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Methionine gamma-lyase

Methionine gamma-lyase (MGL) is an enzyme in the family of PLP-dependent enzymes. It degrades sulfurcontaining amino acids to -keto acids, ammonia, and
thiols. 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.[1] Methionine gammalyase 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).[2]
This enzyme belongs to the family of lyases, specically
the class of carbon-sulfur lyases. The systematic name
of this enzyme class is L-methionine methanethiollyase (deaminating 2-oxobutanoate-forming). Other
names in common use include L-methioninase, methionine lyase, methioninase, methionine dethiomethylase, L-methionine gamma-lyase, and L-methionine
methanethiol-lyase (deaminating). This enzyme participates in selenoamino acid metabolism. It employs one
cofactor, pyridoxal phosphate.


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 re[2]
action, namely Tyr59, Arg61, Tyr114, Cys116, Lys240, Mechanism of methionine gamma-lyase
and Asp241.[2] Unlike the other amino acids, Cys116 is
not typically found in PLP -family enzymes, which intion
stead have glycine or proline. Although there is no direct
contact between Cys116 and either MGL or the methionL-methionine + H2 O methanethiol + NH3
ine substrate, studies show that the amino acid is involved
+ 2-oxobutanoate
in retaining substrate specicity.[3]

Thus, the two substrates of this enzyme are L-methionine

and H2 O, whereas its 3 products are methanethiol, NH3 ,
and 2-oxobutanoate.

Reaction mechanism

In enzymology, a methionine gamma-lyase (EC MGL also catalyzes , -elimination L-cysteine, degra4.4.1.11) is an enzyme that catalyzes the chemical reac- dation of O-substituted serine or homoserine, - or 1


replacement, as well as deamination and -addition of Lvinylglycine. The reaction mechanism initially consists of
the amino group of the substrate connected by a Schibase 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, -keto acid and ammonia are released from PLP.[2]


Because MGL has diering substrate specicity 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 nds 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.[4]
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 rst discovered to have this
protection mechanism, and whether other plants use a
similar technique.[5]
Isozymes of MGL are only found in the parasitic protists E. histolytica and T. vaginalis. The isozymes dier in
their ability to eciently 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

Drug development

Triuoromethionine (TFM) is a uorinated 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 ecacious 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.[7]

5 References
[1] Stipanuk MH (2004). Sulfur amino acid metabolism:
pathways for production and removal of homocysteine and cysteine. Annual Review of Nutrition 24:
539577. doi:10.1146/annurev.nutr.24.012003.132418.
PMID 15189131.
[2] Sato D, Nozaki T (Nov 2009). Methionine gammalyase: the unique reaction mechanism, physiological
roles, and therapeutic applications against infectious diseases and cancers. IUBMB Life 61 (11): 10191028.
doi:10.1002/iub.255. PMID 19859976.
[3] Kudou D, Misaki S, Yamashita M, Tamura T, Esaki
N, Inagaki K (Jul 2008). The role of cysteine 116 in
the active site of the antitumor enzyme L-methionine
gamma-lyase from Pseudomonas putida. Bioscience,
Biotechnology, and Biochemistry 72 (7): 17221730.
doi:10.1271/bbb.80015. PMID 18603802.
[4] Nozaki T, Ali V, Tokoro M (2005). Sulfur-containing
amino acid metabolism in parasitic protozoa. Advances in Parasitology 60: 199. doi:10.1016/S0065308X(05)60001-2. PMID 16230102.
[5] Rouse RL, Onagbola EO, Smoot JM, Stelinski LL
(Oct 2008). Sulfur volatiles in guava (Psidium guajava L.) leaves: possible defense mechanism. Journal
of Agricultural and Food Chemistry 56 (19): 89058910.
doi:10.1021/jf801735v. PMID 18778077.
[6] Alexander FW, Sandmeier E, Mehta PK, Christen P (Feb
1994). Evolutionary relationships among pyridoxal-5'phosphate-dependent enzymes. Regio-specic alpha, beta
and gamma families. European Journal of Biochemistry / FEBS 219 (3): 953960. doi:10.1111/j.14321033.1994.tb18577.x. PMID 8112347.
[7] Coombs GH, Mottram JC (Jun 2001).
Triuoromethionine, a prodrug designed against methionine
gamma-lyase-containing pathogens, has ecacy in vitro
and in vivo against Trichomonas vaginalis.
Antimicrobial Agents and Chemotherapy 45 (6): 1743
1745. doi:10.1128/AAC.45.6.1743-1745.2001. PMID

6 Further reading
Ali V, Nozaki T (Jan 2007). Current therapeutics, their problems, and sulfur-containing-aminoacid metabolism as a novel target against infections by amitochondriate protozoan parasites.
Clinical Microbiology Reviews 20 (1): 164187.
doi:10.1128/CMR.00019-06. PMID 17223627.

Bonnarme P, Psoni L, Spinnler HE (Dec 2000).
Diversity of L-methionine catabolism pathways
in cheese-ripening bacteria. Applied and Environmental Microbiology 66 (12): 55145517.
doi:10.1128/aem.66.12.5514-5517.2000. PMID
Kreis W, Hession C (Aug 1973). Isolation and
L-methionine-alpha-deaminogamma-mercaptomethane-lyase (L-methioninase)
from Clostridium sporogenes. Cancer Research 33
(8): 18625. PMID 4720797.
Sato D, Karaki T, Shimizu A, Kamei K, Harada
S, Nozaki T (Aug 2008). Crystallization and preliminary X-ray analysis of L-methionine gammalyase 1 from Entamoeba histolytica. Acta Crystallographica. Section F, Structural Biology and
Crystallization Communications 64 (Pt 8): 697
699. doi:10.1107/S1744309108018691. PMID
Sato D, Yamagata W, Kamei K, Nozaki T,
Harada S (Oct 2006).
Expression, purication and crystallization of L-methionine gammalyase 2 from Entamoeba histolytica. Acta Crystallographica. Section F, Structural Biology and
Crystallization Communications 62 (Pt 10): 1034
1036. doi:10.1107/S1744309106036694. PMID
Sato D, Yamagata W, Harada S, Nozaki T (Feb
2008). Kinetic characterization of methionine
gamma-lyases from the enteric protozoan parasite Entamoeba histolytica against physiological
substrates and triuoromethionine, a promising
lead compound against amoebiasis. The FEBS
Journal 275 (3): 548560. doi:10.1111/j.17424658.2007.06221.x. PMID 18199285.
Tokoro M, Asai T, Kobayashi S, Takeuchi T, Nozaki
T (Oct 2003). Identication and characterization of two isoenzymes of methionine gammalyase from Entamoeba histolytica: a key enzyme
of sulfur-amino acid degradation in an anaerobic parasitic protist that lacks forward and reverse trans-sulfuration pathways. The Journal
of Biological Chemistry 278 (43): 4271742727.
doi:10.1074/jbc.M212414200. PMID 12920135.
Wald DS, Law M, Morris JK (Nov 2002). Homocysteine and cardiovascular disease: evidence on
causality from a meta-analysis. Bmj 325 (7374):
PMID 12446535.


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