Dihydropteroate synthase

 

Dihydropteroate synthase (DHPS) is essential for the de novo synthesis of folate in prokaryotes, in lower eukaryotes such as protozoa and yeast, and in plants. DHPS is absent in mammals. This makes it an ideal drug target.

 

Reference Protein and Structure

Sequence
P0AC13 UniProt (2.5.1.15) IPR011005 (Sequence Homologues) (PDB Homologues)
Biological species
Escherichia coli K-12 (Bacteria) Uniprot
PDB
1aj0 - CRYSTAL STRUCTURE OF A TERNARY COMPLEX OF E. COLI DIHYDROPTEROATE SYNTHASE (2.0 Å) PDBe PDBsum 1aj0
Catalytic CATH Domains
3.20.20.20 CATHdb (see all for 1aj0)
Click To Show Structure

Enzyme Reaction (EC:2.5.1.15)

4-aminobenzoate
CHEBI:17836ChEBI
+
(7,8-dihydropterin-6-yl)methyl diphosphate(3-)
CHEBI:72950ChEBI
→
7,8-dihydropteroate
CHEBI:17839ChEBI
+
diphosphate(3-)
CHEBI:33019ChEBI
Alternative enzyme names: 7,8-dihydropteroate synthase, 7,8-dihydropteroate synthetase, 7,8-dihydropteroic acid synthetase, DHPS, Dihydropteroate pyrophosphorylase, Dihydropteroate synthetase, Dihydropteroic synthetase, Dihydropteroate diphosphorylase, 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine-diphosphate:4-aminobenzoate 2-amino-4-hydroxydihydropteridine-6-methenyltransferase, (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl-diphosphate:4-aminobenzoate 2-amino-4-hydroxydihydropteridine-6-methenyltransferase,

Enzyme Mechanism

Introduction

DHPS catalyses the reaction of para-aminobenzoic acid (pABA) with 7,8-dihydropterin-pyrophosphate to form pyrophosphate and 7,8-dihydropteroate. The condensation of pABA with DHPPP to form 7,8-dihydropteroate occurs via an SN1 reaction mechanism in an ordered manner in which DHPPP first binds DHPS, which then eliminates its pyrophosphate group (PPi) prior to pABA binding by stabilizing the cationic intermediate DHP+. Two positively charged residues in the enzyme polarise the C6-C9 bond of the substrate, facilitating the nucleophilic attack.

Catalytic Residues Roles

UniProt PDB* (1aj0)
Lys221, Arg255 Lys221A, Arg255A Polarises C6-C9 bond of substrate. activator
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

References

  1. Baca AM et al. (2000), J Mol Biol, 302, 1193-1212. Crystal structure of Mycobacterium tuberculosis 6-hydroxymethyl-7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action. DOI:10.1006/jmbi.2000.4094. PMID:11007651.
  2. Hammoudeh DI et al. (2013), Future Med Chem, 5, 1331-1340. Replacing sulfa drugs with novel DHPS inhibitors. DOI:10.4155/fmc.13.97. PMID:23859210.
  3. Yun MK et al. (2012), Science, 335, 1110-1114. Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase. DOI:10.1126/science.1214641. PMID:22383850.
  4. Babaoglu K et al. (2004), Structure, 12, 1705-1717. Crystal Structure of 7,8-Dihydropteroate Synthase from Bacillus anthracis. DOI:10.1016/j.str.2004.07.011. PMID:15341734.
  5. Achari A et al. (1997), Nat Struct Biol, 4, 490-497. Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase. DOI:10.1038/nsb0697-490. PMID:9187658.
  6. Hampele IC et al. (1997), J Mol Biol, 268, 21-30. Structure and function of the dihydropteroate synthase from staphylococcus aureus. DOI:10.1006/jmbi.1997.0944. PMID:9149138.

Step 1.

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Catalytic Residues Roles

Residue Roles
Lys221A activator
Arg255A activator

Chemical Components

Step 1.

Contributors

Stuart Lucas, Craig Porter, Gemma L. Holliday