DB code: S00826

RLCP classification 4.191.350400.117 : Addition
5.125.526200.114 : Elimination
5.10.552200.114 : Elimination
CATH domain 3.20.20.70 : TIM Barrel Catalytic domain
E.C. 4.1.1.48
CSA
M-CSA
MACiE M0252

CATH domain Related DB codes (homologues)
3.20.20.70 : TIM Barrel S00215 S00217 S00218 S00219 S00532 S00198 S00220 S00745 S00537 S00538 S00539 S00841 S00235 S00239 S00240 S00243 S00244 S00199 S00200 S00201 S00221 S00222 S00847 S00224 S00225 S00226 D00014 D00029 M00141 T00015 T00239 D00664 D00665 D00804 D00863 T00089

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
Q06121 Indole-3-glycerol phosphate synthase
IGPS
EC 4.1.1.48
NP_342387.1 (Protein)
NC_002754.1 (DNA/RNA sequence)
PF00218 (IGPS)
[Graphical View]
Q56319 Indole-3-glycerol phosphate synthase
IGPS
EC 4.1.1.48
NP_227955.1 (Protein)
NC_000853.1 (DNA/RNA sequence)
PF00218 (IGPS)
[Graphical View]
P84126
Indole-3-glycerol phosphate synthase
EC 4.1.1.48
PF00218 (IGPS)
[Graphical View]

KEGG enzyme name
indole-3-glycerol-phosphate synthase
indoleglycerol phosphate synthetase
indoleglycerol phosphate synthase
indole-3-glycerophosphate synthase
1-(2-carboxyphenylamino)-1-deoxy-D-ribulose-5-phosphate carboxy-lyase (cyclizing)

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
Q06121 TRPC_SULSO 1-(2-carboxyphenylamino)-1-deoxy-D-ribulose 5-phosphate = C(1)-(3-indolyl)-glycerol 3-phosphate + CO(2) + H(2)O. Monomer.
Q56319 TRPC_THEMA 1-(2-carboxyphenylamino)-1-deoxy-D-ribulose 5-phosphate = C(1)-(3-indolyl)-glycerol 3-phosphate + CO(2) + H(2)O.
P84126 P84126_THETH

KEGG Pathways
Map code Pathways E.C.
MAP00400 Phenylalanine, tyrosine and tryptophan biosynthesis
MAP02020 Two-component system - General

Compound table
Substrates Products Intermediates
KEGG-id C01302 C03506 C00011 C00001 I00053 I00054
E.C.
Compound 1-(2-carboxyphenylamino)-1-deoxy-D-ribulose 5-phosphate 1-C-(indol-3-yl)glycerol 3-phosphate CO2 H2O CdRP intermediate I1 CdRP intermediate I2
Type amine group,aromatic ring (only carbon atom),carbohydrate,carboxyl group,phosphate group/phosphate ion aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,phosphate group/phosphate ion others H2O
ChEBI 29112
51793
16526
15377
PubChem 446894
444150
280
22247451
962
1a53A Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Bound:IGP Unbound Unbound Unbound
1igsA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1jukA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1julA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1lbfA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Analogue:137 Unbound Unbound Unbound Unbound
1lblA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Analogue:137 Unbound Unbound Unbound Unbound
2c3zA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1i4nA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1i4nB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1j5tA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1vc4A Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1vc4B Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
literature [24], [28]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1a53A Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 51;LYS 53;LYS 110;GLU 159;ASN 180;GLU 210;SER 211
1igsA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 51;LYS 53;LYS 110;GLU 159;ASN 180;GLU 210;SER 211
1jukA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 51;LYS 53;LYS 110;GLU 159;ASN 180;GLU 210;SER 211
1julA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 51;LYS 53;LYS 110;GLU 159;ASN 180;GLU 210;SER 211
1lbfA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 51;LYS 53;LYS 110;GLU 159;ASN 180;GLU 210;SER 211
1lblA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 51;LYS 53;LYS 110;GLU 159;ASN 180;GLU 210;SER 211
2c3zA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 51;LYS 53;LYS 110;GLU 159;ASN 180;GLU 210;SER 211 deletion 1-26
1i4nA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 47;LYS 49;LYS 108;GLU 157;ASN 179;GLU 209;SER 210
1i4nB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 47;LYS 49;LYS 108;GLU 157;ASN 179;GLU 209;SER 210
1j5tA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 25;LYS 27;LYS 86;GLU 135;ASN 157;GLU 187;SER 188
1vc4A Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 51;LYS 53;LYS 112;GLU 160;ASN 181;GLU 214;SER 215
1vc4B Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 51;LYS 53;LYS 112;GLU 160;ASN 181;GLU 214;SER 215

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[2]
p.221
[8]
p.499
[18]
Fig.2, p.1227-1229
[24]
Fig.6, p.764
[27]
[28]
Scheme 2, p.14381-14383

References
[1]
Resource
Comments
Medline ID
PubMed ID 3303031
Journal Proc Natl Acad Sci U S A
Year 1987
Volume 84
Pages 5690-4
Authors Priestle JP, Gr?tter MG, White JL, Vincent MG, Kania M, Wilson E, Jardetzky TS, Kirschner K, Jansonius JN
Title Three-dimensional structure of the bifunctional enzyme N-(5'-phosphoribosyl)anthranilate isomerase-indole-3-glycerol-phosphate synthase from Escherichia coli.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 2494074
Journal FEBS Lett
Year 1989
Volume 245
Pages 219-22
Authors Eberhard M, Kirschner K
Title Modification of a catalytically important residue of indoleglycerol-phosphate synthase from Escherichia coli.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 2184433
Journal Protein Eng
Year 1990
Volume 3
Pages 173-80
Authors Wilmanns M, Schlagenhauf E, Fol B, Jansonius JN
Title Crystallization and structure solution at 4 A resolution of the recombinant synthase domain of N-(5'-phosphoribosyl)anthranilate isomerase:indole-3-glycerol-phosphate synthase from Escherichia coli complexed to a substrate analogue.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 1857718
Journal Protein Eng
Year 1991
Volume 4
Pages 359-70
Authors Niermann T, Kirschner K
Title Improving the prediction of secondary structure of 'TIM-barrel' enzymes.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 1892826
Journal Biochemistry
Year 1991
Volume 30
Pages 9161-9
Authors Wilmanns M, Hyde CC, Davies DR, Kirschner K, Jansonius JN
Title Structural conservation in parallel beta/alpha-barrel enzymes that catalyze three sequential reactions in the pathway of tryptophan biosynthesis.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 1374562
Journal Proteins
Year 1992
Volume 12
Pages 299-313
Authors Scheerlinck JP, Lasters I, Claessens M, De Maeyer M, Pio F, Delhaise P, Wodak SJ
Title Recurrent alpha beta loop structures in TIM barrel motifs show a distinct pattern of conserved structural features.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 1567820
Journal Biochemistry
Year 1992
Volume 31
Pages 3617-25
Authors Eder J, Kirschner K
Title Stable substructures of eightfold beta alpha-barrel proteins: fragment complementation of phosphoribosylanthranilate isomerase.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 1738159
Journal J Mol Biol
Year 1992
Volume 223
Pages 477-507
Authors Wilmanns M, Priestle JP, Niermann T, Jansonius JN
Title Three-dimensional structure of the bifunctional enzyme phosphoribosylanthranilate isomerase: indoleglycerolphosphate synthase from Escherichia coli refined at 2.0 A resolution.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 7947963
Journal Biochim Biophys Acta
Year 1994
Volume 1208
Pages 310-5
Authors Andreotti G, Tutino ML, Sannia G, Marino G, Cubellis MV
Title Indole-3-glycerol-phosphate synthase from Sulfolobus solfataricus as a model for studying thermostable TIM-barrel enzymes.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 8001582
Journal Eur J Biochem
Year 1994
Volume 226
Pages 657-64
Authors Crombie T, Boyle JP, Coggins JR, Brown AJ
Title The folding of the bifunctional TRP3 protein in yeast is influenced by a translational pause which lies in a region of structural divergence with Escherichia coli indoleglycerol-phosphate synthase.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 7556082
Journal EMBO J
Year 1995
Volume 14
Pages 4395-402
Authors Sterner R, Dahm A, Darimont B, Ivens A, Liebl W, Kirschner K
Title (Beta alpha)8-barrel proteins of tryptophan biosynthesis in the hyperthermophile Thermotoga maritima.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 8747452
Journal Structure
Year 1995
Volume 3
Pages 1277-9
Authors Goldman A
Title How to make my blood boil.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 8747456
Journal Structure
Year 1995
Volume 3
Pages 1295-306
Authors Hennig M, Darimont B, Sterner R, Kirschner K, Jansonius JN
Title 2.0 A structure of indole-3-glycerol phosphate synthase from the hyperthermophile Sulfolobus solfataricus: possible determinants of protein stability.
Related PDB 1igs
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 8893859
Journal J Mol Biol
Year 1996
Volume 262
Pages 502-15
Authors Kn?chel TR, Hennig M, Merz A, Darimont B, Kirschner K, Jansonius JN
Title The crystal structure of indole-3-glycerol phosphate synthase from the hyperthermophilic archaeon Sulfolobus solfataricus in three different crystal forms: effects of ionic strength.
Related PDB 1juk 1jul
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 9091315
Journal FEBS Lett
Year 1997
Volume 403
Pages 268-72
Authors Stehlin C, Dahm A, Kirschner K
Title Deletion mutagenesis as a test of evolutionary relatedness of indoleglycerol phosphate synthase with other TIM barrel enzymes.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 9154940
Journal Biochemistry
Year 1997
Volume 36
Pages 5560-5
Authors S?nchez del Pino MM, Fersht AR
Title Nonsequential unfolding of the alpha/beta barrel protein indole-3-glycerol-phosphate synthase.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 9173891
Journal Biochem J
Year 1997
Volume 323
Pages 259-64
Authors Andreotti G, Cubellis MV, Palo MD, Fessas D, Sannia G, Marino G
Title Stability of a thermophilic TIM-barrel enzyme: indole-3-glycerol phosphate synthase from the thermophilic archaeon Sulfolobus solfataricus.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 9605328
Journal Protein Sci
Year 1998
Volume 7
Pages 1221-32
Authors Darimont B, Stehlin C, Szadkowski H, Kirschner K
Title Mutational analysis of the active site of indoleglycerol phosphate synthase from Escherichia coli.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 10653631
Journal Biochemistry
Year 2000
Volume 39
Pages 880-9
Authors Merz A, Yee MC, Szadkowski H, Pappenberger G, Crameri A, Stemmer WP, Yanofsky C, Kirschner K
Title Improving the catalytic activity of a thermophilic enzyme at low temperatures.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 10700266
Journal Nat Struct Biol
Year 2000
Volume 7
Pages 171-3
Authors Gerlt JA
Title New wine from old barrels.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID 10715203
Journal J Mol Biol
Year 2000
Volume 297
Pages 309-19
Authors Cho G, Keefe AD, Liu R, Wilson DS, Szostak JW
Title Constructing high complexity synthetic libraries of long ORFs using in vitro selection.
Related PDB
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 11741953
Journal J Biol Chem
Year 2002
Volume 277
Pages 8626-34
Authors Kn?chel T, Pappenberger A, Jansonius JN, Kirschner K
Title The crystal structure of indoleglycerol-phosphate synthase from Thermotoga maritima. Kinetic stabilization by salt bridges.
Related PDB 1i4n
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 11856350
Journal Eur J Biochem
Year 2002
Volume 269
Pages 1145-53
Authors Ivens A, Mayans O, Szadkowski H, J?rgens C, Wilmanns M, Kirschner K
Title Stabilization of a (betaalpha)8-barrel protein by an engineered disulfide bridge.
Related PDB
Related UniProtKB
[24]
Resource
Comments
Medline ID
PubMed ID 12054868
Journal J Mol Biol
Year 2002
Volume 319
Pages 757-66
Authors Hennig M, Darimont BD, Jansonius JN, Kirschner K
Title The catalytic mechanism of indole-3-glycerol phosphate synthase: crystal structures of complexes of the enzyme from Sulfolobus solfataricus with substrate analogue, substrate, and product.
Related PDB 1a53 1lbf 1lbl
Related UniProtKB
[25]
Resource
Comments
Medline ID
PubMed ID 12686139
Journal Biochim Biophys Acta
Year 2003
Volume 1647
Pages 234-8
Authors Denesyuk AI, Denessiouk KA, Korpela T, Johnson MS
Title Phosphate group binding cup of PLP-dependent and non-PLP-dependent enzymes: leitmotif and variations.
Related PDB
Related UniProtKB
[26]
Resource
Comments
Medline ID
PubMed ID 15110684
Journal Phytochemistry
Year 2004
Volume 65
Pages 1047-55
Authors Frey M, Spiteller D, Boland W, Gierl A
Title Transcriptional activation of Igl, the gene for indole formation in Zea mays: a structure-activity study with elicitor-active N-acyl glutamines from insects.
Related PDB
Related UniProtKB
[27]
Resource
Comments
Medline ID
PubMed ID 15137737
Journal J Am Chem Soc
Year 2004
Volume 126
Pages 5936-7
Authors Mazumder-Shivakumar D, Kahn K, Bruice TC
Title Computational study of the ground state of thermophilic indole glycerol phosphate synthase: structural alterations at the active site with temperature.
Related PDB
Related UniProtKB
[28]
Resource
Comments
Medline ID
PubMed ID 15452341
Journal Proc Natl Acad Sci U S A
Year 2004
Volume 101
Pages 14379-84
Authors Mazumder-Shivakumar D, Bruice TC
Title Molecular dynamics studies of ground state and intermediate of the hyperthermophilic indole-3-glycerol phosphate synthase.
Related PDB
Related UniProtKB
[29]
Resource
Comments
Medline ID
PubMed ID 16342933
Journal Biochemistry
Year 2005
Volume 44
Pages 16405-12
Authors Schneider B, Kn?chel T, Darimont B, Hennig M, Dietrich S, Babinger K, Kirschner K, Sterner R
Title Role of the N-terminal extension of the (betaalpha)8-barrel enzyme indole-3-glycerol phosphate synthase for its fold, stability, and catalytic activity.
Related PDB 2c3z
Related UniProtKB
[30]
Resource
Comments
Medline ID
PubMed ID 16487066
Journal Biochemistry (Mosc)
Year 2006
Volume 71
Pages S38-43
Authors Yang Y, Zhang M, Zhang H, Lei J, Jin R, Xu S, Bao J, Zhang L, Wang H
Title Purification and characterization of Mycobacterium tuberculosis indole-3-glycerol
Related PDB
Related UniProtKB
[31]
Resource
Comments
Medline ID
PubMed ID 17359995
Journal J Mol Biol
Year 2007
Volume 368
Pages 582-94
Authors Gu Z, Zitzewitz JA, Matthews CR
Title Mapping the structure of folding cores in TIM barrel proteins by hydrogen exchange mass spectrometry: the roles of motif and sequence for the indole-3-glycerol phosphate synthase from Sulfolobus solfataricus.
Related PDB
Related UniProtKB
[32]
Resource
Comments
Medline ID
PubMed ID 19032598
Journal FEBS J
Year 2009
Volume 276
Pages 144-54
Authors Shen H, Wang F, Zhang Y, Huang Q, Xu S, Hu H, Yue J, Wang H
Title A novel inhibitor of indole-3-glycerol phosphate synthase with activity against multidrug-resistant Mycobacterium tuberculosis.
Related PDB
Related UniProtKB
[33]
Resource
Comments
Medline ID
PubMed ID 19364491
Journal Arch Biochem Biophys
Year 2009
Volume 486
Pages 19-26
Authors Czekster CM, Neto BA, Lapis AA, Dupont J, Santos DS, Basso LA
Title Steady-state kinetics of indole-3-glycerol phosphate synthase from Mycobacterium tuberculosis.
Related PDB
Related UniProtKB

Comments
This enzyme catalyzes the following reaction, which should be divided into three basic reactions, according to the literature [24] and [28]:
(A) Addition of benzen to carbonyl group, leading to intermediate I1 (see [24]):
(A1) Lys110 acts (of 1a53) as a general acid to protonate the C2' carbonyl oxygen of substrate (protonation site), CdRP, leading to the polarization of the C2' carbon (addition site).
(A2) The electrophilic C2' atom makes an attack on the pi electrons of the benzen ring (added group).
(A3) Meanwhile, Lys53 modulates the distance between C1 atom and C2' atom, by interacting with the anthranilate carboxylate.
(A4) Glu159 stabilizes the positive charge developing on the amine group of the substrate, during the formation of the imine from the amine group.
(A5) Lys53 and Glu51 mediate the reprotonation of Lys110.
(B) Elimination of CO2 (decarboxylation) from intermediate I1 to form intermediate I2 (see [24]):
(B0) Glu159 stabilizes the positive charge on the imine group.
(B1) Lys53 modulates the electrons on the leaving carboxylate group, leading to the pi-electron restoration and neutralization of the positive charge on the imine group. Thus, the amine group recovers from the imine group, leading to intermediate I2.
(B2) This elimination reaction might be E1cB-like.
(C) Elimination of H2O(dehydration) from intermediate I2 to form product (see [28]):
(C1) Lys110 acts as a general acid to protonate the eliminated hydroxyl group.
(C2) Glu210 acts as a genral base to the C1' proton.
(C3) This elimination reaction might be E2-like reaction.
(C4) In the end, proton transfer from Glu210 to Lys110, to restore the activities of these catalytic residues.

Created Updated
2009-07-24 2009-07-27