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6.3.2.17: tetrahydrofolate synthase

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

Word Map on EC 6.3.2.17

Reaction

ATP
+
tetrahydropteroyl-[gamma-Glu]n
+
L-glutamate
=
ADP
+
phosphate
+
tetrahydropteroyl-[gamma-Glu]n+1

Synonyms

100194131, AtDFB, cFPGS, DHFS/FPGS, dihydrofolate synthase/folylpolyglutamate synthase, eFPGS, Folate polyglutamate synthetase, FolC, folyl-gamma-glutamate synthetase, Folylpoly(.gamma.-glutamate) synthase, Folylpoly-.gamma.-glutamate synthase, Folylpoly-gamma-glutamate synthetase, Folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase, Folylpolyglutamate synthase, Folylpolyglutamate synthetase, folylpolyglutamate synthetase 1, Folylpolyglutamyl synthetase, folypoly-gamma-glutamate synthetase, folypolyformyl glutamate synthase, folypolyglutamate synthase, folypolyglutamate synthetase, Formyltetrahydropteroyldiglutamate synthetase, FPGS, FPGS1, FPGS2, GRMZM2G393334, mFGPS, mFPGS, More, MTHFD1L, N10-Formyltetrahydropteroyldiglutamate synthetase, PfDHFS-FPGS, Synthetase, folylpolyglutamate, Tail length regulator, tetrahydrofolate:L-glutamate gamma-ligase (ADP-forming), tetrahydrofolylpolyglutamate synthase

ECTree

     6 Ligases
         6.3 Forming carbon-nitrogen bonds
             6.3.2 Acid—amino-acid ligases (peptide synthases)
                6.3.2.17 tetrahydrofolate synthase

Engineering

Engineering on EC 6.3.2.17 - tetrahydrofolate synthase

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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A173S/Q536E
cell line V79 compared to wild-type CHO-K1 cells, also with silent polymorphisms at codons 94 and 187
R139Q
cell line AUXB3
A155H
drastic increases in Km values
A155W
13fold increase in Km value for dihydropteroate
D154A
mutation in residue specific for dihydropteroate binding, 200fold increase in Km value for substrate 5,6,7,8-tetrahydropteroyl-gamma-(L-Glu)2
E146Q
-
completely inactive, no ATP binding is observed with this mutant
T122H
drastic increases in Km values
T122W
drastic increases in Km values
A22G
-
a naturally occuring mutation, rs10760502 , phenotype, overview. The genotypes of the A22G polymorphism may be risk factors for acute lymphoblastic leukemia (ALL) and may play a role in the survival of patients with ALL
A382T
-
94% of the wild type enzyme activity
A447V
-
does not affect enzyme activity
C209R
-
8% of the wild type enzyme activity
C346A
-
activity comparable with that of wild type enzyme
C346F
C388F
MTXR5 resistant leukemia cells established by repeated cycles of 24 h-pulse exposures to methotrexate (MTX), harbor a C388F substitution resulting in a 91% loss of their cellular FPGS activity. Kinetic analysis reveals that the mutant protein retains parental affinity toward MTX, while the Km toward L-glutamate increases by 23fold. 3D-modeling analysis suggests that C388 is located at the entrance to the active site of this enzyme
D335A
D376A
-
only slightly lower activity than the wild type enzyme
D378A
-
only slightly lower activity than the wild type enzyme
G569C
-
13% of the wild type enzyme activity
H338A
K384A
-
only slightly lower activity than the wild type enzyme
R377A
-
with no significant activity
R377A D335A
site-directed mutagenesis, the substitution results in a 1500fold increase in the Km for glutamate, and a 20fold decrease in the Kcat
R424C
-
reduced efficacy with substrates compared to the wild type enzyme
S457F
-
reduced efficacy with substrates compared to the wild type enzyme
D151A
mutation in residue specific for dihydropteroate binding, mutant is defective in using tetrahydrofolate as substrate
D313A
mutation in the C-terminal of the enzyme
D345C
-
more than 85% of the wild type activity, with 5,10-methylene-5,6,7,8-tetrahydrofolic acid as substrate
E143A
E143D
E143Q
E81A
mutation in the omega-loop of the enzyme
F121A
50fold increase in Km for 5,10-methylene-5,6,7,8-tetrahydrofolic acid
F75A
increase in Km value for 5,10-methylene-5,6,7,8-tetrahydrofolic acid, decreases in Km values for ATP and L-Glu
G411A
mutation in the C-terminal of the enzyme
G51S
no FGPS activity
G51S/S52T
no FGPS activity
H316A
mutation in the C-terminal of the enzyme
K172C
-
more than 85% of the wild type activity, with 5,10-methylene-5,6,7,8-tetrahydrofolic acid as substrate
K185A
mutation in the MgATP2- binding site of the enzyme
P74A
mutation in the omega-loop of the enzyme
R15E
increases in Km values
R82A
mutation in the omega-loop of the enzyme
S152A
decrease in Vmax
S152W
increases in Km values
S412A
mutation in the C-terminal of the enzyme
T119W
100fold increase in Km for 5,10-methylene-5,6,7,8-tetrahydrofolic acid
Y414A
decrease in Km values for ATP, increase in Km for L-Glu
A337V
-
L44 cells
G178E
-
L7 cells
G320D
-
L15 cells
S180F
-
L51 cells
T339I
-
L44 cells
W445stop
-
L15 cells
additional information