methionine gamma-lyase
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The enzyme methionine γ-lyase (EC 4.4.1.11, MGL) is in the γ-family of PLP-dependent enzymes. It degrades sulfur-containing amino acids to α-keto acids, ammonia, and thiols: :L-methionine + H2O = methanethiol + NH3 + 2-oxobutanoate (overall reaction) ::(1a) L-methionine = methanethiol + 2-aminobut-2-enoate ::(1b) 2-aminobut-2-enoate = 2-iminobutanoate (spontaneous) ::(1c) 2-iminobutanoate + H2O = 2-oxobutanoate + NH3 (spontaneous) Because sulfur-containing amino acids play a role in multiple biological processes, the regulation of these amino acids is essential. Additionally, it is crucial to maintain low homocysteine levels for the proper functioning of various pathways and for preventing the toxic effects of the cysteine homologue. Methionine γ-lyase has been found in several bacteria ''(Clostridiums porogenes, Pseudomonas ovalis, Pseudomonas putida, Aeromonas sp., Citrobacter intermedius, Brevibacterium linens, Citrobacter freundii, Porphyromonas gingivalis, Treponema denticola)'', parasitic protozoa ''(Trichomonas vaginalis, Entamoeba histolytica)'', and plants ''(Arabidopsis thaliana)''. This enzyme belongs to the family of lyases, specifically the class of carbon-sulfur lyases. The
systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature. A semisystematic name or semitrivial ...
of this enzyme class is L-methionine methanethiol-lyase (deaminating; 2-oxobutanoate-forming). Other names in common use include L-methioninase, methionine lyase, methioninase, methionine dethiomethylase, L-methionine γ-lyase, and L-methionine methanethiol-lyase (deaminating). This enzyme participates in selenoamino acid metabolism. It employs one cofactor,
pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent a ...
.


Structure

The enzyme is made up of 389-441 amino acids and forms four identical subunits. The active molecule is composed of two tightly associated dimers, the interface at which lies the active site. Each of the dimers has a pyridoxal 5’-phosphate (PLP) cofactor. Six amino acids located near the active site are involved in the reaction, namely Tyr59, Arg61, Tyr114, Cys116, Lys240, and Asp241. Unlike the other amino acids, Cys116 is not typically found in PLP γ-family enzymes, which instead have glycine or proline. Although there is no direct contact between Cys116 and either MGL or the methionine substrate, studies show that the amino acid is involved in retaining substrate specificity.


Reaction mechanism

In enzymology, a methionine gamma-lyase () is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that catalyzes the
chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
:L-methionine + H2O \rightleftharpoons methanethiol + NH3 + 2-oxobutanoate Thus, the two substrates of this enzyme are L-methionine and H2O, whereas its 3
products Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...
are
methanethiol Methanethiol (also known as methyl mercaptan) is an organosulfur compound with the chemical formula . It is a colorless gas with a distinctive putrid smell. It is a natural substance found in the blood, brain and feces of animals (including humans ...
, NH3, and 2-oxobutanoate. MGL also catalyzes α, β-elimination L-cysteine, degradation of O-substituted serine or homoserine, β- or γ-replacement, as well as deamination and γ-addition of L-vinylglycine. The reaction mechanism initially consists of the amino group of the substrate connected by a Schiff-base linkage to PLP. When a lysine residue replaces the amino group, an external aldimine is formed and hydrogens from the substrate are shifted to PLP. A neighboring tyrosine amino acid acts as an acid catalyst and attacks the substrate, consequently eliminating the thiol group from the substrate. Lastly, α-keto acid and ammonia are released from PLP.


Function

Because MGL has differing substrate specificity among organisms, the enzyme also has varying physiological roles among organisms. In anaerobic bacteria and parasitic protozoa, MGL generates 2-oxobutyrate from methionine. 2-oxobutyrate is ultimately decomposed by acetate-CoA ligase and produces ATP, thus contributing to ATP metabolism. MGL also plays a role in the pathogenicity of periodontal bacterium such as ''P. gingivalis''. A study finds a correlation between the presence of MGL and an increase in mice survival after subcutaneous injection of the bacteria. In B. linens, a cheese ripening bacterium, MGL activity is tightly linked with carbohydrate metabolism. In plants, MGL mRNA is found in dry seeds although the protein itself is not. However, the enzyme is highly expressed in wet seeds, suggesting that MGL is a vital part of early germination. MGL may also be involved in the formation of volatile sulfur compounds such as methanethiol on damaged plant leaves to defend against insects. However, it is undetermined whether MGL is present in guava, which was first discovered to have this protection mechanism, and whether other plants use a similar technique. Isozymes of MGL are only found in the parasitic protists ''E. histolytica'' and ''T. vaginalis''. The isozymes differ in their ability to efficiently degrade methionine, homocysteine, and cysteine. ''E. histolytica'' MGL is derived from archaea MGL whereas ''T. vaginalis'' MGL share more similarities with bacterial MGL. Therefore, the inclusion of MGL in the genome of these two species occurred independently.


Drug development

Trifluoromethionine (TFM) is a fluorinated methionine prodrug, which only presents its toxicity after degradation by MGL. Studies show that TFM is toxic to and slows the growth of anaerobic microorganisms ''(Mycobacterium smegmatis, Mycobacterium phlei, Candida lipolytica)'', periodontal bacteria ''(P. gingivalis, F. nucleatum)'', and parasitic protists ''(E. histolytica, T. vaginalis)''. Studies have shown that TFM is also efficacious in vivo. Furthermore, TFM has limited toxicity to mammalian cells, which do not have MGL. Therefore, TFM only exhibits toxic effects on pathogens that contain MGL.


Cancer therapy

Some tumors, such as
glioblastomas Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality cha ...
,
medulloblastoma Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa. The brain is divided into two ...
, and
neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in th ...
, are much more sensitive to the methionine starvation than the normal tissues. Therefore, methionine depletion arises as a relevant therapeutical approach to treat cancer. For that reason, MGL has been studied to decrease the methionine levels in the blood serum and decrease the tumor growth and also to kill, by starvation, those malignant cells.


References


Further reading

* * * * * * * * {{Portal bar, Biology, border=no EC 4.4.1 Pyridoxal phosphate enzymes Enzymes of known structure