MEGL_PSEPU
ID MEGL_PSEPU Reviewed; 398 AA.
AC P13254;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 2.
DT 03-AUG-2022, entry version 115.
DE RecName: Full=L-methionine gamma-lyase {ECO:0000303|PubMed:6742420, ECO:0000303|PubMed:8586629};
DE Short=MGL {ECO:0000303|PubMed:10965031};
DE EC=4.4.1.11 {ECO:0000269|PubMed:22785484, ECO:0000269|PubMed:6742420};
DE AltName: Full=Homocysteine desulfhydrase {ECO:0000305|PubMed:6742420};
DE EC=4.4.1.2 {ECO:0000269|PubMed:22785484, ECO:0000269|PubMed:6742420};
DE AltName: Full=L-methioninase;
GN Name=mdeA {ECO:0000312|EMBL:BAA20553.1};
OS Pseudomonas putida (Arthrobacter siderocapsulatus).
OC Bacteria; Proteobacteria; Gammaproteobacteria; Pseudomonadales;
OC Pseudomonadaceae; Pseudomonas.
OX NCBI_TaxID=303;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RC STRAIN=ICR 3460;
RX PubMed=8586629; DOI=10.1093/oxfordjournals.jbchem.a124816;
RA Inoue H., Sugimoto M., Inagaki K., Esaki N., Soda K., Tanaka H.;
RT "Structural analysis of the L-methionine gamma-lyase gene from Pseudomonas
RT putida.";
RL J. Biochem. 117:1120-1125(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND INDUCTION.
RC STRAIN=ICR 3460;
RX PubMed=9190812; DOI=10.1128/jb.179.12.3956-3962.1997;
RA Inoue H., Inagaki K., Eriguchi S.I., Tamura T., Esaki N., Soda K.,
RA Tanaka H.;
RT "Molecular characterization of the mde operon involved in L-methionine
RT catabolism of Pseudomonas putida.";
RL J. Bacteriol. 179:3956-3962(1997).
RN [3]
RP PROTEIN SEQUENCE OF 91-137 AND 167-213, AND PYRIDOXAL PHOSPHATE AT LYS-211.
RC STRAIN=ICR 3460;
RX PubMed=3365412; DOI=10.1021/bi00405a029;
RA Nakayama T., Esaki N., Tanaka H., Soda K.;
RT "Specific labeling of the essential cysteine residue of L-methionine gamma-
RT lyase with a cofactor analogue, N-(bromoacetyl)pyridoxamine phosphate.";
RL Biochemistry 27:1587-1591(1988).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, SUBSTRATE SPECIFICITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT.
RC STRAIN=ICR 3460;
RX PubMed=6742420; DOI=10.1016/0003-2697(84)90832-7;
RA Nakayama T., Esaki N., Sugie K., Beresov T.T., Tanaka H., Soda K.;
RT "Purification of bacterial L-methionine gamma-lyase.";
RL Anal. Biochem. 138:421-424(1984).
RN [5]
RP REVIEW, AND BIOTECHNOLOGY.
RX PubMed=25439528; DOI=10.1517/14712598.2015.963050;
RA Hoffman R.M.;
RT "Development of recombinant methioninase to target the general cancer-
RT specific metabolic defect of methionine dependence: a 40-year odyssey.";
RL Expert Opin. Biol. Ther. 15:21-31(2015).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS).
RX PubMed=10965031; DOI=10.1093/oxfordjournals.jbchem.a022760;
RA Motoshima H., Inagaki K., Kumasaka T., Furuichi M., Inoue H., Tamura T.,
RA Esaki N., Soda K., Tanaka N., Yamamoto M., Tanaka H.;
RT "Crystal structure of the pyridoxal 5'-phosphate dependent L-methionine
RT gamma-lyase from Pseudomonas putida.";
RL J. Biochem. 128:349-354(2000).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.68 ANGSTROMS) IN COVALENT COMPLEX WITH PLP.
RA Allen T.W., Sridhar V., Prasad G.S., Han Q., Xu M., Tan Y., Hoffman R.M.,
RA Ramaswamy S.;
RT "Crystal structure of L-methionine alpha-, gamma-lyase.";
RL Submitted (MAY-2003) to the PDB data bank.
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COVALENT COMPLEX WITH PLP.
RA Misaki S., Takimoto A., Takakura T., Yoshioka T., Yamashita M., Tamura T.,
RA Tanaka H., Inagaki K.;
RT "Detailed structure of L-methionine-lyase from Pseudomonas putida.";
RL Submitted (AUG-2003) to the PDB data bank.
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) IN COVALENT COMPLEX WITH PLP,
RP COFACTOR, SUBUNIT, AND MUTAGENESIS OF ARG-61 AND CYS-116.
RC STRAIN=ICR 3460;
RX PubMed=17289792; DOI=10.1093/jb/mvm055;
RA Kudou D., Misaki S., Yamashita M., Tamura T., Takakura T., Yoshioka T.,
RA Yagi S., Hoffman R.M., Takimoto A., Esaki N., Inagaki K.;
RT "Structure of the antitumour enzyme L-methionine gamma-lyase from
RT Pseudomonas putida at 1.8 A resolution.";
RL J. Biochem. 141:535-544(2007).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF MUTANT HIS-116 IN COMPLEXES WITH
RP L-HOMOCYSTEINE; METHIONINE AND PLP, FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, COFACTOR, ACTIVITY REGULATION, AND
RP MUTAGENESIS OF CYS-116; LYS-240 AND ASP-241.
RX PubMed=22785484; DOI=10.1271/bbb.110906;
RA Fukumoto M., Kudou D., Murano S., Shiba T., Sato D., Tamura T., Harada S.,
RA Inagaki K.;
RT "The role of amino acid residues in the active site of L-methionine gamma-
RT lyase from Pseudomonas putida.";
RL Biosci. Biotechnol. Biochem. 76:1275-1284(2012).
CC -!- FUNCTION: Catalyzes the alpha,gamma-elimination of L-methionine to
CC produce methanethiol, 2-oxobutanoate and ammonia (PubMed:8586629,
CC PubMed:6742420). Is involved in L-methionine catabolism
CC (PubMed:9190812). In fact, shows a multicatalytic function since it
CC also catalyzes gamma-replacement of L-methionine with thiol compounds,
CC alpha,gamma-elimination and gamma-replacement reactions of L-
CC homocysteine and its S-substituted derivatives, O-substituted-L-
CC homoserines and DL-selenomethionine, and, to a lesser extent,
CC alpha,beta-elimination and beta-replacement reactions of L-cysteine, S-
CC methyl-L-cysteine, and O-acetyl-L-serine (PubMed:6742420,
CC PubMed:22785484). Also catalyzes deamination and gamma-addition
CC reactions of L-vinylglycine (PubMed:6742420). Thus, the enzyme is able
CC to cleave C-S, C-Se, and C-O bonds of sulfur, selenium, and oxygen
CC amino acids, respectively (PubMed:6742420, PubMed:22785484).
CC {ECO:0000269|PubMed:22785484, ECO:0000269|PubMed:6742420,
CC ECO:0000269|PubMed:8586629, ECO:0000305|PubMed:9190812}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + L-methionine = 2-oxobutanoate + methanethiol + NH4(+);
CC Xref=Rhea:RHEA:23800, ChEBI:CHEBI:15377, ChEBI:CHEBI:16007,
CC ChEBI:CHEBI:16763, ChEBI:CHEBI:28938, ChEBI:CHEBI:57844; EC=4.4.1.11;
CC Evidence={ECO:0000269|PubMed:22785484, ECO:0000269|PubMed:6742420};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + L-homocysteine = 2-oxobutanoate + H(+) + hydrogen
CC sulfide + NH4(+); Xref=Rhea:RHEA:14501, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16763, ChEBI:CHEBI:28938,
CC ChEBI:CHEBI:29919, ChEBI:CHEBI:58199; EC=4.4.1.2;
CC Evidence={ECO:0000269|PubMed:22785484, ECO:0000269|PubMed:6742420};
CC -!- COFACTOR:
CC Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;
CC Evidence={ECO:0000269|PubMed:17289792, ECO:0000269|PubMed:22785484,
CC ECO:0000269|PubMed:6742420};
CC -!- ACTIVITY REGULATION: Irreversibly inactivated by DL-propargylglycine.
CC {ECO:0000269|PubMed:22785484}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.0 mM for L-methionine {ECO:0000269|PubMed:6742420};
CC KM=0.5 mM for L-methionine {ECO:0000269|PubMed:22785484};
CC KM=1.1 mM for DL-homocysteine {ECO:0000269|PubMed:22785484};
CC KM=0.2 mM for L-cysteine {ECO:0000269|PubMed:22785484};
CC KM=0.7 mM for S-methyl-L-cysteine {ECO:0000269|PubMed:22785484};
CC KM=7.2 mM for O-succinyl-L-homoserine {ECO:0000269|PubMed:22785484};
CC Note=kcat is 33.4 sec(-1) for the alpha,gamma-elimination of L-
CC methionine. kcat is 71.0 sec(-1) for the alpha,gamma-elimination of
CC DL-homocysteine. kcat is 2.13 sec(-1) for the alpha,beta-elimination
CC of L-cysteine. kcat is 1.58 sec(-1) for the alpha,beta-elimination of
CC S-methyl-L-cysteine. kcat is 2.56 sec(-1) for the alpha,gamma-
CC elimination of O-succinyl-L-homoserine.
CC {ECO:0000269|PubMed:22785484};
CC -!- SUBUNIT: Homotetramer; dimer of active dimers.
CC {ECO:0000269|PubMed:17289792, ECO:0000269|PubMed:6742420}.
CC -!- INDUCTION: Is under the control of the positive transcriptional
CC regulator MdeR. Forms part of an operon with mdeB.
CC {ECO:0000269|PubMed:9190812}.
CC -!- BIOTECHNOLOGY: The recombinant MGL protein cloned form P.putida has
CC been found to have antitumor efficacy in vitro and in vivo. PEGylated
CC MGL is being developed as a cancer drug. {ECO:0000303|PubMed:25439528}.
CC -!- SIMILARITY: Belongs to the trans-sulfuration enzymes family. L-
CC methionine gamma-lyase subfamily. {ECO:0000305}.
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DR EMBL; D88554; BAA13642.1; -; Genomic_DNA.
DR EMBL; D89015; BAA20553.1; -; Genomic_DNA.
DR PIR; A27691; A27691.
DR PIR; JC4174; JC4174.
DR PDB; 1GC0; X-ray; 1.70 A; A/B/C/D=1-398.
DR PDB; 1GC2; X-ray; 2.00 A; A/B/C/D=1-398.
DR PDB; 1PG8; X-ray; 2.68 A; A/B/C/D=1-398.
DR PDB; 1UKJ; X-ray; 1.80 A; A/B/C/D=1-398.
DR PDB; 2O7C; X-ray; 1.70 A; A/B/C/D=1-398.
DR PDB; 3VK2; X-ray; 2.30 A; A/B/C/D=1-398.
DR PDB; 3VK3; X-ray; 2.10 A; A/B/C/D=1-398.
DR PDB; 3VK4; X-ray; 2.61 A; A/B/C/D=1-398.
DR PDB; 5X2V; X-ray; 2.40 A; A/B/C/D=1-398.
DR PDB; 5X2W; X-ray; 2.70 A; A/B/C/D=1-398.
DR PDB; 5X2X; X-ray; 2.00 A; A/B/C/D=1-398.
DR PDB; 5X2Y; X-ray; 1.79 A; A/B/C/D=1-398.
DR PDB; 5X2Z; X-ray; 1.80 A; A/B/C/D=1-398.
DR PDB; 5X30; X-ray; 1.70 A; A/B/C/D=1-398.
DR PDBsum; 1GC0; -.
DR PDBsum; 1GC2; -.
DR PDBsum; 1PG8; -.
DR PDBsum; 1UKJ; -.
DR PDBsum; 2O7C; -.
DR PDBsum; 3VK2; -.
DR PDBsum; 3VK3; -.
DR PDBsum; 3VK4; -.
DR PDBsum; 5X2V; -.
DR PDBsum; 5X2W; -.
DR PDBsum; 5X2X; -.
DR PDBsum; 5X2Y; -.
DR PDBsum; 5X2Z; -.
DR PDBsum; 5X30; -.
DR AlphaFoldDB; P13254; -.
DR SMR; P13254; -.
DR DrugBank; DB04083; N(6)-(pyridoxal phosphate)-L-lysine.
DR BioCyc; MetaCyc:MON-284; -.
DR BRENDA; 4.4.1.11; 5092.
DR SABIO-RK; P13254; -.
DR EvolutionaryTrace; P13254; -.
DR GO; GO:0047982; F:homocysteine desulfhydrase activity; IEA:UniProtKB-EC.
DR GO; GO:0018826; F:methionine gamma-lyase activity; IEA:UniProtKB-EC.
DR GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro.
DR GO; GO:0019346; P:transsulfuration; IEA:InterPro.
DR CDD; cd00614; CGS_like; 1.
DR Gene3D; 3.40.640.10; -; 1.
DR Gene3D; 3.90.1150.10; -; 1.
DR InterPro; IPR000277; Cys/Met-Metab_PyrdxlP-dep_enz.
DR InterPro; IPR006237; L-Met_gamma_lys.
DR InterPro; IPR015424; PyrdxlP-dep_Trfase.
DR InterPro; IPR015421; PyrdxlP-dep_Trfase_major.
DR InterPro; IPR015422; PyrdxlP-dep_Trfase_small.
DR PANTHER; PTHR11808; PTHR11808; 1.
DR Pfam; PF01053; Cys_Met_Meta_PP; 1.
DR PIRSF; PIRSF001434; CGS; 1.
DR SUPFAM; SSF53383; SSF53383; 1.
DR TIGRFAMs; TIGR01328; met_gam_lyase; 1.
DR PROSITE; PS00868; CYS_MET_METAB_PP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Lyase; Pyridoxal phosphate.
FT CHAIN 1..398
FT /note="L-methionine gamma-lyase"
FT /id="PRO_0000114784"
FT BINDING 59..61
FT /ligand="pyridoxal 5'-phosphate"
FT /ligand_id="ChEBI:CHEBI:597326"
FT /ligand_note="ligand shared between dimeric partners"
FT /evidence="ECO:0000269|Ref.7"
FT BINDING 89..90
FT /ligand="pyridoxal 5'-phosphate"
FT /ligand_id="ChEBI:CHEBI:597326"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|Ref.7"
FT BINDING 114
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:22785484,
FT ECO:0007744|PDB:3VK3, ECO:0007744|PDB:3VK4"
FT BINDING 208..210
FT /ligand="pyridoxal 5'-phosphate"
FT /ligand_id="ChEBI:CHEBI:597326"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|Ref.7"
FT BINDING 375
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:22785484,
FT ECO:0007744|PDB:3VK3, ECO:0007744|PDB:3VK4"
FT MOD_RES 211
FT /note="N6-(pyridoxal phosphate)lysine"
FT /evidence="ECO:0000269|PubMed:17289792,
FT ECO:0000269|PubMed:22785484, ECO:0000269|PubMed:3365412,
FT ECO:0000269|Ref.7, ECO:0000269|Ref.8, ECO:0007744|PDB:1UKJ"
FT MUTAGEN 61
FT /note="R->A,E,F: Loss of elimination activity against L-
FT methionine."
FT /evidence="ECO:0000269|PubMed:17289792"
FT MUTAGEN 116
FT /note="C->H: Drastic decrease of the catalytic efficiency
FT of the elimination reaction with L-methionine, by 6700-
FT fold, and increases that with L-cysteine by 7-fold, mainly
FT due to changes in kcat. Loss of ability to catalyze
FT replacement reaction between L-methionine and 2-
FT mercaptoethanol."
FT /evidence="ECO:0000269|PubMed:22785484"
FT MUTAGEN 116
FT /note="C->S: 9% of wild-type elimination activity against
FT L-methionine."
FT /evidence="ECO:0000269|PubMed:17289792"
FT MUTAGEN 116
FT /note="C->T: 40% of wild-type elimination activity against
FT L-methionine."
FT /evidence="ECO:0000269|PubMed:17289792"
FT MUTAGEN 240
FT /note="K->D,E: Marked decrease in elimination activity
FT against both L-methionine and DL-homocysteine."
FT /evidence="ECO:0000269|PubMed:22785484"
FT MUTAGEN 240
FT /note="K->M: 50% reduction in alpha,gamma-elimination
FT activity against DL-homocysteine, while retaining
FT elimination activity against L-methionine and L-cysteine."
FT /evidence="ECO:0000269|PubMed:22785484"
FT MUTAGEN 241
FT /note="D->H,R: 5 to 14-fold reduction in alpha,gamma-
FT elimination activity against L-methionine, while no change
FT in affinity for L-methionine."
FT /evidence="ECO:0000269|PubMed:22785484"
FT STRAND 3..7
FT /evidence="ECO:0007829|PDB:2O7C"
FT HELIX 10..16
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 21..24
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 27..29
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 36..38
FT /evidence="ECO:0007829|PDB:2O7C"
FT STRAND 40..42
FT /evidence="ECO:0007829|PDB:5X30"
FT HELIX 43..50
FT /evidence="ECO:0007829|PDB:2O7C"
FT STRAND 54..56
FT /evidence="ECO:0007829|PDB:5X2X"
FT TURN 60..62
FT /evidence="ECO:0007829|PDB:2O7C"
FT HELIX 65..78
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 81..88
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 89..100
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 106..112
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 116..123
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 125..128
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 131..135
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 140..146
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 151..159
FT /evidence="ECO:0007829|PDB:1GC0"
FT TURN 161..163
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 169..176
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 177..179
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 182..186
FT /evidence="ECO:0007829|PDB:1GC0"
FT TURN 188..190
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 191..194
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 197..200
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 203..208
FT /evidence="ECO:0007829|PDB:1GC0"
FT TURN 209..214
FT /evidence="ECO:0007829|PDB:5X30"
FT STRAND 216..218
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 222..226
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 228..236
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 238..242
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 249..259
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 262..281
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 286..291
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 300..306
FT /evidence="ECO:0007829|PDB:2O7C"
FT STRAND 313..318
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 321..331
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 333..337
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 343..345
FT /evidence="ECO:0007829|PDB:2O7C"
FT STRAND 347..349
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 351..353
FT /evidence="ECO:0007829|PDB:1GC0"
FT TURN 354..356
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 357..359
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 361..366
FT /evidence="ECO:0007829|PDB:1GC0"
FT STRAND 373..377
FT /evidence="ECO:0007829|PDB:1GC0"
FT HELIX 383..397
FT /evidence="ECO:0007829|PDB:1GC0"
SQ SEQUENCE 398 AA; 42627 MW; BD50CD1F34CD71E3 CRC64;
MHGSNKLPGF ATRAIHHGYD PQDHGGALVP PVYQTATFTF PTVEYGAACF AGEQAGHFYS
RISNPTLNLL EARMASLEGG EAGLALASGM GAITSTLWTL LRPGDEVLLG NTLYGCTFAF
LHHGIGEFGV KLRHVDMADL QALEAAMTPA TRVIYFESPA NPNMHMADIA GVAKIARKHG
ATVVVDNTYC TPYLQRPLEL GADLVVHSAT KYLSGHGDIT AGIVVGSQAL VDRIRLQGLK
DMTGAVLSPH DAALLMRGIK TLNLRMDRHC ANAQVLAEFL ARQPQVELIH YPGLASFPQY
TLARQQMSQP GGMIAFELKG GIGAGRRFMN ALQLFSRAVS LGDAESLAQH PASMTHSSYT
PEERAHYGIS EGLVRLSVGL EDIDDLLADV QQALKASA
