Methionine gamma-lyase: the unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers.
Sulfur-containing amino acids (SAAs) are essential components in many biological processes and ubiquitously distributed to all organisms. Both biosynthetic and catabolic pathways of SAAs are heterogeneous among organisms and between developmental stages, and regulated by the environmental changes. Limited lineage of organisms ranging from archaea to plants, but not human, possess a unique enzyme methionine gamma-lyase (MGL, EC 4.4.1.11) to directly degrade SAA to alpha-keto acids, ammonia, and volatile thiols. The reaction mechanisms and the physiological roles of this enzyme are partially demonstrated by the enzymological analyzes, structure determination, isotopic labeling of the intermediate metabolites, and functional analyzes of deficient mutants. MGL has been exploited as a drug target for the infectious diseases caused by parasitic protozoa and anaerobic periodontal bacteria. In addition, MGL has been utilized to develop therapeutic interventions of various cancers, by introducing recombinant proteins to deplete methionine essential for the growth of cancer cells. In this review, we discuss the current understanding of enzymological properties, putative physiological roles, and therapeutic applications of MGL.
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
Dan
D
Sato
Tomoyoshi
T
Nozaki
D000475:Alkenes / Q000494:pharmacology; D000595:Amino Acid Sequence; D000693:Anaerobiosis; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D017360:Arabidopsis / Q000201:enzymology; D001572:Benzofurans / Q000494:pharmacology; D013437:Carbon-Sulfur Lyases / Q000037:antagonists & inhibitors / Q000502:physiology* / Q000627:therapeutic use*; D004748:Entamoeba histolytica / Q000201:enzymology; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010510:Periodontal Diseases / Q000188:drug therapy; D011528:Protozoan Infections / Q000188:drug therapy; D014246:Trichomonas vaginalis / Q000201:enzymology
D000475:Alkenes; D000970:Antineoplastic Agents; D001572:Benzofurans; C468150:myrsinoic acid B; C037646:trifluoromethionine; D008715:Methionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase