Dietary restriction of
l-methionine, an
essential amino acid, exerts potent antitumor effects on
l-methionine-dependent
cancers. However,
dietary restriction of
l-methionine has not been practical for human
therapy because of the problem with the administration of
l-methionine concentration in foods. Here, a thermophilic
methionine γ-
lyase (MGL), that catalyzes the cleavage of the C-S bond in
l-methionine to produce α-ketobutyric
acid,
methanethiol, and
ammonia was engineered from human
cystathionine γ-
lyase and almost completely depleted
l-methionine at 65 °C, a temperature that accelerates the volatilization of
methanethiol and its oxidation products. The high efficiency of
l-methionine lysis may be attributed to the cooperative fluctuation and moderate the structural rigidity of 4 monomers in the thermophilic MGL, which facilitates
l-methionine access to the entrance of the active site. Experimental diets treated with thermophilic MGL markedly inhibited prostate
tumor growth in mice, and in parallel, the in vivo concentrations of
l-methionine, its transformation product
l-cysteine, and the oxidative stress
indicator malondialdehyde significantly decreased. These findings provide a technology for the depletion of
l-methionine in foods with an engineered thermophilic MGL, which efficiently inhibits
tumor growth in mice.