UniProtKB - I6Y0R5 (FOLC_MYCTU)
Protein
Dihydrofolate synthase/folylpolyglutamate synthase
Gene
folC
Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Status
Functioni
Catalyzes the addition of a glutamate residue to dihydropteroate (7,8-dihydropteroate or H2Pte) to form dihydrofolate (7,8-dihydrofolate monoglutamate or H2Pte-Glu) (PubMed:23118010). Also catalyzes successive additions of L-glutamate to tetrahydrofolate, leading to folylpolyglutamate derivatives (By similarity).By similarity1 Publication
Is involved in the bioactivation of the antituberculous drug para-aminosalicylic acid (PAS). Is able to use hydroxy-dihydropteroate (H2PtePAS) as substrate, which is the product formed by the action of DHPS (FolP1) on PAS, leading to hydroxy-dihydrofolate (H2PtePAS-Glu). This compound inhibits dihydrofolate reductase DHFR (DfrA), the next enzyme in the folate pathway, and thus disrupts the folate-dependent metabolic pathways.1 Publication1 Publication
Miscellaneous
Mutations within this gene in the H2Pte binding pocket are responsible for PAS resistance in M.tuberculosis clinical isolates and laboratory strains. FolC-linked PAS resistance is mediated by altered substrate specificity that results in the failure to generate levels of H2PtePAS-Glu that are necessary to inhibit DHFR (DfrA); therefore, a blockage of PAS bioactivation causes PAS resistance.2 Publications
Catalytic activityi
- EC:6.3.2.122 Publications
- (6S)-5,6,7,8-tetrahydrofolyl-(γ-L-Glu)n + ATP + L-glutamate = (6S)-5,6,7,8-tetrahydrofolyl-(γ-L-Glu)n+1 + ADP + H+ + phosphateBy similarityEC:6.3.2.17By similarity
Cofactori
Mg2+By similarityNote: Binds 2 Mg2+ ions per subunit.1 Publication
: tetrahydrofolate biosynthesis Pathwayi
This protein is involved in step 2 of the subpathway that synthesizes 7,8-dihydrofolate from 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate and 4-aminobenzoate.1 PublicationProteins known to be involved in the 2 steps of the subpathway in this organism are:
- Dihydropteroate synthase (folP1)
- Dihydrofolate synthase/folylpolyglutamate synthase (folC)
View all proteins of this organism that are known to be involved in the subpathway that synthesizes 7,8-dihydrofolate from 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate and 4-aminobenzoate, the pathway tetrahydrofolate biosynthesis and in Cofactor biosynthesis.
Pathwayi: tetrahydrofolylpolyglutamate biosynthesis
This protein is involved in the pathway tetrahydrofolylpolyglutamate biosynthesis, which is part of Cofactor biosynthesis.By similarityView all proteins of this organism that are known to be involved in the pathway tetrahydrofolylpolyglutamate biosynthesis and in Cofactor biosynthesis.
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Metal bindingi | 76 | Magnesium 11 Publication | 1 | |
Metal bindingi | 98 | Magnesium 11 Publication | 1 | |
Metal bindingi | 174 | Magnesium 11 Publication | 1 | |
Metal bindingi | 201 | Magnesium 21 Publication | 1 | |
Metal bindingi | 203 | Magnesium 21 Publication | 1 | |
Binding sitei | 301 | ATPCombined sources1 Publication | 1 | |
Binding sitei | 338 | ATPCombined sources1 Publication | 1 | |
Metal bindingi | 384 | Magnesium 21 Publication | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 74 – 77 | ATPCombined sources1 Publication | 4 | |
Nucleotide bindingi | 351 – 354 | ATPCombined sources1 Publication | 4 |
GO - Molecular functioni
- ATP binding Source: UniProtKB-KW
- dihydrofolate synthase activity Source: GO_Central
- metal ion binding Source: UniProtKB-KW
- tetrahydrofolylpolyglutamate synthase activity Source: GO_Central
GO - Biological processi
- folic acid biosynthetic process Source: UniProtKB-KW
- folic acid-containing compound biosynthetic process Source: GO_Central
- response to antibiotic Source: UniProtKB-KW
- tetrahydrofolate biosynthetic process Source: UniProtKB-UniPathway
Keywordsi
Molecular function | Ligase |
Biological process | Antibiotic resistance, Folate biosynthesis |
Ligand | ATP-binding, Magnesium, Metal-binding, Nucleotide-binding |
Enzyme and pathway databases
BioCyci | MTBH37RV:G185E-6679-MONOMER |
BRENDAi | 6.3.2.12 3445 |
UniPathwayi | UPA00077;UER00157 UPA00850 |
Names & Taxonomyi
Protein namesi | |
Gene namesi | Name:folCImported Ordered Locus Names:Rv2447cImported, LH57_13380Imported |
Organismi | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
Taxonomic identifieri | 83332 [NCBI] |
Taxonomic lineagei | Bacteria › Actinobacteria › Corynebacteriales › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis complex › |
Proteomesi |
|
Organism-specific databases
TubercuListi | Rv2447c |
Pathology & Biotechi
Disruption phenotypei
Cells lacking this gene display impaired growth.1 Publication
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000439040 | 1 – 487 | Dihydrofolate synthase/folylpolyglutamate synthaseAdd BLAST | 487 |
Proteomic databases
PaxDbi | I6Y0R5 |
PRIDEi | I6Y0R5 |
Interactioni
Subunit structurei
Monomer.
1 PublicationProtein-protein interaction databases
STRINGi | 83332.Rv2447c |
Family & Domainsi
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 44 – 46 | 7,8-dihydropteroate bindingBy similarity | 3 | |
Regioni | 150 – 153 | 7,8-dihydropteroate bindingBy similarity | 4 | |
Regioni | 181 – 183 | 7,8-dihydropteroate bindingBy similarity | 3 |
Domaini
Is folded into two distinct domains, an N-terminal ATPase domain and a C-terminal Rossmann-fold domain, which are joined by a flexible linker.1 Publication
Sequence similaritiesi
Belongs to the folylpolyglutamate synthase family.Curated
Phylogenomic databases
eggNOGi | ENOG4105DPM Bacteria COG0285 LUCA |
KOi | K11754 |
OMAi | YFEMGTL |
PhylomeDBi | I6Y0R5 |
Family and domain databases
Gene3Di | 3.40.1190.10, 1 hit 3.90.190.20, 1 hit |
InterProi | View protein in InterPro IPR001645 Folylpolyglutamate_synth IPR018109 Folylpolyglutamate_synth_CS IPR036565 Mur-like_cat_sf IPR004101 Mur_ligase_C IPR036615 Mur_ligase_C_dom_sf IPR013221 Mur_ligase_cen |
PANTHERi | PTHR11136 PTHR11136, 1 hit |
Pfami | View protein in Pfam PF02875 Mur_ligase_C, 1 hit PF08245 Mur_ligase_M, 1 hit |
SUPFAMi | SSF53244 SSF53244, 1 hit SSF53623 SSF53623, 1 hit |
TIGRFAMsi | TIGR01499 folC, 1 hit |
PROSITEi | View protein in PROSITE PS01012 FOLYLPOLYGLU_SYNT_2, 1 hit |
i Sequence
Sequence statusi: Complete.
I6Y0R5-1 [UniParc]FASTAAdd to basket
10 20 30 40 50
MNSTNSGPPD SGSATGVVPT PDEIASLLQV EHLLDQRWPE TRIDPSLTRI
60 70 80 90 100
SALMDLLGSP QRSYPSIHIA GTNGKTSVAR MVDALVTALH RRTGRTTSPH
110 120 130 140 150
LQSPVERISI DGKPISPAQY VATYREIEPL VALIDQQSQA SAGKGGPAMS
160 170 180 190 200
KFEVLTAMAF AAFADAPVDV AVVEVGMGGR WDATNVINAP VAVITPISID
210 220 230 240 250
HVDYLGADIA GIAGEKAGII TRAPDGSPDT VAVIGRQVPK VMEVLLAESV
260 270 280 290 300
RADASVARED SEFAVLRRQI AVGGQVLQLQ GLGGVYSDIY LPLHGEHQAH
310 320 330 340 350
NAVLALASVE AFFGAGAQRQ LDGDAVRAGF AAVTSPGRLE RMRSAPTVFI
360 370 380 390 400
DAAHNPAGAS ALAQTLAHEF DFRFLVGVLS VLGDKDVDGI LAALEPVFDS
410 420 430 440 450
VVVTHNGSPR ALDVEALALA AGERFGPDRV RTAENLRDAI DVATSLVDDA
460 470 480
AADPDVAGDA FSRTGIVITG SVVTAGAART LFGRDPQ
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural varianti | 40 | E → A in a spontaneous PAS-resistant mutant strain; complementation with wild-type folC restores PAS susceptibility, confirmimg that this mutation confers high level resistance to PAS. 1 Publication | 1 | |
Natural varianti | 40 | E → G in clinical isolates: Q274 and 501063; PAS-resistant; complementation with wild-type folC restores PAS susceptibility. 1 Publication | 1 | |
Natural varianti | 43 | I → A in clinical isolate: Q36; PAS-resistant; complementation with wild-type folC restores PAS susceptibility. 1 Publication | 1 | |
Natural varianti | 43 | I → T in clinical isolates: Q449 and 1314; PAS-resistant; complementation with wild-type folC restores PAS susceptibility; 7-fold reduction in DHFS activity relative to wild-type; loss of the ability to glutaminate H2PtePAS. 1 Publication | 1 | |
Natural varianti | 73 | N → S in a spontaneous PAS-resistant mutant strain. 1 Publication | 1 | |
Natural varianti | 150 | S → G in a spontaneous PAS-resistant mutant strain; complementation with wild-type folC restores PAS susceptibility. 1 Publication | 1 | |
Natural varianti | 152 | F → S in a spontaneous PAS-resistant mutant strain; complementation with wild-type folC restores PAS susceptibility. 1 Publication | 1 | |
Natural varianti | 153 | E → A in a spontaneous PAS-resistant mutant strain; complementation with wild-type folC restores PAS susceptibility; 5-fold reduction in DHFS activity relative to wild-type; loss of the ability to glutaminate H2PtePAS. 1 Publication | 1 | |
Natural varianti | 153 | E → G in a spontaneous PAS-resistant mutant strain; complementation with wild-type folC restores PAS susceptibility. 1 Publication | 1 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AL123456 Genomic DNA Translation: CCP45240.1 CP009480 Genomic DNA Translation: AIR15214.1 |
RefSeqi | NP_216963.1, NC_000962.3 WP_003899324.1, NZ_NVQJ01000024.1 |
Genome annotation databases
EnsemblBacteriai | AIR15214; AIR15214; LH57_13380 CCP45240; CCP45240; Rv2447c |
GeneIDi | 885902 |
KEGGi | mtu:Rv2447c mtv:RVBD_2447c |
PATRICi | fig|83332.111.peg.2739 |
Similar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AL123456 Genomic DNA Translation: CCP45240.1 CP009480 Genomic DNA Translation: AIR15214.1 |
RefSeqi | NP_216963.1, NC_000962.3 WP_003899324.1, NZ_NVQJ01000024.1 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2VOR | X-ray | 2.30 | A | 1-487 | [»] | |
2VOS | X-ray | 2.00 | A | 1-487 | [»] | |
SMRi | I6Y0R5 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
STRINGi | 83332.Rv2447c |
Proteomic databases
PaxDbi | I6Y0R5 |
PRIDEi | I6Y0R5 |
Genome annotation databases
EnsemblBacteriai | AIR15214; AIR15214; LH57_13380 CCP45240; CCP45240; Rv2447c |
GeneIDi | 885902 |
KEGGi | mtu:Rv2447c mtv:RVBD_2447c |
PATRICi | fig|83332.111.peg.2739 |
Organism-specific databases
TubercuListi | Rv2447c |
Phylogenomic databases
eggNOGi | ENOG4105DPM Bacteria COG0285 LUCA |
KOi | K11754 |
OMAi | YFEMGTL |
PhylomeDBi | I6Y0R5 |
Enzyme and pathway databases
UniPathwayi | UPA00077;UER00157 UPA00850 |
BioCyci | MTBH37RV:G185E-6679-MONOMER |
BRENDAi | 6.3.2.12 3445 |
Family and domain databases
Gene3Di | 3.40.1190.10, 1 hit 3.90.190.20, 1 hit |
InterProi | View protein in InterPro IPR001645 Folylpolyglutamate_synth IPR018109 Folylpolyglutamate_synth_CS IPR036565 Mur-like_cat_sf IPR004101 Mur_ligase_C IPR036615 Mur_ligase_C_dom_sf IPR013221 Mur_ligase_cen |
PANTHERi | PTHR11136 PTHR11136, 1 hit |
Pfami | View protein in Pfam PF02875 Mur_ligase_C, 1 hit PF08245 Mur_ligase_M, 1 hit |
SUPFAMi | SSF53244 SSF53244, 1 hit SSF53623 SSF53623, 1 hit |
TIGRFAMsi | TIGR01499 folC, 1 hit |
PROSITEi | View protein in PROSITE PS01012 FOLYLPOLYGLU_SYNT_2, 1 hit |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | FOLC_MYCTU | |
Accessioni | I6Y0R5Primary (citable) accession number: I6Y0R5 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | February 15, 2017 |
Last sequence update: | October 3, 2012 | |
Last modified: | September 18, 2019 | |
This is version 58 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Prokaryotic Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
3D-structure, Complete proteome, Reference proteomeDocuments
- SIMILARITY comments
Index of protein domains and families - Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh
Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh: entries and gene names - PATHWAY comments
Index of metabolic and biosynthesis pathways - PDB cross-references
Index of Protein Data Bank (PDB) cross-references