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2.5.1.15: dihydropteroate synthase

This is an abbreviated version!
For detailed information about dihydropteroate synthase, go to the full flat file.

Word Map on EC 2.5.1.15

Reaction

(7,8-dihydropterin-6-yl)methyl diphosphate
+
4-Aminobenzoate
=
diphosphate
 +
7,8-dihydropteroate

Synonyms

6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase-dihydropteroate synthase, 6-hydroxymethyl-7,8-dihydropterin-pyrophosphokinase-dihydropteroate synthase, 6-hydroxymethyl-7,8-dihydropteroate synthase, 7,8-dihydropteroate synthase, 7,8-dihydropteroate synthetase, 7,8-dihydropteroic acid synthetase, BCG3672c, DHP synthase, DHPS, DHPS-HPPK, DHPS/DHPR, dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase, dihydropteroate diphosphorylase, dihydropteroate synthase, dihydropteroate synthase/hydroxymethyldihydropterin pyrophosphokinase, dihydropteroate synthetase, dihydropteroic synthetase, FolP, folP1, folP2, HPPK-DHPS, hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase, MbDHPS, MtDHPS, Mycobacterium tuberculosis dihydropteroate synthase, PfDHPS, pfPPK-DHPS, PPPK-DHPS, putative dihydropteroate synthase ortholog, pvdhps, PvHPPK-DHPS, PVX_123230, Rv1207, synthase, dihydropteroate

ECTree

     2 Transferases
         2.5 Transferring alkyl or aryl groups, other than methyl groups
             2.5.1 Transferring alkyl or aryl groups, other than methyl groups (only sub-subclass identified to date)
                2.5.1.15 dihydropteroate synthase

Crystallization

Crystallization on EC 2.5.1.15 - dihydropteroate synthase

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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant apo-enzyme and enzyme in complex with inhibitor sulphadoxine or product 7,8-dihydropteroate, sitting drop vapor diffusion method, mixing of 0.001 ml of protein solution, containing 7.5 mg/ml protein in 50 mM Tris-HCl, 250 mM NaCl pH 7.5, with 0.001 ml of reservoir solution, containing 0.1 M Tris-HCl, pH 8, 10% PEG 8000, 0.3 M MgCl2, 4°C, X-ray diffraction structure determinationation and analysis at 1.95-2.35 A resolution, molecular replacement and modeling
in complex with inhibitors
apo-enzyme, and enzyme in complex with HPPK substrate 6-hydroxymethyl-7,8-dihydropterin or inhibitor 2-(7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydorpyrimido[4,5-c]pyridazin-3-yl)propanoic acid, X-ray diffraction structure determination and analysis at 2.2-2.3 A resolution
-
PDB: 2VP8, conforms classical triosephosphate isomerase (TIM) barrel arrangement, 6-hydroxymethyl-7,8-dihydropterin-diphosphate-binding pocket occupied by the histidine 220 side chain compared to leucine 180 in the functional ortholog MtDHPS (PDB: 1EYE), crystals: space group P3(1)21, 2 molecules per asymmetric unit, noncrystallographic dimer in the crystal structure, unit cell parameters: a, b: 80.73, c: 215.94, hanging drop vapour method: 25% ethylene glycole + protein solution (16 mg/ml), 2 days, 18°C
structure-based molecular modelling of the missing loop 2 (PDB: 1EYE) using Escherichia coli DHPS (PDB: 1AJZ) for further docking approaches, (i) extraction and docking of pterin monophosphate (PtP), KD(PtP): 0.5 microM, (ii) ternary complex of dapson docked with enzyme-PtP complex, KD(dapson): 0.2 microM, contacts with residues S53, R54, P55, F182, K213, (iii) ternary complex of pteroic acid (PTA) docked with enzyme-PtP complex, contacts with pterin- and 4-aminobenzoate-binding regions, (iv) inhibitor complex with dipeptide Trp-Lys (WK), contacts with residues E51, S53, D21, D86, K213, R253, and four water molecules, KD(WK): 0.23 nM
HPPK-DHPS from wild type and sulfa-resistant parasites, in complex with pteroate, sulfathiazole-dihydropteroate, and sulfadoxine-dihydropteroate, microbatch method, using 0.1 mM bicine pH 9.0, 0.5-0.6 M calcium acetate-Ca(OAc)2, 20% (w/v) PEG 4000 at 25°C
more putative structural model of five mutations in DHPS to explain sulfadoxine resistance, structural model based on crystal structures of Saccharomyces cerevisiae (PPPK-DHPS), Mycobacterium tuberculosis (DHPS), Bacillus anthracis (DHPS), and Escherichia coli (PPPK)
structures of the enzyme from wild-type and sulfa-resistant mutants, both as apoenzyme and as complexes with pteroate and sulfa derivatives. Pteroate stays in active sites without steric constraint. In contrast, parts of the sulfa compounds situated outside of the substrate envelope are in the vicinity of the resistance mutations. Steric conflict between compound and mutant residue along with increased flexibility of loop D2 in the mutants can account for the reduced compound binding affinity to the mutants
hanging-drop vapor-diffusion method at 20°C, crystal structure of the enzyme in complex with four substrates/analogs
in complex with 6-hydroxymethylpterin diphosphate, pterin, the ATP analog AMPCPP, and 4-aminobenzoate, at 20°C, hanging drop vapor diffusion method, using 20% (w/v) PEG 3350, 0.2 M potassium citrate tribasic monohydrate
structure of HPPk-DHPS in complex with four substrates/analogs.
a complex of the purified bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/dihydropteroate synthase with a pterin monophosphate substrate analogue, structure solved by molecular replacement and refined to 2.3 A resolution
-
recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
apoenzyme (PDB: 2VEF), complex with 6-hydroxymethyl-7,8-dihydropterin monophosphate (DHPP) (PDB: 2VEG), TIM alpha/beta barrel fold with highly conserved 6-hydroxymethyl-7,8-dihydropterin diphosphate-binding pocket, crystals: space group P2(1)2(1)2(1), unit cell parameters: a: 45, b: 90, c: 137, loop 1 and 2 highly flexible, dimer of two identical monomers in the asymmetric unit, in complex with DHPP only one monomer of the dimer has substrate bound wide-scale rearrangement of active site upon 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPPP) binding mediated by diphosphate moiety, hanging-drop method: 2 microlitre protein solution (13 mg/ml) + 2 microl precipitant (0.2 M ammonium iodide, 20% (w/v) poly(ethylene glycol) 3350) +/-2.5 mM DHPPP (hydrolysis to DHPP during crystallization), 7-14 days, molecular replacement-based structure determination
an inhibitor is soaked into the apo crystals of the enzyme and the structure of the complex is determined to 2.1 A resolution. Thed inhibitor occupies both the pterin and 4-aminobenzoate binding pocket of the enzyme
A0A384KP04
apo-structure and structure of the complex with pteroate, analysis, overview
-