EzCatDB: D00826
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DB codeD00826
RLCP classification3.1177.220080.38 : Transfer
5.115.129300.66 : Elimination
3.1197.15020.136 : Transfer
CATH domainDomain 13.40.47.10 : Peroxisomal Thiolase; Chain A, domain 1Catalytic domain
Domain 23.40.47.10 : Peroxisomal Thiolase; Chain A, domain 1Catalytic domain
E.C.2.3.1.180

CATH domainRelated DB codes (homologues)
3.40.47.10 : Peroxisomal Thiolase; Chain A, domain 1D00090,D00411,D00509,D00825,D00867,D00871

Enzyme Name
UniProtKBKEGG

P0A574Q7SI99Q9F6D4
Protein name3-oxoacyl-[acyl-carrier-protein] synthase 33-oxoacyl-[acyl-carrier-protein] synthase 33-oxoacyl-[acyl-carrier-protein] synthase 3Beta-ketoacyl-acyl-carrier-protein synthase III
3-Oxoacyl:ACP synthase III
3-Ketoacyl-acyl carrier protein synthase III
KASIII
KAS III
FabH
Beta-ketoacyl-acyl carrier protein synthase III
Beta-ketoacyl-ACP synthase III
Beta-ketoacyl (acyl carrier protein) synthase III
Beta-ketoacyl-[acyl-carrier-protein] synthase III
Acetyl-CoA:malonyl-[acyl-carrier-protein] C-acyltransferase
SynonymsEC 2.3.1.180
3-oxoacyl-[acyl-carrier-protein] synthase III
Beta-ketoacyl-ACP synthase III
KAS III
MtFabH
EC 2.3.1.180
3-oxoacyl-[acyl-carrier-protein] synthase III
Beta-ketoacyl-ACP synthase III
EC 2.3.1.180
3-oxoacyl-[acyl-carrier-protein] synthase III
Beta-ketoacyl-ACP synthase III
KAS III
RefSeqNP_215047.1 (Protein)
NC_000962.3 (DNA/RNA sequence)
NP_334966.1 (Protein)
NC_002755.2 (DNA/RNA sequence)
YP_006513866.1 (Protein)
NC_018143.1 (DNA/RNA sequence)


PfamPF08545 (ACP_syn_III)
PF08541 (ACP_syn_III_C)
[Graphical view]
PF08545 (ACP_syn_III)
PF08541 (ACP_syn_III_C)
[Graphical view]
PF08545 (ACP_syn_III)
PF08541 (ACP_syn_III_C)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00061Fatty acid biosynthesis

UniProtKB:Accession NumberP0A574Q7SI99Q9F6D4
Entry nameFABH_MYCTUQ7SI99_THETHFABH_STRLI
ActivityAcetyl-CoA + malonyl-[acyl-carrier-protein] = acetoacetyl-[acyl-carrier-protein] + CoA + CO(2).Acetyl-CoA + malonyl-[acyl-carrier-protein] = acetoacetyl-[acyl-carrier-protein] + CoA + CO(2).Acetyl-CoA + malonyl-[acyl-carrier-protein] = acetoacetyl-[acyl-carrier-protein] + CoA + CO(2).
SubunitHomodimer.Homodimer (By similarity).Homodimer.
Subcellular locationCytoplasm.Cytoplasm (By similarity).Cytoplasm (Probable).
Cofactor



Compound table: links to PDB-related databases & PoSSuM

SubstratesProductsintermediates
KEGG-idC00024C01209C05744C00010C00011I00132I00133I00134I00135
Compoundacetyl-CoAmalonyl-[acyl-carrier protein]acetoacetyl-[acyl-carrier protein]CoACO2Peptidyl-Cys-tetrahedral-acetyl-CoAPeptidyl-Cys-S-acetyl[Acyl-carrier protein]-decarboxylated malonyl group (Peptidyl-Ser-phosphopantetheine-S-enolate)Peptidyl-Cys-tetrahedral-acetyl-keto-[acyl-carrier protein]
Typeamine group,carbohydrate,nucleotide,peptide/protein,sulfide groupcarbohydrate,carboxyl group,peptide/protein,phosphate group/phosphate ion,sulfide groupcarbohydrate,peptide/protein,phosphate group/phosphate ion,sulfide groupamine group,carbohydrate,nucleotide,peptide/protein,sulfhydryl groupothers



ChEBI15351


15346
16526




PubChem6302
444493


87642
6816
280




                 
1hzpA01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1hzpB01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1m1mA01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1m1mB01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1u6eA01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1u6eB01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1u6sA01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1u6sB01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2ahbA01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2ahbB01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2aj9A01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2aj9B01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2qnxA01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:MDX-CYS 112UnboundUnbound
2qnxB01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:MDX-CYS 112UnboundUnbound
2qnyA01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:DFD-CYS 112UnboundUnbound
2qnyB01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:DFD-CYS 112UnboundUnbound
2qnzA01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:DFD-CYS 112UnboundUnbound
2qnzB01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:DFD-CYS 112UnboundUnbound
2qo0A01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:D1T-CYS 112UnboundUnbound
2qo0B01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:D1T-CYS 112UnboundUnbound
2qo1A01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:D1T-CYS 112UnboundUnbound
2qo1B01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:D1T-CYS 112UnboundUnbound
2qx1A01UnboundUnboundUnboundBound:COAUnboundUnboundIntermediate-analogue:D1T-CYS 112UnboundUnbound
2qx1B01UnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:D1T-CYS 112UnboundUnbound
1ub7A01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1ub7B01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1ub7C01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1ub7D01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1mzjA01UnboundUnboundUnboundUnboundUnboundTransition-state-analogue:COA-ACE-CYS 121UnboundUnboundUnbound
1mzjB01UnboundUnboundUnboundUnboundUnboundTransition-state-analogue:COA-ACE-CYS 121UnboundUnboundUnbound
1hzpA02UnboundAnalogue:DAOUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1hzpB02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1m1mA02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1m1mB02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1u6eA02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1u6eB02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1u6sA02Analogue:DCCUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1u6sB02Analogue:DCCUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2ahbA02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2ahbB02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2aj9A02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2aj9B02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2qnxA02UnboundUnboundUnboundUnboundUnboundUnboundUnboundTransition-state-analogue:UDTUnbound
2qnxB02UnboundUnboundUnboundUnboundUnboundUnboundUnboundTransition-state-analogue:UDTUnbound
2qnyA02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2qnyB02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2qnzA02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2qnzB02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2qo0A02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2qo0B02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2qo1A02UnboundUnboundUnboundUnboundUnboundUnboundUnboundTransition-state-analogue:VZZUnbound
2qo1B02UnboundUnboundUnboundUnboundUnboundUnboundUnboundTransition-state-analogue:VZZUnbound
2qx1A02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2qx1B02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1ub7A02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1ub7B02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1ub7C02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1ub7D02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1mzjA02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1mzjB02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
literature [2], [3], [5], [9], [10], [13], [14], [15], [18], [21] & Swiss-prot;A5TZR3, P0A574, Q9F6D4
pdbCatalytic residuesModified residuesMain-chain involved in catalysiscomment
            
1hzpA01CYS 112;GLU 140
                         
CYS 112
 
1hzpB01CYS 112;GLU 140
                         
CYS 112
 
1m1mA01CYS 123;GLU 151
                         
CYS 123
 
1m1mB01CYS 123;GLU 151
                         
CYS 123
 
1u6eA01       ;GLU 140
                         
       
mutant C112A
1u6eB01       ;GLU 140
                         
       
mutant C112A
1u6sA01       ;GLU 140
                         
       
mutant C112A
1u6sB01       ;GLU 140
                         
       
mutant C112A
2ahbA01CYS 122;GLU 150
                         
CYS 122
mutant R46A, R161A
2ahbB01CYS 122;GLU 150
                         
CYS 122
mutant R46A, R161A
2aj9A01CYS 122;GLU 150
                         
CYS 122
mutant W42A, R161A
2aj9B01CYS 122;GLU 150
                         
CYS 122
mutant W42A, R161A
2qnxA01CYS 112;GLU 140
                         
CYS 112
 
2qnxB01CYS 112;GLU 140
                         
CYS 112
 
2qnyA01CYS 112;GLU 140
                         
CYS 112
 
2qnyB01CYS 112;GLU 140
                         
CYS 112
 
2qnzA01CYS 112;GLU 140
                         
CYS 112
 
2qnzB01CYS 112;GLU 140
                         
CYS 112
 
2qo0A01CYS 112;GLU 140
                         
CYS 112
 
2qo0B01CYS 112;GLU 140
                         
CYS 112
 
2qo1A01CYS 112;GLU 140
                         
CYS 112
 
2qo1B01CYS 112;GLU 140
                         
CYS 112
 
2qx1A01CYS 112;GLU 140
                         
CYS 112
 
2qx1B01CYS 112;GLU 140
                         
CYS 112
 
1ub7A01       ;GLU 138
CSO 110(S-hydroxycystein)
CSO 110
 
1ub7B01       ;GLU 138
CSO 110(S-hydroxycystein)
CSO 110
 
1ub7C01       ;GLU 138
CSO 110(S-hydroxycystein)
CSO 110
 
1ub7D01       ;GLU 138
CSO 110(S-hydroxycystein)
CSO 110
 
1mzjA01CYS 121;GLU 149
                         
CYS 121
 
1mzjB01CYS 121;GLU 149
                         
CYS 121
 
1hzpA02HIS 244;ASN 274;SER 276
 
ALA 306
 
1hzpB02HIS 244;ASN 274;SER 276
 
ALA 306
 
1m1mA02HIS 259;ASN 290;SER 292
 
ALA 322
 
1m1mB02HIS 259;ASN 290;SER 292
 
ALA 322
 
1u6eA02HIS 244;ASN 274;SER 276
 
ALA 306
 
1u6eB02HIS 244;ASN 274;SER 276
 
ALA 306
 
1u6sA02HIS 244;ASN 274;SER 276
 
ALA 306
 
1u6sB02HIS 244;ASN 274;SER 276
 
ALA 306
 
2ahbA02HIS 258;ASN 289;SER 291
 
ALA 321
 
2ahbB02HIS 258;ASN 289;SER 291
 
ALA 321
 
2aj9A02HIS 258;ASN 289;SER 291
 
ALA 321
 
2aj9B02HIS 258;ASN 289;SER 291
 
ALA 321
 
2qnxA02HIS 244;ASN 274;SER 276
 
ALA 306
 
2qnxB02HIS 244;ASN 274;SER 276
 
ALA 306
 
2qnyA02HIS 244;ASN 274;SER 276
 
ALA 306
mutant A246F
2qnyB02HIS 244;ASN 274;SER 276
 
ALA 306
mutant A246F
2qnzA02HIS 244;ASN 274;SER 276
 
ALA 306
 
2qnzB02HIS 244;ASN 274;SER 276
 
ALA 306
 
2qo0A02HIS 244;ASN 274;SER 276
 
ALA 306
mutant A246F
2qo0B02HIS 244;ASN 274;SER 276
 
ALA 306
mutant A246F
2qo1A02HIS 244;ASN 274;SER 276
 
ALA 306
 
2qo1B02HIS 244;ASN 274;SER 276
 
ALA 306
 
2qx1A02HIS 244;ASN 274;SER 276
 
ALA 306
 
2qx1B02HIS 244;ASN 274;SER 276
 
ALA 306
 
1ub7A02HIS 246;ASN 276;SER 278
 
ALA 308
 
1ub7B02HIS 246;ASN 276;SER 278
 
ALA 308
 
1ub7C02HIS 246;ASN 276;SER 278
 
ALA 308
 
1ub7D02HIS 246;ASN 276;SER 278
 
ALA 308
 
1mzjA02HIS 257;ASN 288;SER 290
 
ALA 320
 
1mzjB02HIS 257;ASN 288;SER 290
 
ALA 320
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[2]Fig.6A, p.36467-36470
[3]Scheme 1, p.158-160
[5]Fig.7b, 3p.190-192
[9]p.349-352
[10]p.1561-1565
[13]Fig.6b, p.806-809
[14]Fig.6, p.32544-32547
[15]Fig.1
[18]Fig.1B
[21]Fig.5, p.696-697

references
[1]
CommentsX-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
PubMed ID10571059
JournalFEBS Lett
Year1999
Volume460
Pages46-52
AuthorsOlsen JG, Kadziola A, von Wettstein-Knowles P, Siggaard-Andersen M, Lindquist Y, Larsen S
TitleThe X-ray crystal structure of beta-ketoacyl [acyl carrier protein] synthase I.
Related PDB1dd8
Related UniProtKBP0A953
[2]
CommentsX-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
PubMed ID10593943
JournalJ Biol Chem
Year1999
Volume274
Pages36465-71
AuthorsQiu X, Janson CA, Konstantinidis AK, Nwagwu S, Silverman C, Smith WW, Khandekar S, Lonsdale J, Abdel-Meguid SS
TitleCrystal structure of beta-ketoacyl-acyl carrier protein synthase III. A key condensing enzyme in bacterial fatty acid biosynthesis.
Related PDB1d9b,1hn9
Related UniProtKBP0A6R0
[3]
PubMed ID10600651
JournalBiochem J
Year2000
Volume345 Pt 1
Pages153-60
AuthorsAbbadi A, Brummel M, Schutt BS, Slabaugh MB, Schuch R, Spener F
TitleReaction mechanism of recombinant 3-oxoacyl-(acyl-carrier-protein) synthase III from Cuphea wrightii embryo, a fatty acid synthase type II condensing enzyme.
[4]
PubMed ID11006298
JournalJ Biol Chem
Year2000
Volume275
Pages39640-6
AuthorsJez JM, Noel JP
TitleMechanism of chalcone synthase. pKa of the catalytic cysteine and the role of the conserved histidine in a plant polyketide synthase.
[5]
CommentsX-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
PubMed ID10673437
JournalStructure
Year2000
Volume8
Pages185-95
AuthorsDavies C, Heath RJ, White SW, Rock CO
TitleThe 1.8 A crystal structure and active-site architecture of beta-ketoacyl-acyl carrier protein synthase III (FabH) from escherichia coli.
Related PDB1ebl
Related UniProtKBP0A6R0
[6]
PubMed ID11502177
JournalBiochemistry
Year2001
Volume40
Pages9836-45
AuthorsMcGuire KA, Siggaard-Andersen M, Bangera MG, Olsen JG, von Wettstein-Knowles P
Titlebeta-Ketoacyl-[acyl carrier protein] synthase I of Escherichia coli: aspects of the condensation mechanism revealed by analyses of mutations in the active site pocket.
[7]
CommentsX-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
PubMed ID11278743
JournalJ Biol Chem
Year2001
Volume276
Pages20516-22
AuthorsScarsdale JN, Kazanina G, He X, Reynolds KA, Wright HT
TitleCrystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III.
Related PDB1hzp
Related UniProtKBP0A574
[8]
PubMed ID11078736
JournalJ Biol Chem
Year2001
Volume276
Pages8231-8
AuthorsZhang YM, Rao MS, Heath RJ, Price AC, Olson AJ, Rock CO, White SW
TitleIdentification and analysis of the acyl carrier protein (ACP) docking site on beta-ketoacyl-ACP synthase III.
[9]
CommentsX-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
PubMed ID11243824
JournalJ Mol Biol
Year2001
Volume307
Pages341-56
AuthorsQiu X, Janson CA, Smith WW, Head M, Lonsdale J, Konstantinidis AK
TitleRefined structures of beta-ketoacyl-acyl carrier protein synthase III.
Related PDB1hnd,1hnh,1hnj,1hnk
Related UniProtKBP0A6R0
[10]
CommentsX-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
PubMed ID12429097
JournalStructure
Year2002
Volume10
Pages1559-68
AuthorsPan H, Tsai S, Meadows ES, Miercke LJ, Keatinge-Clay AT, O'Connell J, Khosla C, Stroud RM
TitleCrystal structure of the priming beta-ketosynthase from the R1128 polyketide biosynthetic pathway.
Related PDB1mzj
Related UniProtKBQ9F6D4
[11]
PubMed ID12502353
JournalJ Med Chem
Year2003
Volume46
Pages5-8
AuthorsDaines RA, Pendrak I, Sham K, Van Aller GS, Konstantinidis AK, Lonsdale JT, Janson CA, Qiu X, Brandt M, Khandekar SS, Silverman C, Head MS
TitleFirst X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling.
Related PDB1mzs
[12]
PubMed ID12866053
JournalProteins
Year2003
Volume52
Pages427-35
AuthorsDawe JH, Porter CT, Thornton JM, Tabor AB
TitleA template search reveals mechanistic similarities and differences in beta-ketoacyl synthases (KAS) and related enzymes.
[13]
PubMed ID15952903
JournalAnnu Rev Biochem
Year2005
Volume74
Pages791-831
AuthorsWhite SW, Zheng J, Zhang YM, Rock
TitleThe structural biology of type II fatty acid biosynthesis.
[14]
PubMed ID16040614
JournalJ Biol Chem
Year2005
Volume280
Pages32539-47
AuthorsBrown AK, Sridharan S, Kremer L, Lindenberg S, Dover LG, Sacchettini JC, Besra GS
TitleProbing the mechanism of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III mtFabH: factors influencing catalysis and substrate specificity.
Related PDB1m1m,2ahb,2aj9
[15]
PubMed ID15713483
JournalJ Mol Biol
Year2005
Volume346
Pages1313-21
AuthorsMusayev F, Sachdeva S, Scarsdale JN, Reynolds KA, Wright HT
TitleCrystal structure of a substrate complex of Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FabH) with lauroyl-coenzyme A.
Related PDB1u6e,1u6s
[16]
PubMed ID15987898
JournalProtein Sci
Year2005
Volume14
Pages2087-94
AuthorsQiu X, Choudhry AE, Janson CA, Grooms M, Daines RA, Lonsdale JT, Khandekar SS
TitleCrystal structure and substrate specificity of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus.
Related PDB1zow
[17]
PubMed ID16356722
JournalTrends Biochem Sci
Year2005
Volume31
Pages64-71
AuthorsHaapalainen AM, Merilainen G, Wierenga RK
TitleThe thiolase superfamily: condensing enzymes with diverse reaction specificities.
[18]
PubMed ID17524982
JournalChem Biol
Year2007
Volume14
Pages513-24
AuthorsAlhamadsheh MM, Musayev F, Komissarov AA, Sachdeva S, Wright HT, Scarsdale N, Florova G, Reynolds KA
TitleAlkyl-CoA disulfides as inhibitors and mechanistic probes for FabH enzymes.
Related PDB2eft,2gyo
[19]
PubMed ID18096200
JournalBioorg Chem
Year2008
Volume36
Pages85-90
AuthorsSachdeva S, Musayev F, Alhamadsheh MM, Neel Scarsdale J, Tonie Wright H, Reynolds KA
TitleProbing reactivity and substrate specificity of both subunits of the dimeric Mycobacterium tuberculosis FabH using alkyl-CoA disulfide inhibitors and acyl-CoA substrates.
[20]
PubMed ID18420147
JournalChem Biol
Year2008
Volume15
Pages402-12
AuthorsSachdeva S, Musayev FN, Alhamadsheh MM, Scarsdale JN, Wright HT, Reynolds KA
TitleSeparate entrance and exit portals for ligand traffic in Mycobacterium tuberculosis FabH.
Related PDB2qnz,2qny,2qnx,2qo0,2qo1
[21]
PubMed ID18824113
JournalMol Phylogenet Evol
Year2008
Volume49
Pages691-701
AuthorsJiang C, Kim SY, Suh DY
TitleDivergent evolution of the thiolase superfamily and chalcone synthase family.
[22]
PubMed ID19665020
JournalFEBS Lett
Year2009
Volume583
Pages2939-46
AuthorsGajiwala KS, Margosiak S, Lu J, Cortez J, Su Y, Nie Z, Appelt K
TitleCrystal structures of bacterial FabH suggest a molecular basis for the substrate specificity of the enzyme.
Related PDB3il3,3il4,3il5,3il6,3il7,3il9

comments
This enzyme belongs to chalcone synthase family in thiolase superfamily (see [21]). This enzyme is homologous to the counterpart enzyme from different bacteria (D00825 and D00867 in EzCatDB), with a slightly different catalytic site. Moreover, these enzymes are categorized in type III of beta-ketoacyl-acyl-carrier protein synthases (KAS).
According to the literature, the catalysis proceeds through the Ping-Pong reaction mechanism.
According to the literature [2], [3], [5], [9], [10], [14], [15] and [21], this enzyme catalyzes the following reactions:
(A) Transfer of acyl group from sulfur atom of acetyl-CoA to catalytic cysteine (see [9]):
(A0) Asn274 (of 1hzp) modulate the pKa of His244, whereas His244 may lower the pKa of the sidechain of Cys112.
(A1) Glu140 (of 1hzp) acts as a general base to deprotonate the nucleophile, Cys112, through the sidechain of Ser276. (Helix dipole moment may also activate the cysteine sidechain.)
(A2) The activated thiol group of Cys112 makes a nucleophilic attack on the acetyl group of acetyl-CoA, leading to a transition-state (I00132). The oxyanion hole, composed of the mainchain amide groups of Cys112 and Ala306, stabilizes the negative charge of the oxyanion on the tetrahedral transition-state (I00132).
(A3) His244 acts as a general acid to protonate the leaving sulfur atom of CoA, generating an acetyl group on Cys112 (I00133).
(B) Decarboxylation of malonyl-ACP (Elimination of carboxylate group from malonyl group) forming carbanion/enolate transition-state (I00134):
(B0) Asn274 and His244 interact with the carbonyl oxygen of the second substrate, malonyl-ACP, and stabilize it.
(B1) His244 may act as a general base to deprotonate the carboxylic group of malonyl-ACP, to facilitate the decarboxylation. This reaction generates a carbanion/enolate transition-state (I00134). The enolate is stabilized by Asn274 and His244.
(C) Transfer of acetyl group from catalytic cysteine to carbanion on the transition-state (I00134):
(C0) Asn274 and His244 stabilize the enol group of the transition-state (I00134).
(C1) The carbanion makes a nucleophilic attack on the acetyl group of the acetyl intermediate (I00133), forming a tetrahedral transition-state (I00135). The oxyanion of the tetrahedral transition-state (I00135) is stabilized by the oxyanion hole composed of the mainchain amide groups of Cys112 and Ala306.
(C2) Glu140 may act as a general acid to protonate the leaving catalytic residue, Cys112, through the sidechain of Ser276.

createdupdated
2009-11-262012-07-10


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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© Computational Biology Research Center, AIST, 2004-2016 All Rights Reserved.