Abstract
Cancer is an increasing cause of mortality and morbidity throughout the world. L-methionase has potential application against many types of cancers. L-Methionase is an intracellular enzyme in bacterial species, an extracellular enzyme in fungi, and absent in mammals. L-Methionase producing bacterial strain(s) can be isolated by 5,5′-dithio-bis-(2-nitrobenzoic acid) as a screening dye. L-Methionine plays an important role in tumour cells. These cells become methionine dependent and eventually follow apoptosis due to methionine limitation in cancer cells. L-Methionine also plays an indispensable role in gene activation and inactivation due to hypermethylation and/or hypomethylation. Membrane transporters such as GLUT1 and ion channels like Na2+, Ca2+, K+, and Cl− become overexpressed. Further, the α-subunit of ATP synthase plays a role in cancer cells growth and development by providing them enhanced nutritional requirements. Currently, selenomethionine is also used as a prodrug in cancer therapy along with enzyme methionase that converts prodrug into active toxic chemical(s) that causes death of cancerous cells/tissue. More recently, fusion protein (FP) consisting of L-methionase linked to annexin-V has been used in cancer therapy. The fusion proteins have advantage that they have specificity only for cancer cells and do not harm the normal cells.
Highlights
L-Methionine-γ-lyase (EC 4.4.1.11; MGL), known as methionase, methioninase, L-methionine-γ-demethiolase, and L-methionine methanethiol-lyase, is a pyridoxal phosphate (PLP) dependent enzyme
PLP reduces the energy for conversion of amino acids to a zwitterionic carbonion [1] and substantially the apoenzyme catalyzes the cleavage of substrate bond yielding the product [2]
MGL has a molecular weight (Mr) of about 149 kDa to 173 kDa and consists of four subunits with identical Mr of about 41 kDa to 45 kDa each except MGL purified to homogeneity from Pseudomonas putida which was found to consist of two nonidentical subunits of 40 kDa and 48 kDa [4]
Summary
L-Methionine-γ-lyase (EC 4.4.1.11; MGL), known as methionase, methioninase, L-methionine-γ-demethiolase, and L-methionine methanethiol-lyase (deaminating), is a pyridoxal phosphate (PLP) dependent enzyme. Escherichia coli and plants utilize the forward trans-sulfuration pathway such that methionine is biosynthesized from cysteine or they may utilize inorganic sulphate via de novo cysteine biosynthesis [7, 8]. Corynebacterium glutamicum, Leptospira meyeri, and Saccharomyces cerevisiae follow methionine biosynthesis-III pathway that performs homoserine methionine biosynthesis and methionine biosynthesis by sufhdrylation. Corynebacterium glutamicum, Leptospira meyeri, Pseudomonas aeruginosa, Pseudomonas putida and Saccharomyces cerevisiae possess a unique superpathway of methionine biosynthesis (by sulfhydrylation). E. histolytica and T. vaginalis have a methionine catabolic pathway and elements of a de novo sulphide biosynthetic pathway for cysteine biosynthesis in E. histolytica. These differences in cysteine metabolism between humans and parasites are of particular interest, especially for the future development of antiparasitic compounds. De novo engineering of a human MGL has been followed for achieving systemic Lmethionine depletion in cancer therapy [10]
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