Literature summary extracted from
Qi, J.; Virga, K.G.; Das, S.; Zhao, Y.; Yun, M.K.; White, S.W.; Lee, R.E.
Synthesis of bi-substrate state mimics of dihydropteroate synthase as potential inhibitors and molecular probes (2011), Bioorg. Med. Chem., 19, 1298-1305.
Application
EC Number |
Application |
Comment |
Organism |
---|
2.5.1.15 |
drug development |
targeting approach of the dihydropteroate synthase enzyme, which serves as the site of action for the sulfonamide class of antimicrobial agents, exploring a class of transition state mimics, that can bind to the pterin, phosphate and para-amino binding sites, as trivalent inhibitors, binding modeling, overview |
Bacillus anthracis |
Inhibitors
EC Number |
Inhibitors |
Comment |
Organism |
Structure |
---|
2.5.1.15 |
additional information |
compounds 4-([(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-(2-phosphono-ethyl)-amino]-methyl)-benzoic acid and 4-([(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-(3-phosphono-propyl)-amino]-methyl)-benzoic acid are inactive in inhibition of DHPS, sp2 centers are required at the pterin 5-6 positions for inhibition |
Bacillus anthracis |
|
2.5.1.15 |
potassium 4-([(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-(2-phosphonoethyl)-amino]-methyl)-benzoate |
the oxidized analogue shows significant DHPS inhibition and significant antimicrobial activity |
Bacillus anthracis |
|
2.5.1.15 |
potassium 4-([(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-(3-phosphonopropyl)-amino]-methyl)-benzoate |
the oxidized analogue shows significant DHPS inhibition and significant antimicrobial activity |
Bacillus anthracis |
|
2.5.1.15 |
Sulfonamides |
act as competitive inhibitors with respect to the 4-amino benzoic acid substrate within the DHPS enzyme active site. The 4-amino benzoic acid/sulfonamide binding site is formed close to the protein surface by flexible protein loops facilitating rapid development of sulfonamide resistance. Study of inhibitors designed to target the conserved central pterin binding site within DHPS, molecular dynamics simulation and molecular modeling, overview. Design and synthesis of transition state analogues with ability to mimic the intermediate transient carbocation by the incorporation of a basic amine at the 6-position of the pterin ring |
Bacillus anthracis |
|
Metals/Ions
EC Number |
Metals/Ions |
Comment |
Organism |
Structure |
---|
2.5.1.15 |
Mg2+ |
required |
Bacillus anthracis |
|
Natural Substrates/ Products (Substrates)
EC Number |
Natural Substrates |
Organism |
Comment (Nat. Sub.) |
Natural Products |
Comment (Nat. Pro.) |
Rev. |
Reac. |
---|
2.5.1.15 |
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate |
Bacillus anthracis |
- |
diphosphate + 7,8-dihydropteroate |
- |
? |
|
Organism
EC Number |
Organism |
UniProt |
Comment |
Textmining |
---|
2.5.1.15 |
Bacillus anthracis |
- |
- |
- |
Reaction
EC Number |
Reaction |
Comment |
Organism |
Reaction ID |
---|
2.5.1.15 |
(7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate = diphosphate + 7,8-dihydropteroate |
the reaction catalyzed by DHPS involves a nucleophilic attack by the amino nitrogen of 4-aminobenzoate on the exocyclic methyl carbon of DHPP. This results in the formation of the N-C bond and the elimination of the pyrophosphate moiety as a leaving group. A partial carbocation intermediate is believed to form at the extra-cyclic methylene in the transition state, which is stabilized by delocalization of the charge in the adjacent double bond of the pterin ring. Evidence supporting transient carbocation intermediate is shown by the inability of the oxidized form of DHPP (pterin-6-hydroxymethyl pyrophosphate) to act as a DHPS substrate |
Bacillus anthracis |
|
Substrates and Products (Substrate)
EC Number |
Substrates |
Comment Substrates |
Organism |
Products |
Comment (Products) |
Rev. |
Reac. |
---|
2.5.1.15 |
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate |
- |
Bacillus anthracis |
diphosphate + 7,8-dihydropteroate |
- |
? |
|
Synonyms
EC Number |
Synonyms |
Comment |
Organism |
---|
2.5.1.15 |
DHPS |
- |
Bacillus anthracis |
Temperature Optimum [°C]
EC Number |
Temperature Optimum [°C] |
Temperature Optimum Maximum [°C] |
Comment |
Organism |
---|
2.5.1.15 |
37 |
- |
assay at |
Bacillus anthracis |
pH Optimum
EC Number |
pH Optimum Minimum |
pH Optimum Maximum |
Comment |
Organism |
---|
2.5.1.15 |
7.6 |
- |
assay at |
Bacillus anthracis |
General Information
EC Number |
General Information |
Comment |
Organism |
---|
2.5.1.15 |
additional information |
the 4-amino benzoic acid/sulfonamide binding site is formed close to the protein surface by flexible protein loops |
Bacillus anthracis |