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Literature summary extracted from

  • Yogavel, M.; Nettleship, J.E.; Sharma, A.; Harlos, K.; Jamwal, A.; Chaturvedi, R.; Sharma, M.; Jain, V.; Chhibber-Goel, J.; Sharma, A.
    Structure of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase-dihydropteroate synthase from Plasmodium vivax sheds light on drug resistance (2018), J. Biol. Chem., 293, 14962-14972 .
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.5.1.15
-
 Plasmodium vivax
2.5.1.15 expressed in Escherichia coli Rosetta pLysS cells Plasmodium vivax

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
2.5.1.15 hanging-drop vapor-diffusion method at 20°C, crystal structure of the enzyme in complex with four substrates/analogs Plasmodium vivax
2.5.1.15 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 Plasmodium vivax
2.5.1.15 structure of HPPk-DHPS in complex with four substrates/analogs. Plasmodium vivax
2.7.6.3 crystal structure of HPPk-DHPS in complex with four substrates/analogs. Sulfadoxine's effect on HPPK-DHPS is due to 4-amino benzoic acid mimicry, and resistance mutations surrounding the 4-amino benzoic acid-binding site are present within loop 2 (S382/F/A/Cand A383G), loop 5 (Lys512), loop 6 (Ala553), and 7' helix in loop7 (Val585) Plasmodium vivax
2.7.6.3 structure of HPPk-DHPS in complex with four substrates/analogs. Plasmodium vivax

Protein Variants

EC Number Protein Variants Comment Organism
2.5.1.15 A383G drug resistance mutation. Resistance mutations subtly alters the intricate enzyme/4-aminobenzoate/sulfadoxine interactions such that DHPS affinity for 4-aminobenzoate is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 A383G the mutation confers resistance to sulfadoxine Plasmodium vivax
2.5.1.15 A383G dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 A553G drug resistance mutation. Resistance mutations subtly alters the intricate enzyme/4-aminobenzoate/sulfadoxine interactions such that DHPS affinity for 4-aminobenzoate is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 A553G the mutation confers resistance to sulfadoxine Plasmodium vivax
2.5.1.15 A553G dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 K512D drug resistance mutation. Resistance mutations subtly alters the intricate enzyme/4-aminobenzoate/sulfadoxine interactions such that DHPS affinity for 4-aminobenzoate is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 K512D the mutation confers resistance to sulfadoxine Plasmodium vivax
2.5.1.15 K512D dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 K512E drug resistance mutation. Resistance mutations subtly alters the intricate enzyme/4-aminobenzoate/sulfadoxine interactions such that DHPS affinity for 4-aminobenzoate is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 K512E the mutation confers resistance to sulfadoxine Plasmodium vivax
2.5.1.15 K512E dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 S382A drug resistance mutation. Resistance mutations subtly alters the intricate enzyme/4-aminobenzoate/sulfadoxine interactions such that DHPS affinity for 4-aminobenzoate is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 S382A the mutation confers resistance to sulfadoxine Plasmodium vivax
2.5.1.15 S382A dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 V585A drug resistance mutation. Resistance mutations subtly alters the intricate enzyme/4-aminobenzoate/sulfadoxine interactions such that DHPS affinity for 4-aminobenzoate is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.5.1.15 V585A the mutation confers resistance to sulfadoxine Plasmodium vivax
2.5.1.15 V585A dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 A383G dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 A383G natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 A553G dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 A553G natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 K512D dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 K512D natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 K512E dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 K512E natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 S382A dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 S382A natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 V585A dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax
2.7.6.3 V585A natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially Plasmodium vivax

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.5.1.15 sulfadoxine
-
 Plasmodium vivax
2.7.6.3 sulfadoxine
-
 Plasmodium vivax

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.5.1.15 (7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate Plasmodium vivax
-
 diphosphate + 7,8-dihydropteroate
-
 ?
2.5.1.15 (7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate Plasmodium vivax Salvador 1
-
 diphosphate + 7,8-dihydropteroate
-
 ?
2.5.1.15 (7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate Plasmodium vivax Salvador I
-
 diphosphate + 7,8-dihydropteroate
-
 ?
2.5.1.15 6-hydroxymethyl-7,8-dihydropterin diphosphate + 4-aminobenzoate Plasmodium vivax
-
 diphosphate + 7,8-dihydropteroate
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.5.1.15 Plasmodium vivax
-
-
-
2.5.1.15 Plasmodium vivax A5JZS1
-
-
2.5.1.15 Plasmodium vivax A5JZS1 bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase, cf. EC 2.7.6.3
-
2.5.1.15 Plasmodium vivax Salvador I A5JZS1
-
-
2.5.1.15 Plasmodium vivax Salvador I A5JZS1 bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase, cf. EC 2.7.6.3
-
2.7.6.3 Plasmodium vivax A5JZS1 bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase, cf. EC 2.5.1.15
-
2.7.6.3 Plasmodium vivax A5JZS1 cf. EC 2.5.1.15
-
2.7.6.3 Plasmodium vivax Salvador 1 A5JZS1 cf. EC 2.5.1.15
-
2.7.6.3 Plasmodium vivax Salvador I A5JZS1 bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase, cf. EC 2.5.1.15
-

Purification (Commentary)

EC Number Purification (Comment) Organism
2.5.1.15 Ni-NTA agarose column chromatography, Q-Sepharose column chromatography, phenyl FF 16/10 column chromatography, and Superdex S-200 gel filtration Plasmodium vivax

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.5.1.15 (7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate
-
 Plasmodium vivax diphosphate + 7,8-dihydropteroate
-
 ?
2.5.1.15 (7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate
-
 Plasmodium vivax Salvador 1 diphosphate + 7,8-dihydropteroate
-
 ?
2.5.1.15 (7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate
-
 Plasmodium vivax Salvador I diphosphate + 7,8-dihydropteroate
-
 ?
2.5.1.15 6-hydroxymethyl-7,8-dihydropterin diphosphate + 4-aminobenzoate
-
 Plasmodium vivax diphosphate + 7,8-dihydropteroate
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.5.1.15 6-hydroxymethyl-7,8-dihydropterin-pyrophosphokinase-dihydropteroate synthase bifunctional enzyme Plasmodium vivax
2.5.1.15 HPPK-DHPS
-
 Plasmodium vivax
2.5.1.15 HPPK-DHPS bifunctional enzyme with 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase and dihydropteroate synthase activities Plasmodium vivax
2.5.1.15 PvHPPK-DHPS
-
 Plasmodium vivax
2.5.1.15 PVX_123230
-
 Plasmodium vivax
2.7.6.3 HPPK-DHPS cf. EC 2.5.1.15 Plasmodium vivax
2.7.6.3 PVX_123230
-
 Plasmodium vivax

General Information

EC Number General Information Comment Organism
2.5.1.15 drug target the enzyme is target of drugs like sulfadoxine (SDX). The SDX effectiveness as an antimalarial drug is increasingly diminished by the rise and spread of drug-resistant mutations Plasmodium vivax
2.5.1.15 metabolism reactions in the folate biosynthetic pathway Plasmodium vivax
2.7.6.3 physiological function gene encodes a protein fused of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) domains that catalyze sequential reactions in the folate biosynthetic pathway Plasmodium vivax