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FPGS_LACCA
ID   FPGS_LACCA              Reviewed;         428 AA.
AC   P15925;
DT   01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT   01-APR-1990, sequence version 1.
DT   03-AUG-2022, entry version 119.
DE   RecName: Full=Folylpolyglutamate synthase {ECO:0000305};
DE            Short=FPGS {ECO:0000303|PubMed:11501996};
DE            EC=6.3.2.17 {ECO:0000269|PubMed:6138353};
DE   AltName: Full=Folylpoly-gamma-glutamate synthetase {ECO:0000303|PubMed:2105929};
DE   AltName: Full=Tetrahydrofolylpolyglutamate synthase;
GN   Name=fpgS {ECO:0000312|EMBL:AAA88210.1};
OS   Lactobacillus casei.
OC   Bacteria; Firmicutes; Bacilli; Lactobacillales; Lactobacillaceae;
OC   Lacticaseibacillus.
OX   NCBI_TaxID=1582;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=ATCC 7469;
RX   PubMed=2105929; DOI=10.1016/s0021-9258(19)39827-8;
RA   Toy J., Bognar A.L.;
RT   "Cloning and expression of the gene encoding Lactobacillus casei folylpoly-
RT   gamma-glutamate synthetase in Escherichia coli and determination of its
RT   primary structure.";
RL   J. Biol. Chem. 265:2492-2499(1990).
RN   [2]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, BIOPHYSICOCHEMICAL
RP   PROPERTIES, COFACTOR, ACTIVITY REGULATION, SUBUNIT, AND REACTION MECHANISM.
RX   PubMed=6138353; DOI=10.1016/s0021-9258(17)44215-3;
RA   Bognar A.L., Shane B.;
RT   "Purification and properties of Lactobacillus casei folylpoly-gamma-
RT   glutamate synthetase.";
RL   J. Biol. Chem. 258:12574-12581(1983).
RN   [3]
RP   FUNCTION, MUTAGENESIS OF ASP-151, CHIMERA PROTEINS, CATALYTIC ACTIVITY, AND
RP   BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=18232714; DOI=10.1021/bi701670y;
RA   Sheng Y., Khanam N., Tsaksis Y., Shi X.M., Lu Q.S., Bognar A.L.;
RT   "Mutagenesis of folylpolyglutamate synthetase indicates that
RT   dihydropteroate and tetrahydrofolate bind to the same site.";
RL   Biochemistry 47:2388-2396(2008).
RN   [4]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
RX   PubMed=9618466; DOI=10.1073/pnas.95.12.6647;
RA   Sun X., Bognar A.L., Baker E.N., Smith C.A.;
RT   "Structural homologies with ATP- and folate-binding enzymes in the crystal
RT   structure of folylpolyglutamate synthetase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 95:6647-6652(1998).
RN   [5]
RP   X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) IN COMPLEXES WITH ATP ANALOG;
RP   MAGNESIUM AND 5,10-METHYLENETETRAHYDROFOLATE, COFACTOR, CARBOXYLATION AT
RP   LYS-185, AND MUTAGENESIS OF HIS-316 AND SER-412.
RX   PubMed=11501996; DOI=10.1006/jmbi.2001.4815;
RA   Sun X., Cross J.A., Bognar A.L., Baker E.N., Smith C.A.;
RT   "Folate-binding triggers the activation of folylpolyglutamate synthetase.";
RL   J. Mol. Biol. 310:1067-1078(2001).
RN   [6]
RP   X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF WILD-TYPE AND MUTANTS SER-51;
RP   51-SER-THR-52 AND ALA-73.
RX   PubMed=16627949; DOI=10.1107/s0907444906009796;
RA   Smith C.A., Cross J.A., Bognar A.L., Sun X.;
RT   "Mutation of Gly51 to serine in the P-loop of Lactobacillus casei
RT   folylpolyglutamate synthetase abolishes activity by altering the
RT   conformation of two adjacent loops.";
RL   Acta Crystallogr. D 62:548-558(2006).
CC   -!- FUNCTION: Involved in the conversion of folates to polyglutamate
CC       derivatives, and likely functions in the retention of cellular folate
CC       pools. Catalyzes successive MgATP-dependent additions of glutamate to a
CC       pteroylmonoglutamate substrate, with a high preference for 5,10-
CC       methylenetetrahydrofolate (mTHF). Thus, metabolizes mTHF to the
CC       tetraglutamate derivative, but longer glutamate chain length products
CC       are not observed. Tetrahydrofolate (H4PteGlu) and 10-formyl-H4PteGlu
CC       are poorer folate substrates. In contrast to E.coli FolC, this enzyme
CC       does not display dihydrofolate synthase activity.
CC       {ECO:0000269|PubMed:18232714, ECO:0000269|PubMed:6138353}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n) + ATP + L-
CC         glutamate = (6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n+1) + ADP +
CC         H(+) + phosphate; Xref=Rhea:RHEA:10580, Rhea:RHEA-COMP:14738,
CC         Rhea:RHEA-COMP:14740, ChEBI:CHEBI:15378, ChEBI:CHEBI:29985,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:141005,
CC         ChEBI:CHEBI:456216; EC=6.3.2.17;
CC         Evidence={ECO:0000269|PubMed:6138353};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(6R)-5,10-methylenetetrahydrofolyl-(gamma-L-Glu)(n) + ATP + L-
CC         glutamate = (6R)-5,10-methylenetetrahydrofolyl-(gamma-L-Glu)(n+1) +
CC         ADP + H(+) + phosphate; Xref=Rhea:RHEA:51912, Rhea:RHEA-COMP:13257,
CC         Rhea:RHEA-COMP:13258, ChEBI:CHEBI:15378, ChEBI:CHEBI:29985,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:136572,
CC         ChEBI:CHEBI:456216; EC=6.3.2.17;
CC         Evidence={ECO:0000269|PubMed:18232714, ECO:0000269|PubMed:6138353};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=10-formyltetrahydrofolyl-(gamma-L-Glu)(n) + ATP + L-glutamate
CC         = 10-formyltetrahydrofolyl-(gamma-L-Glu)(n+1) + ADP + H(+) +
CC         phosphate; Xref=Rhea:RHEA:51904, Rhea:RHEA-COMP:13088, Rhea:RHEA-
CC         COMP:14300, ChEBI:CHEBI:15378, ChEBI:CHEBI:29985, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:43474, ChEBI:CHEBI:134413, ChEBI:CHEBI:456216;
CC         EC=6.3.2.17; Evidence={ECO:0000269|PubMed:6138353};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:6138353};
CC       Note=Binds 2 Mg(2+) ions per subunit. {ECO:0000269|PubMed:11501996};
CC   -!- ACTIVITY REGULATION: Competitively inhibited by adenosine 5'-(3-
CC       thio)triphosphate and beta,gamma-methylene-ATP.
CC       {ECO:0000269|PubMed:6138353}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=2.3 uM for (6R)-5,10-methylenetetrahydropteroyldiglutamate
CC         {ECO:0000269|PubMed:6138353};
CC         KM=5.6 mM for ATP {ECO:0000269|PubMed:6138353};
CC         KM=423 uM for glutamate {ECO:0000269|PubMed:6138353};
CC         KM=32 uM for (6RS)-5,10-methylenetetrahydrofolate
CC         {ECO:0000269|PubMed:18232714};
CC         KM=3.4 mM for ATP {ECO:0000269|PubMed:18232714};
CC         KM=470 uM for glutamate {ECO:0000269|PubMed:18232714};
CC         KM=27 uM for (6RS)-5,10-methylenetetrahydropteroyldiglutamate
CC         {ECO:0000269|PubMed:18232714};
CC         Vmax=67.5 umol/h/mg enzyme with (6R)-5,10-
CC         methylenetetrahydropteroyldiglutamate as substrate
CC         {ECO:0000269|PubMed:6138353};
CC         Vmax=19 umol/h/mg enzyme with (6RS)-5,10-methylenetetrahydrofolate as
CC         substrate {ECO:0000269|PubMed:18232714};
CC         Vmax=14 umol/h/mg enzyme with (6RS)-5,10-
CC         methylenetetrahydropteroyldiglutamate as substrate
CC         {ECO:0000269|PubMed:18232714};
CC       pH dependence:
CC         Optimum pH is about 10. {ECO:0000269|PubMed:6138353};
CC   -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:6138353}.
CC   -!- MISCELLANEOUS: In contrast to many bacteria such as E.coli and
CC       Corynebacterium spp., L.casei cannot synthesize folate de novo, and
CC       requires exogenous folates for growth. L.casei metabolizes folate to
CC       polyglutamates of chain length up to 11, with octa- and nonaglutamates
CC       predominating. {ECO:0000305|PubMed:6138353}.
CC   -!- MISCELLANEOUS: Kinetic studies are consistent with an ordered Ter-Ter
CC       mechanism with MgATP binding first to the enzyme, folate second, and
CC       glutamate last. The order of product dissociation from the enzyme is
CC       ADP, folate product, and Pi. {ECO:0000269|PubMed:6138353}.
CC   -!- SIMILARITY: Belongs to the folylpolyglutamate synthase family.
CC       {ECO:0000305}.
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DR   EMBL; J05221; AAA88210.1; -; Genomic_DNA.
DR   PIR; A35534; A35534.
DR   PDB; 1FGS; X-ray; 2.40 A; A=1-428.
DR   PDB; 1JBV; X-ray; 1.95 A; A=1-428.
DR   PDB; 1JBW; X-ray; 1.85 A; A=1-428.
DR   PDB; 2GC5; X-ray; 1.85 A; A=1-428.
DR   PDB; 2GC6; X-ray; 1.90 A; A=1-428.
DR   PDB; 2GCA; X-ray; 2.40 A; A=1-428.
DR   PDB; 2GCB; X-ray; 2.30 A; A=1-428.
DR   PDBsum; 1FGS; -.
DR   PDBsum; 1JBV; -.
DR   PDBsum; 1JBW; -.
DR   PDBsum; 2GC5; -.
DR   PDBsum; 2GC6; -.
DR   PDBsum; 2GCA; -.
DR   PDBsum; 2GCB; -.
DR   AlphaFoldDB; P15925; -.
DR   SMR; P15925; -.
DR   DrugBank; DB02301; 5,10-Methylene-6-Hydrofolic Acid.
DR   DrugBank; DB03755; Adenosine-5'-[Beta, Gamma-Methylene]Tetraphosphate.
DR   DrugBank; DB03909; Adenosine-5'-[Beta, Gamma-Methylene]Triphosphate.
DR   DrugBank; DB03801; Lysine Nz-Carboxylic Acid.
DR   BRENDA; 6.3.2.17; 2854.
DR   SABIO-RK; P15925; -.
DR   EvolutionaryTrace; P15925; -.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0004326; F:tetrahydrofolylpolyglutamate synthase activity; IEA:UniProtKB-EC.
DR   GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW.
DR   Gene3D; 3.40.1190.10; -; 1.
DR   Gene3D; 3.90.190.20; -; 1.
DR   InterPro; IPR001645; Folylpolyglutamate_synth.
DR   InterPro; IPR018109; Folylpolyglutamate_synth_CS.
DR   InterPro; IPR036565; Mur-like_cat_sf.
DR   InterPro; IPR004101; Mur_ligase_C.
DR   InterPro; IPR036615; Mur_ligase_C_dom_sf.
DR   InterPro; IPR013221; Mur_ligase_cen.
DR   PANTHER; PTHR11136; PTHR11136; 1.
DR   Pfam; PF02875; Mur_ligase_C; 1.
DR   Pfam; PF08245; Mur_ligase_M; 1.
DR   PIRSF; PIRSF001563; Folylpolyglu_synth; 1.
DR   SUPFAM; SSF53244; SSF53244; 1.
DR   SUPFAM; SSF53623; SSF53623; 1.
DR   TIGRFAMs; TIGR01499; folC; 1.
DR   PROSITE; PS01011; FOLYLPOLYGLU_SYNT_1; 1.
DR   PROSITE; PS01012; FOLYLPOLYGLU_SYNT_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; ATP-binding; Ligase; Magnesium; Metal-binding;
KW   Nucleotide-binding; One-carbon metabolism.
FT   CHAIN           1..428
FT                   /note="Folylpolyglutamate synthase"
FT                   /id="PRO_0000168305"
FT   BINDING         49..52
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000305|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBV, ECO:0007744|PDB:1JBW"
FT   BINDING         73
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000269|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBV, ECO:0007744|PDB:1JBW"
FT   BINDING         75
FT                   /ligand="(6R)-5,10-methylenetetrahydrofolyl-(gamma-L-Glu)n"
FT                   /ligand_id="ChEBI:CHEBI:136572"
FT                   /evidence="ECO:0000305|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBW"
FT   BINDING         82
FT                   /ligand="(6R)-5,10-methylenetetrahydrofolyl-(gamma-L-Glu)n"
FT                   /ligand_id="ChEBI:CHEBI:136572"
FT                   /evidence="ECO:0000305|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBW"
FT   BINDING         143
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000269|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBV, ECO:0007744|PDB:1JBW"
FT   BINDING         170
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000269|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBV"
FT   BINDING         264
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000305|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBW"
FT   BINDING         300
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000305|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBV, ECO:0007744|PDB:1JBW"
FT   BINDING         313..316
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000305|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBV, ECO:0007744|PDB:1JBW"
FT   BINDING         417
FT                   /ligand="(6R)-5,10-methylenetetrahydrofolyl-(gamma-L-Glu)n"
FT                   /ligand_id="ChEBI:CHEBI:136572"
FT                   /evidence="ECO:0000305|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBW"
FT   MOD_RES         185
FT                   /note="N6-carboxylysine"
FT                   /evidence="ECO:0000269|PubMed:11501996,
FT                   ECO:0007744|PDB:1JBV, ECO:0007744|PDB:1JBW"
FT   MUTAGEN         151
FT                   /note="D->A: 220-fold decrease in catalytic efficiency with
FT                   mTHF as substrate, but only 4-fold decrease in catalytic
FT                   efficiency with 5,10-methylenetetrahydropteroyldiglutamate
FT                   as substrate."
FT                   /evidence="ECO:0000269|PubMed:18232714"
FT   MUTAGEN         316
FT                   /note="H->A: Loss of activity."
FT                   /evidence="ECO:0000303|PubMed:11501996"
FT   MUTAGEN         412
FT                   /note="S->A: Loss of activity."
FT                   /evidence="ECO:0000303|PubMed:11501996"
FT   HELIX           3..10
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           23..31
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           35..37
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          41..45
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          47..49
FT                   /evidence="ECO:0007829|PDB:2GC5"
FT   HELIX           50..63
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          68..71
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          76..78
FT                   /evidence="ECO:0007829|PDB:1FGS"
FT   HELIX           79..82
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          83..85
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           92..112
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           120..134
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          138..143
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          145..148
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          159..163
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           168..170
FT                   /evidence="ECO:0007829|PDB:2GC5"
FT   HELIX           171..174
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           178..185
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           186..188
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          195..197
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           202..215
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          219..221
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   TURN            222..224
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          225..233
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          235..244
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          247..255
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           260..278
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           285..293
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          300..305
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   TURN            306..309
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          310..313
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           318..331
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          337..341
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          343..345
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           348..358
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          360..364
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           391..401
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   STRAND          407..412
FT                   /evidence="ECO:0007829|PDB:1JBW"
FT   HELIX           413..423
FT                   /evidence="ECO:0007829|PDB:1JBW"
SQ   SEQUENCE   428 AA;  46589 MW;  E4B0B9ED62140181 CRC64;
     MNYTETVAYI HSFPRLAKTG DHRRILTLLH ALGNPQQQGR YIHVTGTNGK GSAANAIAHV
     LEASGLTVGL YTSPFIMRFN ERIMIDHEPI PDAALVNAVA FVRAALERLQ QQQADFNVTE
     FEFITALGYW YFRQRQVDVA VIEVGIGGDT DSTNVITPVV SVLTEVALDH QKLLGHTITA
     IAKHKAGIIK RGIPVVTGNL VPDAAAVVAA KVATTGSQWL RFDRDFSVPK AKLHGWGQRF
     TYEDQDGRIS DLEVPLVGDY QQRNMAIAIQ TAKVYAKQTE WPLTPQNIRQ GLAASHWPAR
     LEKISDTPLI VIDGAHNPDG INGLITALKQ LFSQPITVIA GILADKDYAA MADRLTAAFS
     TVYLVPVPGT PRALPEAGYE ALHEGRLKDS WQEALAASLN DVPDQPIVIT GSLYLASAVR
     QTLLGGKS
 
 
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