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Information on EC 1.1.1.95 - phosphoglycerate dehydrogenase and Organism(s) Mycobacterium tuberculosis and UniProt Accession P9WNX3
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1.1.1.95 phosphoglycerate dehydrogenaseIUBMB Comments
This enzyme catalyses the first committed and rate-limiting step in the phosphoserine pathway of serine biosynthesis. The reaction occurs predominantly in the direction of reduction. The enzyme from the bacterium Escherichia coli also catalyses the activity of EC 1.1.1.399, 2-oxoglutarate reductase .
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Word Map
- 1.1.1.95
- l-serine
- aminotransferase
- microcephaly
-
psychomotor
- hydroxymethyltransferase
-
one-carbon
- hydroxypyruvate
- l-ser
-
2-hydroxyacid
- biotechnology
- molecular biology
- synthesis
The taxonomic range for the selected organisms is: Mycobacterium tuberculosis
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
phgdh, phosphoglycerate dehydrogenase, 3-phosphoglycerate dehydrogenase, d-3-phosphoglycerate dehydrogenase, 3-pgdh, 3pgdh, pgdh3, pgdh1, ehpgdh, d-phosphoglycerate dehydrogenase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3-PGDH
-
-
-
-
3-phosphoglycerate dehydrogenase
-
-
-
-
3-phosphoglyceric acid dehydrogenase
-
-
-
-
A10
-
-
-
-
alpha-phosphoglycerate dehydrogenase
-
-
-
-
D-3-phosphoglycerate dehydrogenase
D-3-phosphoglycerate:NAD oxidoreductase
-
-
-
-
dehydrogenase, phosphoglycerate
-
-
-
-
glycerate 3-phosphate dehydrogenase
-
-
-
-
glycerate-1,3-phosphate dehydrogenase
-
-
-
-
PGDH
phosphoglycerate oxidoreductase
-
-
-
-
phosphoglyceric acid dehydrogenase
-
-
-
-
D-3-phosphoglycerate dehydrogenase
-
-
-
-
PGDH
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
-
-, -
SYSTEMATIC NAME
IUBMB Comments
3-phospho-D-glycerate:NAD+ 2-oxidoreductase
This enzyme catalyses the first committed and rate-limiting step in the phosphoserine pathway of serine biosynthesis. The reaction occurs predominantly in the direction of reduction. The enzyme from the bacterium Escherichia coli also catalyses the activity of EC 1.1.1.399, 2-oxoglutarate reductase [6].
CAS REGISTRY NUMBER
COMMENTARY
9075-29-0
-
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
2-oxoglutarate + NADH + H+
D-2-hydroxyglutarate + NAD+
wild-type enzyme shows no activity. Mutant enzymes R72A and R72L utilize 2-oxoglutarate as substrate
-
-
?
3-phospho-D-glycerate + NAD+
3-phosphonooxypyruvate + NADH + H+
-
-
-
-
?
3-phosphohydroxypyruvate + NADH
3-phosphoglycerate + NAD+
-
specific for
-
-
?
additional information
?
-
-
no activity with alpha-ketoglutarate
-
-
?
3-phospho-D-glycerate + NAD+
3-phosphooxypyruvate + NADH + H+
-
-
-
r
3-phospho-D-glycerate + NAD+
3-phosphooxypyruvate + NADH + H+
-
-
-
-
r
3-phospho-D-glycerate + NAD+
3-phosphooxypyruvate + NADH + H+
enzyme in the L-serine biosynthetic pathway
-
-
?
3-phospho-D-glycerate + NAD+
3-phosphooxypyruvate + NADH + H+
first step of L-serine biosynthesis
-
-
r
3-phosphooxypyruvate + NADH + H+
3-phospho-D-glycerate + NAD+
-
-
-
r
3-phosphooxypyruvate + NADH + H+
3-phospho-D-glycerate + NAD+
-
-
-
-
r
phosphonooxypyruvate + NADH + H+
?
catalytic His280, active site, regulatory, and substrate binding site structures, overview
-
-
?
phosphonooxypyruvate + NADH + H+
?
very slow NADH binding in absence of substrate, productive NADH binding, that would support catalytic turnover, is dependent on the presence of substrate, active site structure with the catalytic His280, modelling of ligand-free and substrate-bound active site, overview
-
-
?
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
3-phospho-D-glycerate + NAD+
3-phosphonooxypyruvate + NADH + H+
-
-
-
-
?
3-phospho-D-glycerate + NAD+
3-phosphooxypyruvate + NADH + H+
enzyme in the L-serine biosynthetic pathway
-
-
?
3-phospho-D-glycerate + NAD+
3-phosphooxypyruvate + NADH + H+
first step of L-serine biosynthesis
-
-
r
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NADH
cofactor binding site structure and binding mechanism, overview
NADH
NADH can bind to the enzyme in the absence of substrate but that the binding constants were too slow to account for the catalytic reaction
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
potassium phosphate
-
optimal activity at 75-100 mM, only about 30% of the optimal activity in 5 mM potassium phosphate
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3-phosphohydroxypyruvate
uncompetitive substrate inhibition at high substrate concentration
3-phosphooxypyruvate
significant substrate inhibition. NADH bound at or near the ASB site and reduces the amount of substrate inhibition due to substrate interaction at the ASB site
L-serine
two serine molecules bound to the regulatory domain, anion- and serine-binding sites between two adjacent subunits
L-serine
-
I0.5: 0.03 mM. In presence of KCl, the binding and the inhibition of L-serine, are cooperative and in the absence of KCl they are not
additional information
mechanism of substrate inhibition, linked to this pH-dependent depression in activity, overview
-
additional information
-
mechanism of substrate inhibition, linked to this pH-dependent depression in activity, overview
-
additional information
CBR5884, a potent inhibitor of the human enzyme (PGDH), does not inhibit the enzyme from Mycobacterium tuberculosis
-
additional information
-
CBR5884, a potent inhibitor of the human enzyme (PGDH), does not inhibit the enzyme from Mycobacterium tuberculosis
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.54
3-phospho-D-glycerate
pH and temperature not specified in the publication
30.6
2-oxoglutarate
mutant enzyme R72L, pH 7.0, temperature not specified in the publication
53.1
2-oxoglutarate
mutant enzyme R72A, pH 7.0, temperature not specified in the publication
0.015
3-phosphooxypyruvate
mutant enzyme R132K, pH 7.0, temperature not specified in the publication
0.153
3-phosphooxypyruvate
wild-type enzyme, pH 7.0, temperature not specified in the publication
0.169
3-phosphooxypyruvate
mutant enzyme R72A/R132K, pH 7.0, temperature not specified in the publication
0.17
3-phosphooxypyruvate
pH and temperature not specified in the publication
0.025
3-phospho-D-glycerate
-
in 50 mM MOPS buffer, pH 7.0, temperature not specified in the publication
0.153
3-phospho-D-glycerate
-
in 200 mM KPO4 buffer, pH 7.0, temperature not specified in the publication
additional information
additional information
kinetic analysis of wild-type and mutant enzymes
-
additional information
additional information
-
kinetic analysis of wild-type and mutant enzymes
-
additional information
additional information
stopped flow and steady-state kinetic analysis
-
additional information
additional information
-
stopped flow and steady-state kinetic analysis
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1.4
3-phospho-D-glycerate
pH and temperature not specified in the publication
4.3
2-oxoglutarate
mutant enzyme R72L, pH 7.0, temperature not specified in the publication
16.1
2-oxoglutarate
mutant enzyme R72A, pH 7.0, temperature not specified in the publication
458
3-phosphooxypyruvate
mutant enzyme R132K, pH 7.0, temperature not specified in the publication
490
3-phosphooxypyruvate
mutant enzyme R72A/R132K, pH 7.0, temperature not specified in the publication
606
3-phosphooxypyruvate
wild-type enzyme, pH 7.0, temperature not specified in the publication
2400
3-phosphooxypyruvate
pH and temperature not specified in the publication
1515
3-phospho-D-glycerate
-
in 50 mM MOPS buffer, pH 7.0, temperature not specified in the publication
2425
3-phospho-D-glycerate
-
in 200 mM KPO4 buffer, pH 7.0, temperature not specified in the publication
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.14
2-oxoglutarate
mutant enzyme R72L, pH 7.0, temperature not specified in the publication
0.3
2-oxoglutarate
mutant enzyme R72A, pH 7.0, temperature not specified in the publication
2900
3-phosphooxypyruvate
mutant enzyme R72A/R132K, pH 7.0, temperature not specified in the publication
4000
3-phosphooxypyruvate
wild-type enzyme, pH 7.0, temperature not specified in the publication
10000
3-phosphooxypyruvate
pH and temperature not specified in the publication
31000
3-phosphooxypyruvate
mutant enzyme R132K, pH 7.0, temperature not specified in the publication
6100
3-phospho-D-glycerate
-
in 50 mM MOPS buffer, pH 7.0, temperature not specified in the publication
15800
3-phospho-D-glycerate
-
in 200 mM KPO4 buffer, pH 7.0, temperature not specified in the publication
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.082
L-serine
-
in 50 mM MOPS buffer, pH 7.0, temperature not specified in the publication
0.628
L-serine
-
in 200 mM KPO4 buffer, pH 7.0, temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.2
enzyme possess a dual pH optimum. A significant decrease in the Ki for substrate inhibition at pH values corresponding to the valley between these optima is responsible for this phenomenon
7.5
8
enzyme possess a dual pH optimum. A significant decrease in the Ki for substrate inhibition at pH values corresponding to the valley between these optima is responsible for this phenomenon
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.2 - 5.7
at approximately pH 5.7 the activity starts increasing again and reaches a new optimum at approximately pH 5.2 before decreasing once again
7.5 - 9.5
activity is relatively constant between pH 7.5-9.5. Above pH 9.5 and below pH 7.5 activity falls off rapidly
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
tetramer
tetramer
-
although the tetramer is composed of identical subunits, significant asymmetry is seen in the tertiary structure of the subunits
additional information
tetramer
intervening domains are the two four-stranded beta-sheet structures located next to the substrate binding domains and below the regulatory domains, structure model, overview
additional information
the apo-enzyme shows an extreme asymmetry in the orientation of the domains from one subunit to another. The poly glycine stretch in the loop that contains the locus for the 160° rotation leads to subunit asymmetry, structure modelling, overview
additional information
-
the apo-enzyme shows an extreme asymmetry in the orientation of the domains from one subunit to another. The poly glycine stretch in the loop that contains the locus for the 160° rotation leads to subunit asymmetry, structure modelling, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
D-3-phosphoglycerate dehydrogenase with bound effector L-serine or with bound substrate hydroxypyruvic acid phosphate, PGDH at 10 mg/ml is mixed with 5 mM hydroxypyruvic acid phosphate and 5 mM NAD+ analogue 3-acetyl pyridine adenine dinucleotide, or with 5 mM NADH and 5 mM L-serine, from 1 M Na K tartrate, 0.1 M MES, pH 6.5, cryoprotection in 25% propylene glycol, X-ray diffraction structure determination and analysis at resolutions of 2.7 A and 2.4 A, respectively
vapor diffusion in hanging drops, structure refined to 2.3 A resolution using SeMet multiwavelength anamolous dispersion
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D463A
site-directed mutagenesis, a very large reduction in the sensitivity of the mutant enzyme to L-serine
G316V
site-directed mutagenesis, the mutant shows slightly reduced activity and decreased sensitivity to L-serine compared to the wild-type
G316V/G317V
site-directed mutagenesis, the mutant shows reduced activity and decreased sensitivity to L-serine compared to the wild-type
G316V/G317V/G318V
site-directed mutagenesis, the mutant is not producable
G316V/G318V
site-directed mutagenesis, the mutant shows reduced activity and decreased sensitivity to L-serine compared to the wild-type
G317V
site-directed mutagenesis, the mutant shows slightly reduced activity and decreased sensitivity to L-serine compared to the wild-type
G317V/G318V
site-directed mutagenesis, the mutant shows reduced activity and decreased sensitivity to L-serine compared to the wild-type
G318V
site-directed mutagenesis, the mutant shows slightly reduced activity and decreased sensitivity to L-serine compared to the wild-type
H447A
K439A
K439A/R451A/R501A
site-directed mutagenesis, the mutation eliminates substrate inhibition and pH-dependent depression in activity
N481A
site-directed mutagenesis, a very large reduction in the sensitivity of the mutant enzyme to L-serine. Mutant N481A co-elutes with native PGDH in gel filtration, it shows loss of cooperativity, which cannot be explained by a change in the quaternary structure of the enzyme from tetramer to dimer or monomer
R132K
mutation decreases the Km-value for 3-phosphooxypyruvate by approximately 10fold
R446A
R451A
R451A/R501A/K439A
site-directed mutagenesis, the mutation eliminates substrate inhibition and pH-dependent depression in activity
R501A
R501A/R451A/K439A
anion binding site mutant: Km (mM) (3-phosphohydroxypyruvate): 0.243, kcat: 1558, Ki (mM) (3-phosphohydroxypyruvate): 7.218, mutant displays only little uncompetitive substrate inhibition, no dual pH optima compared to wild-type
W130F
site-directed mutagenesis, catalytically inactive mutant
W29F
site-directed mutagenesis, the mutant shows increased activity compared to the wild-type enzyme
W327F
site-directed mutagenesis, the mutant shows increased activity compared to the wild-type enzyme
Y461A
site-directed mutagenesis, a very large reduction in the sensitivity of the mutant enzyme to L-serine
H447A
anion binding site mutant: Km (mM) (3-phosphohydroxypyruvate): 0.16, kcat: 1446, Ki (mM) (3-phosphohydroxypyruvate): 0.87, mutant displays complete uncompetitive substrate inhibition, no dual pH optima compared to wild-type
H447A
site-directed mutagenesis, the mutant shows altered L-serine binding, kinetics for NADH, and activity compared to the wild-type enzyme
K439A
anion binding site mutant: Km (mM) (3-phosphohydroxypyruvate): 0.075, kcat: 368, Ki (mM) (3-phosphohydroxypyruvate): 0.054, mutant displays partial uncompetitive substrate inhibition, mutant retains dual pH optima
K439A
site-directed mutagenesis, the mutant shows altered L-serine binding, kinetics for NADH, and activity compared to the wild-type enzyme
R446A
anion binding site mutant: Km (mM) (3-phosphohydroxypyruvate): 0.123 kcat: 467, Ki (mM) (3-phosphohydroxypyruvate): 0.289, mutant displays partial uncompetitive substrate inhibition, no dual pH optima compared to wild-type
R446A
site-directed mutagenesis, the mutant shows altered L-serine binding, kinetics for NADH, and activity compared to the wild-type enzyme
R451A
anion binding site mutant: Km (mM) (3-phosphohydroxypyruvate): 0.19, kcat: 1881, Ki (mM) (3-phosphohydroxypyruvate): 0.95, mutant displays complete uncompetitive substrate inhibition, no dual pH optima compared to wild-type
R451A
site-directed mutagenesis, the mutant shows altered L-serine binding, kinetics for NADH, and activity compared to the wild-type enzyme
R501A
anion binding site mutant: Km (mM) (3-phosphohydroxypyruvate): 0.18, kcat: 1989, Ki (mM) (3-phosphohydroxypyruvate): 1.02, mutant displays complete uncompetitive substrate inhibition, no dual pH optima compared to wild-type
R501A
site-directed mutagenesis, the mutant shows altered L-serine binding, kinetics for NADH, and activity compared to the wild-type enzyme
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
at low ionic strength the enzyme irreversibly loses activity with time. In 20 mM phosphate buffer, pH 7.5, most of the activity is lost within 24 h. The activity loss is prevented if the ionic strength is kept above approximately 100 mM salt
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Talon cobalt based immobilized metal affinity column chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Dey, S.; Hu, Z.; Xu, X.L.; Sacchettini, J.C.; Grant, G.A.
D-3-phosphoglycerate dehydrogenase from Mycobacterium tuberculosis is a link between the E. coli and mammalian enzymes
J. Biol. Chem.
280
1484-14891
2005
Mycobacterium tuberculosis
Dey, S.; Grant, G.A.; Sacchettini, J.C.
Crystal structure of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase: extreme asymmetry in a tetramer of identical subunits
J. Biol. Chem.
280
14892-14899
2005
Mycobacterium tuberculosis
Burton, R.L.; Chen, S.; Xu, X.L.; Grant, G.A.
A novel mechanism for substrate inhibition in Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase
J. Biol. Chem.
282
31517-31524
2007
Mycobacterium tuberculosis (P9WNX3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNX3)
Dey, S.; Burton, R.L.; Grant, G.A.; Sacchettini, J.C.
Structural analysis of substrate and effector binding in Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase
Biochemistry
47
8271-8282
2008
Mycobacterium tuberculosis (P9WNX3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNX3)
Burton, R.L.; Chen, S.; Xu, X.L.; Grant, G.A.
Role of the anion-binding site in catalysis and regulation of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase
Biochemistry
48
4808-4815
2009
Mycobacterium tuberculosis (P9WNX3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNX3)
Xu, X.L.; Chen, S.; Salinas, N.D.; Tolia, N.H.; Grant, G.A.
Comparison of type 1 D-3-phosphoglycerate dehydrogenases reveals unique regulation in pathogenic Mycobacteria
Arch. Biochem. Biophys.
570
32-39
2015
Bacillus subtilis, Corynebacterium glutamicum, Homo sapiens, Mycobacterium marinum, Mycobacterium tuberculosis, Mycolicibacterium smegmatis, Streptomyces coelicolor (Q9Z564)
Xu, X.L.; Grant, G.A.
Regulation of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase by phosphate-modulated quaternary structure dynamics and a potential role for polyphosphate in enzyme regulation
Biochemistry
53
4239-4249
2014
Mycobacterium tuberculosis
Xu, X.L.; Grant, G.A.
Determinants of substrate specificity in D-3-phosphoglycerate dehydrogenase. Conversion of the M. tuberculosis enzyme from one that does not use alpha-ketoglutarate as a substrate to one that does
Arch. Biochem. Biophys.
671
218-224
2019
Escherichia coli (P0A9T0), Escherichia coli, Mycobacterium tuberculosis (P9WNX3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNX3), Escherichia coli K12 (P0A9T0)
Grant, G.A.
D-3-Phosphoglycerate dehydrogenase
Front. Mol. Biosci.
5
110
2018
Escherichia coli (C3SVM7), Escherichia coli, Rattus norvegicus (O08651), Homo sapiens (O43175), Homo sapiens, Mycobacterium tuberculosis (P9WNX3), Mycobacterium tuberculosis, Mycobacterium tuberculosis ATCC 25618 (P9WNX3)
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