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Information on EC 2.1.2.1 - glycine hydroxymethyltransferase and Organism(s) Plasmodium vivax and UniProt Accession A5K8L9

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IUBMB Comments
A pyridoxal-phosphate protein. Also catalyses the reaction of glycine with acetaldehyde to form L-threonine, and with 4-trimethylammoniobutanal to form 3-hydroxy-N6,N6,N6-trimethyl-L-lysine.
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This record set is specific for:
Plasmodium vivax
UNIPROT: A5K8L9
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The taxonomic range for the selected organisms is: Plasmodium vivax
The enzyme appears in selected viruses and cellular organisms
Synonyms
serine hydroxymethyltransferase, shmt2, shmt1, serine hydroxymethyl transferase, serine transhydroxymethylase, serine hydroxymethyltransferase 2, mitochondrial serine hydroxymethyltransferase, serine hydroxymethyltransferase 1, bsshmt, pvshmt, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
serine hydroxymethyltransferase
-
L-serine hydroxymethyltransferase
-
-
-
-
serine hydroxymethylase hydroxymethyltransferase, serine
-
-
-
-
serine hydroxymethyltransferase
serine transhydroxymethylase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydroxymethyl group transfer
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
5,10-methylenetetrahydrofolate:glycine hydroxymethyltransferase
A pyridoxal-phosphate protein. Also catalyses the reaction of glycine with acetaldehyde to form L-threonine, and with 4-trimethylammoniobutanal to form 3-hydroxy-N6,N6,N6-trimethyl-L-lysine.
CAS REGISTRY NUMBER
COMMENTARY hide
9029-83-8
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
5,10-methylenetetrahydrofolate + glycine + H2O
tetrahydrofolate + D-serine
show the reaction diagram
-
-
-
r
5,10-methylenetetrahydrofolate + glycine + H2O
tetrahydrofolate + L-serine
show the reaction diagram
tetrahydrofolate + L-serine
5,10-methylenetetrahydrofolate + glycine + H2O
show the reaction diagram
-
-
-
r
(6S)-tetrahydrofolate + D-serine
5,10-methylenetetrahydrofolate + glycine + H2O
show the reaction diagram
-
-
-
-
r
(6S)-tetrahydrofolate + L-serine
5,10-methylenetetrahydrofolate + glycine + H2O
show the reaction diagram
-
-
-
-
r
5,10-methylenetetrahydrofolate + glycine + H2O
tetrahydrofolate + D-serine
show the reaction diagram
-
-
-
-
r
5,10-methylenetetrahydrofolate + glycine + H2O
tetrahydrofolate + L-serine
show the reaction diagram
-
-
-
-
r
D-serine + tetrahydrofolate
glycine + 5,10-methylenetetrahydrofolate + H2O
show the reaction diagram
-
the binding affinity for D-serine is 150fold lower than that of L-serine
-
-
?
L-serine + tetrahydrofolate
glycine + 5,10-methylenetetrahydrofolate + H2O
show the reaction diagram
-
L-serine is the physiological substrate
-
-
?
tetrahydrofolate + L-serine
5,10-methylenetetrahydrofolate + glycine + H2O
show the reaction diagram
-
-
-
-
r
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
5,10-methylenetetrahydrofolate + glycine + H2O
tetrahydrofolate + L-serine
show the reaction diagram
-
-
-
r
tetrahydrofolate + L-serine
5,10-methylenetetrahydrofolate + glycine + H2O
show the reaction diagram
-
-
-
r
(6S)-tetrahydrofolate + D-serine
5,10-methylenetetrahydrofolate + glycine + H2O
show the reaction diagram
-
-
-
-
r
(6S)-tetrahydrofolate + L-serine
5,10-methylenetetrahydrofolate + glycine + H2O
show the reaction diagram
-
-
-
-
r
5,10-methylenetetrahydrofolate + glycine + H2O
tetrahydrofolate + D-serine
show the reaction diagram
-
-
-
-
r
5,10-methylenetetrahydrofolate + glycine + H2O
tetrahydrofolate + L-serine
show the reaction diagram
-
-
-
-
r
tetrahydrofolate + L-serine
5,10-methylenetetrahydrofolate + glycine + H2O
show the reaction diagram
-
-
-
-
r
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
5,10-methylenetetrahydrofolate
-
pyridoxal 5'-phosphate
tetrahydrofolate
binding structure analysis
5,10-methylenetetrahydrofolate
-
-
pyridoxal 5'-phosphate
tetrahydrofolate
-
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(4R)-6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
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(4R,4S)-5-cyano-4-(3-cyano-5-[5-[((S)-1,3-dicarboxypropyl)-carbamoyl]thiophen-2-yl]phenyl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-6-aminium trifluoroacetate
-
(4S)-6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
3'-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5'-cyano[1,1'-biphenyl]-3-carboxylic acid
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5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]-N,N-dimethylthiophene-2-carboxamide
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5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]-N-[3-(diethylamino)propyl]thiophene-2-carboxamide
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5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylic acid
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6-amino-3-methyl-4-[3-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
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6-amino-4-(3,5-dichlorophenyl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
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6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
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6-amino-4-[3-cyano-5-(piperazin-1-yl)phenyl]-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
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6-amino-5-cyano-4-[3-cyano-5-(5-[[3-(morpholin-4-ium-4-yl)propyl]carbamoyl]thiophen-2-yl)phenyl]-3-methyl-4-isopropyl-2,4-dihydropyrano[2,3-c]pyrazol-1-ium bis-(trifluoroacetate)
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benzyl 4-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]piperazine-1-carboxylate
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benzyl 5-[3-[(4R)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
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benzyl 5-[3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
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benzyl 5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
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ethyl 4-[[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl](methyl)amino]butanoate
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methyl 3'-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5'-chloro[1,1'-biphenyl]-4-carboxylate
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methyl 5-[3-[(4R)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
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methyl 5-[3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
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Thiosemicarbazide
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-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
47
D-serine
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apparent value, in 50 mM HEPES buffer (pH 7.0), at 25°C
0.11 - 0.3
L-serine
0.038 - 0.14
tetrahydrofolate
additional information
additional information
-
kinetic analysis of ternary complex mechanism, determination of ligand binding, transient, single-turnover and bi-substrate steady-state kinetics, detailed overview. The enzyme can bind first to either L-serine or tetrahydrofolate. The dissociation constants for the enzyme-L-serine and enzyme-tetrahydrofolate complexes are 0.18 mM and 0.35 mM, respectively. The kinetic mechanism of PvSHMT occurs via a random-order model and glycine formation is the rate-limiting step of the enzyme reaction
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.26
D-serine
-
in 50 mM HEPES buffer (pH 7.0), at 25°C
0.41 - 1.41
L-serine
0.41 - 1.41
tetrahydrofolate
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
3.4 - 6.1
L-serine
11 - 29
tetrahydrofolate
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.16
-
crude extract, in 50 mM HEPES (pH 7.0), 1 mM dithiothreitol and 0.5 mM EDTA at 25°C
1.86
-
after 3.8fold purification, in 50 mM HEPES (pH 7.0), 1 mM dithiothreitol and 0.5 mM EDTA at 25°C
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 8
-
assay at
8
-
in 50 mM HEPES
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5 - 10
-
-
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5 - 30
-
the catalytic activity increases upon temperature increment
additional information
-
unlike Plasmodium enzymes in which the activity is almost abolished at lower temperatures, the activity of human cytosolic SHMT still remains active below the temperature breakpoint
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
predicted to tbe cytosolic
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
the enzyme is involved in folate recycling and dTMP synthesis
evolution
-
the enzyme belongs to the alpha class of PLP-dependent enzymes. The ligand binding environment of enzymes SHMT from human and Plasmodium are different, overview
physiological function
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
49000
-
2 * 49000, SDS-PAGE
72400
-
gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
predicted to be a dimer
homodimer
-
2 * 49000, SDS-PAGE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in complex with inhibitor, microbatch method, using 20-24% (w/v) PEG 4000, 0.06-0.12 M NaCl, 0.1 M Tris-HCl buffer, pH 8.5, and 10% (v/v) trifluoroethanol
purified enzyme in a binary complex with L-serine and in a ternary complex with D-serine and (6R)-5-formyltetrahydrofolate, microbatch method, mixing of 0.001 ml of 0.38 mM protein in 0.86 mM PLP, 62 mM 2-mercaptoethanol, 87 mM Gly, L-Ser, or D-Ser, and 43 mM tetrahydrofolate, with 0.001 ml of well solution containing 20-21% w/v PEG 4000, 70-90 mM NaCl, 100 mM Tris-HCl, pH 8.5, 15% v/v trifluoroethanol, 20°C, 1-4 days, X-ray diffraction structure determination and analysis at 2.4-2.5 A resolution, molecular replacement
substrate binding structure analysis using crystal structure of the homodimeric PvSHMT in complex with D-serine and formyltetrahydrofolate, PDB ID 4OYT
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
DEAE-Sepharose column chromatography, SP-Sepharose column chromatography, and Sephadex G-25 gel filtration
-
polyethyleneimine precipitation, SP-Sepharose column chromatography and DEAE-Sepharose column chromatography
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recombinant enzyme from Escherichia coli strain BL21(DE3) by polyethyleneimine precipitation, anion and cation exchange chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli
expressed in Escherichia coli BL21(DE3) cells
-
recombinant expression in Escherichia coli strain BL21(DE3)
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Leartsakulpanich, U.; Kongkasuriyachai, D.; Imwong, M.; Chotivanich, K.; Yuthavong, Y.
Cloning and characterization of Plasmodium vivax serine hydroxymethyltransferase
Parasitol. Int.
57
223-228
2008
Plasmodium vivax (A5K8L9), Plasmodium vivax
Manually annotated by BRENDA team
Sopitthummakhun, K.; Maenpuen, S.; Yuthavong, Y.; Leartsakulpanich, U.; Chaiyen, P.
Serine hydroxymethyltransferase from Plasmodium vivax is different in substrate specificity from its homologues
FEBS J.
276
4023-4036
2009
Plasmodium vivax
Manually annotated by BRENDA team
Chitnumsub, P.; Jaruwat, A.; Riangrungroj, P.; Ittarat, W.; Noytanom, K.; Oonanant, W.; Vanichthanankul, J.; Chuankhayan, P.; Maenpuen, S.; Chen, C.J.; Chaiyen, P.; Yuthavong, Y.; Leartsakulpanich, U.
Structures of Plasmodium vivax serine hydroxymethyltransferase: implications for ligand-binding specificity and functional control
Acta Crystallogr. Sect. D
70
3177-3186
2014
Plasmodium vivax (A5K8L9), Plasmodium vivax
Manually annotated by BRENDA team
Pinthong, C.; Maenpuen, S.; Amornwatcharapong, W.; Yuthavong, Y.; Leartsakulpanich, U.; Chaiyen, P.
Distinct biochemical properties of human serine hydroxymethyltransferase compared with the Plasmodium enzyme: implications for selective inhibition
FEBS J.
281
2570-2583
2014
Plasmodium falciparum, Plasmodium vivax, Homo sapiens (P34896), Homo sapiens
Manually annotated by BRENDA team
Maenpuen, S.; Amornwatcharapong, W.; Krasatong, P.; Sucharitakul, J.; Palfey, B.A.; Yuthavong, Y.; Chitnumsub, P.; Leartsakulpanich, U.; Chaiyen, P.
Kinetic mechanism and the rate-limiting step of Plasmodium vivax serine hydroxymethyltransferase
J. Biol. Chem.
290
8656-8665
2015
Plasmodium vivax
Manually annotated by BRENDA team
Amornwatcharapong, W.; Maenpuen, S.; Chitnumsub, P.; Leartsakulpanich, U.; Chaiyen, P.
Human and Plasmodium serine hydroxymethyltransferases differ in rate-limiting steps and pH-dependent substrate inhibition behavior
Arch. Biochem. Biophys.
630
91-100
2017
Homo sapiens, Plasmodium vivax
Manually annotated by BRENDA team
Witschel, M.C.; Rottmann, M.; Schwab, A.; Leartsakulpanich, U.; Chitnumsub, P.; Seet, M.; Tonazzi, S.; Schwertz, G.; Stelzer, F.; Mietzner, T.; McNamara, C.; Thater, F.; Freymond, C.; Jaruwat, A.; Pinthong, C.; Riangrungroj, P.; Oufir, M.; Hamburger, M.; Maeser, P.; Sanz-Alonso, L.M.; Charman, S.
Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT) cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities
J. Med. Chem.
58
3117-3130
2015
Plasmodium berghei, Plasmodium falciparum, Plasmodium vivax (A5K8L9), Plasmodium vivax, Plasmodium vivax Salvador I (A5K8L9)
Manually annotated by BRENDA team