents active against cells in S/G2.

Keywords: Escherichia coli; PEGylation; S/G2; cancer; combination chemotherapy; gene cloning; methioninase; methionine dependence; purification; recombinant rMETase; selective cancer-cell-cycle arrest; trap.

Publication types

  • Review

MeSH terms

  • Animals
  • Carbon-Sulfur Lyases / genetics
  • Carbon-Sulfur Lyases / metabolism
  • Carbon-Sulfur Lyases / therapeutic use*
  • Clinical Trials, Phase I as Topic
  • Cloning, Molecular
  • Combined Modality Therapy
  • Humans
  • Macaca
  • Methionine / metabolism*
  • Mice
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Pseudomonas putida / enzymology
  • Pseudomonas putida / genetics
  • Recombinant Proteins / therapeutic use*


  • Recombinant Proteins
  • Methionine
  • Carbon-Sulfur Lyases
  • L-methionine gamma-lyase