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Literature summary for 2.5.1.15 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.
    View publication on PubMedView publication on EuropePMC
Search for more literature for 2.5.1.15

Application

Application Comment Organism
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

Inhibitors Comment Organism Structure
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
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
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
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

Metals/Ions Comment Organism Structure
Mg2+ required Bacillus anthracis

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate Bacillus anthracis
-
 diphosphate + 7,8-dihydropteroate
-
 ?

Organism

Organism UniProt Comment Textmining
Bacillus anthracis
-
-
-

Reaction

Reaction Comment Organism Reaction ID
(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
a

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
-
 Bacillus anthracis diphosphate + 7,8-dihydropteroate
-
 ?

Synonyms

Synonyms Comment Organism
DHPS
-
 Bacillus anthracis

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
 assay at Bacillus anthracis

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.6
-
 assay at Bacillus anthracis

General Information

General Information Comment Organism
additional information the 4-amino benzoic acid/sulfonamide binding site is formed close to the protein surface by flexible protein loops Bacillus anthracis