DB code: S00192

CATH domain 3.20.20.20 : TIM Barrel Catalytic domain
E.C. 2.5.1.15
CSA 1aj0
M-CSA 1aj0
MACiE

CATH domain Related DB codes (homologues)

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P0AC13 Dihydropteroate synthase
DHPS
EC 2.5.1.15
Dihydropteroate pyrophosphorylase
NP_417644.4 (Protein)
NC_000913.2 (DNA/RNA sequence)
YP_491362.1 (Protein)
NC_007779.1 (DNA/RNA sequence)
PF00809 (Pterin_bind)
[Graphical View]
O05701 Dihydropteroate synthase
DHPS
EC 2.5.1.15
Dihydropteroate pyrophosphorylase
PF00809 (Pterin_bind)
[Graphical View]
P0A578 Dihydropteroate synthase 1
DHPS 1
EC 2.5.1.15
Dihydropteroate pyrophosphorylase 1
NP_338257.1 (Protein)
NC_002755.2 (DNA/RNA sequence)
YP_006517097.1 (Protein)
NC_018143.1 (DNA/RNA sequence)
YP_177997.1 (Protein)
NC_000962.3 (DNA/RNA sequence)
PF00809 (Pterin_bind)
[Graphical View]

KEGG enzyme name
dihydropteroate synthase
dihydropteroate pyrophosphorylase
DHPS
7,8-dihydropteroate synthase
7,8-dihydropteroate synthetase
7,8-dihydropteroic acid synthetase
dihydropteroate synthetase
dihydropteroic synthetase
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine-diphosphate:4-aminobenzoate2-amino-4-hydroxydihydropteridine-6-methenyltransferase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P0AC13 DHPS_ECOLI (2-amino-4-hydroxy-7,8-dihydropteridin-6- yl)methyl diphosphate + 4-aminobenzoate = diphosphate + dihydropteroate. Homodimer.
O05701 DHPS_STAAU (2-amino-4-hydroxy-7,8-dihydropteridin-6- yl)methyl diphosphate + 4-aminobenzoate = diphosphate + dihydropteroate. Homodimer.
P0A578 DHPS1_MYCTU (2-amino-4-hydroxy-7,8-dihydropteridin-6- yl)methyl diphosphate + 4-aminobenzoate = diphosphate + dihydropteroate. Homodimer (By similarity).

KEGG Pathways
Map code Pathways E.C.
MAP00790 Folate biosynthesis

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00034 C04807 C00568 C00013 C00921
E.C.
Compound Manganese 2-Amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate 4-Aminobenzoate Pyrophosphate Dihydropteroate
Type heavy metal amine group,aromatic ring (with nitrogen atoms),phosphate group/phosphate ion amine group,aromatic ring (only carbon atom),carboxyl group phosphate group/phosphate ion amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group
ChEBI 18291
 35154
 18291
 35154
 		15998
 73083
 15998
 73083
 		30753
 30753
 		29888
 29888
 		4581
 4581
PubChem 23930
 23930
 		666
 666
 		7057990
 978
 7057990
 978
 		1023
 21961011
 1023
 21961011
 		170
 170
1ad1A Unbound Unbound Unbound Unbound Unbound Unbound
1ad1B Unbound Unbound Unbound Unbound Unbound Unbound
1ad4A Bound:_MN Analogue:HH2 Unbound Unbound Unbound Unbound
1ad4B Unbound Unbound Unbound Unbound Unbound Unbound
1aj0A Unbound Analogue:PH2 Analogue:SAN Analogue:SO4 Unbound Unbound
1aj2A Unbound Bound:2PH Unbound Unbound Unbound Unbound
1ajzA Unbound Unbound Unbound Analogue:SO4_283 Unbound Unbound
1eyeA Analogue:_MG Unbound Unbound Unbound Unbound Transition-state-analogue:PMM

Reference for Active-site residues
resource references E.C.
literature [8]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1ad1A ASN 11;ASP 19;ARG 52;LYS 203;ARG 239;HIS 241 ASN 11(Manganese binding) THR 51
1ad1B ASN 11; ; ;LYS 203;ARG 239;HIS 241 ASN 11(Manganese binding) THR 51 invisible 15-24, 52-56
1ad4A ASN 11; ;ARG 52;LYS 203;ARG 239;HIS 241 ASN 11(Manganese binding) THR 51 invisible 13-24
1ad4B ASN 11; ; ;LYS 203;ARG 239;HIS 241 ASN 11(Manganese binding) invisible 14-24, 50-56
1aj0A ASN 22;ASP 30;ARG 63;LYS 221;ARG 255;HIS 257 ASN 22(Manganese binding) THR 62
1aj2A ASN 22;ASP 30;ARG 63;LYS 221;ARG 255;HIS 257 ASN 22(Manganese binding) THR 62
1ajzA ASN 22;ASP 30;ARG 63;LYS 221;ARG 255;HIS 257 ASN 22(Manganese binding) THR 62
1eyeA ASN 13;ASP 21; ;LYS 213;ARG 253;HIS 255 ASN 13(Manganese binding) invisible 51-64

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[3]
p.27-28
[4]
[8]
p.1203-1205, Fig.6

References
[1]
Resource
Comments
Medline ID
PubMed ID 8397083
Journal Eur J Biochem
Year 1993
Volume 216
Pages 449-58
Authors Volpe F, Ballantine SP, Delves CJ
Title The multifunctional folic acid synthesis fas gene of Pneumocystis carinii encodes dihydroneopterin aldolase, hydroxymethyldihydropterin pyrophosphokinase and dihydropteroate synthase
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 9118956
Journal EMBO J
Year 1997
Volume 16
Pages 947-57
Authors Rebeille F, Macherel D, Mouillon JM, Garin J, Douce R
Title Folate biosynthesis in higher plants: purification and molecular cloning of a bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/7,8-dihydropteroate synthase localized in mitochondria
Related PDB
Related UniProtKB
[3]
Resource
Comments SEQUENCE FROM NUCLEIC ACID, AND X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS)
Medline ID 97293085
PubMed ID 9149138
Journal J Mol Biol
Year 1997
Volume 268
Pages 21-30
Authors Hampele IC, D'Arcy A, Dale GE, Kostrewa D, Nielsen J, Oefner C, Page MG, Schonfeld HJ, Stuber D, Then RL
Title Structure and function of the dihydropteroate synthase from Staphylococcus aureus
Related PDB 1ad1 1ad4
Related UniProtKB O05701
[4]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS)
Medline ID 97331326
PubMed ID 9187658
Journal Nat Struct Biol
Year 1997
Volume 4
Pages 490-7
Authors Achari A, Somers DO, Champness JN, Bryant PK, Rosemond J, Stammers DK
Title Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase
Related PDB 1aj0 1aj2 1ajz
Related UniProtKB P0AC13
[5]
Resource
Comments
Medline ID
PubMed ID 10329458
Journal Biochem Biophys Res Commun
Year 1999
Volume 258
Pages 752-7
Authors Vinnicombe HG, Derrick JP
Title Dihydropteroate synthase from Streptococcus pneumoniae: characterization of substrate binding order and sulfonamide inhibition
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 10452528
Journal FEBS Lett
Year 1999
Volume 456
Pages 49-53
Authors Stammers DK, Achari A, Somers DO, Bryant PK, Rosemond J, Scott DL, Champness JN
Title 2.0 A X-ray structure of the ternary complex of 7,8-dihydro-6-hydroxymethylpterinpyrophosphokinase from Escherichia coli with ATP and a substrate analogue
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 11076529
Journal Biochemistry
Year 2000
Volume 39
Pages 13880-90
Authors Smith AE, Matthews RG
Title Protonation state of methyltetrahydrofolate in a binary complex with cobalamin-dependent methionine synthase
Related PDB
Related UniProtKB
[8]
Resource
Comments Erratum in: J Mol Biol 2000 Nov 10;303(5):843
Medline ID
PubMed ID 11007651
Journal J Mol Biol
Year 2000
Volume 302
Pages 1193-212
Authors Baca AM, Sirawaraporn R, Turley S, Sirawaraporn W, Hol WG
Title Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action
Related PDB 1eye
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 11426433
Journal Trends Parasitol
Year 2001
Volume 17
Pages 265-6
Authors Hyde JE, Sims PF
Title Sulfa-drug resistance in Plasmodium falciparum
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 11931659
Journal Biochem J
Year 2002
Volume 363
Pages 313-9
Authors Mouillon JM, Ravanel S, Douce R, Rebeille F
Title Folate synthesis in higher-plant mitochondria: coupling between the dihydropterin pyrophosphokinase and the dihydropteroate synthase activities
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 12039964
Journal J Biol Chem
Year 2002
Volume 277
Pages 28841-7
Authors Illarionova V, Eisenreich W, Fischer M, Haussmann C, Romisch W, Richter G, Bacher A
Title Biosynthesis of tetrahydrofolate. Stereochemistry of dihydroneopterin aldolase
Related PDB
Related UniProtKB

Comments
Although the detailed catalytic mechanism has not been elucidated for this enzyme, the following information on catalytic residues are available, according to the literature [8]:
(a) Asp30 (of 1aj0) on the flexible loop-1 may act as a general acid to protonate the leaving phoshpate oxygen.
(b) Asn22, Arg63, Arg255, and His257 seem to stabilize the leaving phosphate group, along with the bound manganese, and the mainchain amide of Thr62.
(c) The positive charges on the sidechains from Lys221 and Arg255 might give an electron-withdrawing effect on the pyrazine ring of the substrate H2PtPP (C04807), so that the incoming amino group of the second substrate pABA (C00568) could attack on the C9 atom of H2PtPP.

Created Updated
2004-03-22 2009-03-17