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Information on EC 6.3.2.12 - dihydrofolate synthase and Organism(s) Mycobacterium tuberculosis and UniProt Accession I6Y0R5
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6.3.2.12 dihydrofolate synthaseIUBMB Comments
In some bacteria, a single protein catalyses both this activity and that of EC 6.3.2.17, tetrahydrofolate synthase , the combined activity of which leads to the formation of the coenzyme polyglutamated tetrahydropteroate (H4PteGlun), i.e. various tetrahydrofolates. In contrast, the activities are located on separate proteins in most eukaryotes studied to date . This enzyme is reponsible for attaching the first glutamate residue to dihydropteroate to form dihydrofolate and is present only in those organisms that have the ability to synthesize tetrahydrofolate de novo, e.g. plants, most bacteria, fungi and protozoa .
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Word Map
- 6.3.2.12
- tetrahydrofolate
-
polyglutamylated
- analysis
- medicine
- drug development
- biotechnology
The taxonomic range for the selected organisms is: Mycobacterium tuberculosis
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
dhfs, dihydrofolate synthetase, dihydrofolate synthase, dihydrofolate synthetase-folylpolyglutamate synthetase, h2-folate synthetase, pfdhfs-fpgs, folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
7,8-Dihydrofolate synthetase
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7,8-Dihydropteroate:L-glutamate ligase (ADP)
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Dihydrofolate synthetase
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dihydropteroate:L-glutamate ligase (ADP-forming)
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FHFS
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FHFS/FPGS
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Folylpoly-(gamma-glutamate) synthetase-dihydrofolate synthase
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Folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase
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Synthetase, dihydrofolate
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
carboxylic acid amide formation
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carboxamide formation
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SYSTEMATIC NAME
IUBMB Comments
7,8-dihydropteroate:L-glutamate ligase (ADP-forming)
In some bacteria, a single protein catalyses both this activity and that of EC 6.3.2.17, tetrahydrofolate synthase [2], the combined activity of which leads to the formation of the coenzyme polyglutamated tetrahydropteroate (H4PteGlun), i.e. various tetrahydrofolates. In contrast, the activities are located on separate proteins in most eukaryotes studied to date [3]. This enzyme is reponsible for attaching the first glutamate residue to dihydropteroate to form dihydrofolate and is present only in those organisms that have the ability to synthesize tetrahydrofolate de novo, e.g. plants, most bacteria, fungi and protozoa [3].
CAS REGISTRY NUMBER
COMMENTARY
37318-62-0
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + 7,8-dihydropteroate + L-glutamate
ADP + phosphate + 7,8-dihydropteroylglutamate
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + 7,8-dihydropteroate + L-glutamate
ADP + phosphate + 7,8-dihydropteroylglutamate
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
additional information
malfunction
in Mycobacterium tuberculosis clinical isolates missense mutations within the coding sequence of the folC gene cause alterations within the 7,8-dihydropteroate binding pocket resulting in 4-aminosalicylic acid resistance. The alterations in the substrate binding pocket result in reduced dihydrofolate synthase activity and abolish the bioactivation of hydroxydihydropteroate to hydroxydihydrofolate. Introduction of a wild-type copy of folC fully restores PAS susceptibility in folC mutant strains
malfunction
mutations at residues E40, I43, and S150 can alter the structure of FolC's putative binding pocket, causing the PAS derivative to bind outside of the then deformed pocket
additional information
homology modeling of wild-type and mutated FolC, docking study using hydroxydihydropteroate, the metabolic derivative of para-aminosalicylic acid (PAS), to evaluate the binding affinity changes. Para-aminosalicylic acid (PAS) is an example of an anti-tuberculosis agent that blocks the folate pathway in Mycobacterium tuberculosis
additional information
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homology modeling of wild-type and mutated FolC, docking study using hydroxydihydropteroate, the metabolic derivative of para-aminosalicylic acid (PAS), to evaluate the binding affinity changes. Para-aminosalicylic acid (PAS) is an example of an anti-tuberculosis agent that blocks the folate pathway in Mycobacterium tuberculosis
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A132E
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
A171A
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
A420V
naturally occuring mutation in enzyme FolC in clinical isolates of both drug-resistant and drug-susceptible Mycobacterium tuberculosis
A457V
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
D111A
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
D135A
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
D324G
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
D384A
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
E153A
E153G
E40G
E40K
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
E434Q
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
F461F
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
G112S
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
G284G
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
G422G
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
I43A
I43F
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
I43S
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
I43T
I43V
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
P21L
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
P356L
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
P8P
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
P9P
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
R268R
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
R410W
R49G
naturally occuring mutation in enzyme FolC in clinical isolates of drug-susceptible Mycobacterium tuberculosis
S150G
S335I
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
V256A
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
additional information
E153A
naturally occuring conserved mutation, the mutant shows reduced enzyme activity
E153A
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
E153G
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
E40G
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
I43A
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
I43T
naturally occuring mutation, the mutant shows reduced enzyme activity
I43T
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
R410W
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
S150G
naturally occuring mutation in enzyme FolC in clinical isolates of drug-resistant Mycobacterium tuberculosis
additional information
4-aminosalicylic acid susceptibility of mutant strains, overview
additional information
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4-aminosalicylic acid susceptibility of mutant strains, overview
additional information
phylogenetic and structural significance of mutations in gene folC in drug-resistant Mycobacterium tuberculosis, overview. Genotyping of 254 clinical isolates. Enzyme residues E40, I43, S150, and E153 are the most frequently affected amino acid residues in resistant isolates with mutant enzymes, distribution of mutations in the genome-based phylogenetic tree, overview. Mutations at E40, I43, and S150 can alter the structure of the FolC putative binding pocket, causing the PAS derivative to bind outside of the then deformed pocket
additional information
-
phylogenetic and structural significance of mutations in gene folC in drug-resistant Mycobacterium tuberculosis, overview. Genotyping of 254 clinical isolates. Enzyme residues E40, I43, S150, and E153 are the most frequently affected amino acid residues in resistant isolates with mutant enzymes, distribution of mutations in the genome-based phylogenetic tree, overview. Mutations at E40, I43, and S150 can alter the structure of the FolC putative binding pocket, causing the PAS derivative to bind outside of the then deformed pocket
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant wild-type and mutant enzymes with maltose binding protein-tag linked by a factor Xa cleavage site from Escherichia coli strain BL21(DE3) by amylose affinity chromatography, tag cleavage by faxtor Xa, dialysis, and anion exchange chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene folC, cloning and expression of wild-type and mutant enzymes with maltose binding protein-tag linked by a factor Xa cleavage site in Escherichia coli strain BL21(DE3)
gene folC, DNA and amino acid sequence determination and analysis, genetic structure and sequence comparisons, genotyping of 254 clinical isolates, phylogenetic analysis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Zhao, F.; Wang, X.D.; Erber, L.N.; Luo, M.; Guo, A.Z.; Yang, S.S.; Gu, J.; Turman, B.J.; Gao, Y.R.; Li, D.F.; Cui, Z.Q.; Zhang, Z.P.; Bi, L.J.; Baughn, A.D.; Zhang, X.E.; Deng, J.Y.
Binding pocket alterations in dihydrofolate synthase confer resistance to para-aminosalicylic acid in clinical isolates of Mycobacterium tuberculosis
Antimicrob. Agents Chemother.
58
1479-1487
2014
Mycobacterium tuberculosis (I6Y0R5), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (I6Y0R5), Mycobacterium tuberculosis variant bovis (A0A0H3M8P3), Mycobacterium tuberculosis variant bovis
Cheng, V.W.; Leung, K.S.; Kwok, J.S.; Leung, R.K.; Yang, K.Y.; Chan, R.C.; Kam, K.M.; Tsui, S.K.
Phylogenetic and structural significance of dihydrofolate synthase (folC) mutations in drug-resistant Mycobacterium tuberculosis
Microb. Drug Resist.
22
545-551
2016
Mycobacterium tuberculosis (I6Y0R5), Mycobacterium tuberculosis, Mycobacterium tuberculosis ATCC 25618 / H37Rv (I6Y0R5)
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