Methionine gamma‐lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers

Abstract

SummarySulfur-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 gammalyase (MGL, EC 4.4.1.11) to directly degrade SAA to a-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.

PLP-Dependent Enzymes: a Potent Therapeutic Approach for Cancer and Cardiovascular Diseases

“…Interestingly, methionine/ valine depleted, tyrosine lowered and arginine enriched was the most rationalized form for inhibition of tumor growth (Chen et al, 2001, He et al, 2003. L-Methioninase was extensively tested a potent anti-proliferative enzyme towards Lewis lung (Yoshioka et al, 1998), human colon (Tan et al, 1998), glioblastoma (Kokkinakis et al, 2001), neuroblastoma (Hu and Cheung, 2009) as reviewed by Nozaki (2009) andEl-Sayed (2010). Recently, Parenteral nutrition is a common cosupportive strategy for various aspects of tumor therapy (Buchman et al, 2006).…”

“…Uniqueness distribution of L-methioninase as intracellular enzyme among all microbial pathogens, but not humans makes this enzyme is a novel target for antibacterial, antifungal and anti-protozoal therapies (Ali andNozaki, 2007, Sato andNozaki, 2009). Trifluoromethionine (TFM), a fluorinated methionine that undergoes , -elimination forming trifluoro-methanethiol (CF 3 SH) that converted to carbonothionic difluoride which subsequently interacted with primary amino groups of the enzymes lysine moieties, causing cellular toxicities (Alston andBright, 1983, Sato et al, 2008).…”

“…Trifluoromethionine (TFM), a fluorinated methionine that undergoes , -elimination forming trifluoro-methanethiol (CF 3 SH) that converted to carbonothionic difluoride which subsequently interacted with primary amino groups of the enzymes lysine moieties, causing cellular toxicities (Alston andBright, 1983, Sato et al, 2008). TFM was reported as a potent antibacterial agent towards the growth of Mycobacterium smegmatis, M. phlei and Candida lipolytica (Zygmunt andTavormina, 1966, Sato andNozaki, 2009), P. gingivalis, F. nucleatum (Yoshimura et al, 2002) and antiprotozoal agent Entaemoba histolytica (Coombs and Mottram, 2001). Also, TFM is highly effective against many anaerobic bacteria as Clostridium botulinum (botulism), C. difficile (colitis), Porphyromonas sp (tooth decay) and Bacteroides sp (intra-abdominal infections) (Finegold and Wexler, 1996).…”

Pre-steady-state Kinetic and Structural Analysis of Interaction of Methionine γ-Lyase from Citrobacter freundii with Inhibitors

“…In addition, MGL has been utilized to develop the therapeutic treatment of tumors by introducing recombinant proteins to deplete methionine, which is essential for the growth of cancer cells (11)(12)(13).…”

Biochemical and Pharmacokinetic Properties of Aspergillus flavipes Glutathione-Homocystine Transhydrogenase of Unique Affinity for Homocystine Reduction using GSH as Hydrogen Donor

“…This enzyme was firstly isolated from human liver [2], and this is first report to characterize this enzyme from microbes. To date, the information about fungal GST is limited, only few classes were studied, and the property of each class was dependent on the fungal isolate producing it [37]. However, the distribution of different forms of GSTs, could be to maintains the cellular redox state by sequestering the ROS [38].…”