2.5.1.15: dihydropteroate synthase

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

Reaction

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

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Results	in table
4	Activating Compound
36488	AA Sequence
12	Application
1	CAS Registry Number
32	Cloned(Commentary)
2	Cofactor
18	Crystallization (Commentary)
25	General Information
18	IC50 Value
282	Inhibitors
16	kcat/KM [mM/s]
138	Ki Value [mM]
65	KM Value [mM]
5	Localization
11	Metals/Ions
24	Molecular Weight [Da]
61	Natural Substrates/ Products (Substrates)
114	Organism
6	Pathway
162	PDB ID
14	pH Optimum
3	pH Range
1	pH Stability
1	pI Value
93	Protein Variants
30	Purification (Commentary)
4	Reaction
7	Reaction Type
99	Reference
11	Source Tissue
25	Specific Activity [micromol/min/mg]
8	Storage Stability
109	Substrates and Products (Substrate)
14	Subunits
144	Synonyms
1	Systematic Name
11	Temperature Optimum [°C]
1	Temperature Range [°C]
4	Temperature Stability [°C]
35	Turnover Number [1/s]

General Information

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General Information on EC 2.5.1.15 - dihydropteroate synthase

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GENERAL INFORMATION

ORGANISM

UNIPROT

COMMENTARY

LITERATURE

drug target

8 entries

evolution

2 entries

malfunction

Plasmodium falciparum

-

prevalence and frequency of the dihydropteroate synthetase mutations associated with sulfadoxine-pyrimethamine resistance in southern Mozambique are examined between 1999 and 2004. The dihydropteroate synthetase double mutation frequency peaks in 2001 but declines to baseline levels by 2004. Parasites with both dihydrofolate reductase triple and dihydropteroate synthetase double mutations increase in 2001 but decrease by 2004. The peaking of sulfadoxine-pyrimethamine resistance markers in 2001 coincides with a sulfadoxine-pyrimethamine-resistant malaria epidemic in neighboring KwaZulu-Natal, South Africa. The decline in dihydropteroate synthetase (but not dihydrofolate reductase) mutations correspond with replacement of sulfadoxine-pyrimethamine with artemether-lumefantrine as malaria treatment policy in KwaZulu-Natal

684380

metabolism

9 entries

physiological function

2 entries

additional information

4 entries

drug target

Staphylococcus aureus

O05701

dihydropteroate synthase is the target of the sulfonamide class of drugs

759244

drug target

Helicobacter pylori

G2MFH6

drug-resistant strains of Helicobacter pylori and multitudinous drug reactions are obstacles in the treatment of Helicobacter pylori infections a reliable tertiary structure of dihydropteroate synthase in complex with inhibitor 4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzene-1-sulfonamide is constructed by Modeler 9v19. DrugBank compounds of DHPS, published inhibitors, and co-crystal ligand (4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzene-1-sulfonamide) are docked against dihydropteroate synthase. The best docked compounds are screened against 28.5 million compounds result 1186 structural analogs. Virtual screening workflow and quantum polarized ligand dockings of these compounds against dihydropteroate synthase result three leads that show better XP Gscores, ADME properties, and binding-free energies compared to 4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzene-1-sulfonamide, DrugBank compounds, and published inhibitors. The proposed leads are also validated by receiver operative characteristic (ROC) curve metrics in the presence of thousand decoys and the best docked existing compounds against DHPS. Long-range molecular dynamics (MD) simulations for 100 ns are executed after post-docking evaluations. Trajectory analysis shows that inter-molecular interactions of the lead-dihydropteroate synthase docking complex are stable throughout the entire runtime of MD simulations than 6MB-DHPS complex and Eliglustat-DHPS complex. The study outcomes show good competitive binding propensity and active-tunneling of leads over the existing inhibitors, thereby these leads could be ideal inhibitors against dihydropteroate synthase to target Helicobacter pylori

759674

drug target

Yersinia pestis

A0A384KP04

target for anti-malarial and anti-bacterial drugs

759889

drug target

Plasmodium vivax

-

the enzyme is a sulfa drug target in malaria treatment

758651

drug target

Plasmodium vivax

A5JZS1

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

759490

drug target

Plasmodium vivax Salvador 1

-

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

-

drug target

Plasmodium vivax Salvador I

-

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

-

drug target

Helicobacter pylori SNT49

-

drug-resistant strains of Helicobacter pylori and multitudinous drug reactions are obstacles in the treatment of Helicobacter pylori infections a reliable tertiary structure of dihydropteroate synthase in complex with inhibitor 4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzene-1-sulfonamide is constructed by Modeler 9v19. DrugBank compounds of DHPS, published inhibitors, and co-crystal ligand (4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzene-1-sulfonamide) are docked against dihydropteroate synthase. The best docked compounds are screened against 28.5 million compounds result 1186 structural analogs. Virtual screening workflow and quantum polarized ligand dockings of these compounds against dihydropteroate synthase result three leads that show better XP Gscores, ADME properties, and binding-free energies compared to 4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzene-1-sulfonamide, DrugBank compounds, and published inhibitors. The proposed leads are also validated by receiver operative characteristic (ROC) curve metrics in the presence of thousand decoys and the best docked existing compounds against DHPS. Long-range molecular dynamics (MD) simulations for 100 ns are executed after post-docking evaluations. Trajectory analysis shows that inter-molecular interactions of the lead-dihydropteroate synthase docking complex are stable throughout the entire runtime of MD simulations than 6MB-DHPS complex and Eliglustat-DHPS complex. The study outcomes show good competitive binding propensity and active-tunneling of leads over the existing inhibitors, thereby these leads could be ideal inhibitors against dihydropteroate synthase to target Helicobacter pylori

-

evolution

Yersinia pestis

-

dihydropteroate synthase is a key enzyme in the folate pathway of bacteria and primitive eukaryotes

723771

evolution

Bacillus anthracis

-

dihydropteroate synthase is a key enzyme in the folate pathway of bacteria and primitive eukaryotes

723771

metabolism

Yersinia pestis

-

dihydropteroate synthase is a key enzyme in the folate pathway of bacteria and primitive eukaryotes

723771

metabolism

Bacillus anthracis

-

dihydropteroate synthase is a key enzyme in the folate pathway of bacteria and primitive eukaryotes

723771

metabolism

Burkholderia cenocepacia

A0A0H2XP43

the enzyme supports the biosynthesis of folate, a key metabolite required to support the synthesis of DNA, and proteins

721948

metabolism

Plasmodium vivax

A5JZS1

reactions in the folate biosynthetic pathway

759490

metabolism

Yersinia pestis

A0A384KP04

the enzyme catalyzes the condensation between (7,8-dihydropterin-6-yl)methyl diphosphate and 4-aminobenzoate to produce 7,8-dihydropteroate, a precursor of tetrahydrofolate. It plays a great role in folate synthesis pathway essential for amino acids biosynthesis

759674

metabolism

Helicobacter pylori

G2MFH6

the enzyme catalyzes the condensation between (7,8-dihydropterin-6-yl)methyl diphosphate and 4-aminobenzoate to produce 7,8-dihydropteroate, a precursor of tetrahydrofolate. It plays a great role in folate synthesis pathway essential for amino acids biosynthesis

759674

metabolism

Plasmodium vivax Salvador 1

-

reactions in the folate biosynthetic pathway

-

metabolism

Plasmodium vivax Salvador I

-

reactions in the folate biosynthetic pathway

-

metabolism

Helicobacter pylori SNT49

-

the enzyme catalyzes the condensation between (7,8-dihydropterin-6-yl)methyl diphosphate and 4-aminobenzoate to produce 7,8-dihydropteroate, a precursor of tetrahydrofolate. It plays a great role in folate synthesis pathway essential for amino acids biosynthesis

-

physiological function

Pneumocystis jirovecii

-

mutation at DHPS locus amongst Pneumocystis jiroveci isolates obtained at a tertiary care hospital in north India are investigated. Using microscopic examination Pneumocystis jiroveci is detected in four cases and major surface glycoprotein gene is amplified in five cases. Further, amplification of DHPS gene is successful in four of the five cases positive by major surface glycoprotein gene PCR. No point mutation is observed and all four isolates presented wild-type sequences at DHPS gene by RFLP analysis

703994

physiological function

Pneumocystis jirovecii

-

the prevalence of DHPS mutations in Pneumocystis jirovecii strains isolated from South African Pneumocystis jirovecii pneumonia patients are examined. Mutations resulting in amino-acid substitutions Thr55Ala and/or Pro57Ser are detected in Pneumocystis jirovecii from 85/151 (56%) patients. The high frequency of PCP episodes with Pneumocystis jirovecii harbouring DHPS mutations in South Africa indicates that populations of this fungus are evolving under considerable selective pressure exerted by sulfa-containing antibiotics

702229

additional information

Burkholderia cenocepacia

A0A0H2XP43

analysis of DHPS active site and interactions with the enzyme product 7,8-dihydropteroate, overview. DHPS shows plasticity near the substrate-binding pocket and a range of loop conformations that contribute to the architecture of the DHPS active site

721948

additional information

Burkholderia cenocepacia

-

analysis of DHPS active site and interactions with the enzyme product 7,8-dihydropteroate, overview. DHPS shows plasticity near the substrate-binding pocket and a range of loop conformations that contribute to the architecture of the DHPS active site

721948

additional information

Bacillus anthracis

-

the 4-amino benzoic acid/sulfonamide binding site is formed close to the protein surface by flexible protein loops

721829

additional information

Francisella tularensis

-

the enzyme is bifunctional exhibiting 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, HPPK, EC 2.7.6.3, and dihydropteroate synthase, DHPS, activities, that catalyze sequential metabolic reactions in the folate biosynthetic pathway of bacteria and lower eukaryotes, structural organization between FtHPPK and FtDHPS which are tethered together by a short linker, overview. Each active site binds substrate in the same manner observed in the monofunctional forms. Structures of the active site loops in the DHPS module

723522