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Information on EC 2.3.3.14 - homocitrate synthase and Organism(s) Saccharomyces cerevisiae and UniProt Accession P48570

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EC Tree
     2 Transferases
         2.3 Acyltransferases
             2.3.3 Acyl groups converted into alkyl groups on transfer
                2.3.3.14 homocitrate synthase
IUBMB Comments
Belongs in the alpha-aminoadipate pathway of lysine synthesis, along with EC 4.2.1.36, homoaconitate hydratase. The enzyme also acts with oxaloacetate as substrate, but more slowly [2,3].
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Saccharomyces cerevisiae
UNIPROT: P48570
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The taxonomic range for the selected organisms is: Saccharomyces cerevisiae
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
hcs, homocitrate synthase, lys22, nifv2, sphcs, tthcs, lys21p, homocitrate synthetase, lys22p, saci_1304, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
2-hydroxybutane-1,2,4-tricarboxylate 2-oxoglutarate-lyase (CoA-acetylating)
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-
-
-
acetyl-coenzyme A: 2-ketoglutarate C-transferase
-
-
acetyl-coenzyme A:2-ketoglutarate C-acetyl transferase
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-
-
-
homocitrate synthetase
-
-
-
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homocitrate-condensing enzyme
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-
-
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homocondensing enzyme
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-
-
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LYS20
synthase, homocitrate
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-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
acetyl-CoA + H2O + 2-oxoglutarate = (2R)-2-hydroxybutane-1,2,4-tricarboxylate + CoA
show the reaction diagram
mechanism: 2-oxoglutarate first binds to the active site zinc via its alpha-carboxylate and 2-oxo groups, followed by acetyl-CoA. A general base then accepts a proton from the methyl of acetyl-CoA, and a general acid protonates the carbonyl of 2-oxoglutarate in the formation of homocitryl-CoA. The general acid then acts as a base in deprotonating Zn-OH2 in the hydrolysis of homocitryl-CoA to give homocitrate and CoA
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
condensation
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-
-
-
SYSTEMATIC NAME
IUBMB Comments
acetyl-CoA:2-oxoglutarate C-acetyltransferase (thioester-hydrolysing, carboxymethyl forming)
Belongs in the alpha-aminoadipate pathway of lysine synthesis, along with EC 4.2.1.36, homoaconitate hydratase. The enzyme also acts with oxaloacetate as substrate, but more slowly [2,3].
CAS REGISTRY NUMBER
COMMENTARY hide
9075-60-9
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
acetyl-CoA + H2O + 2-oxoglutarate
(2R)-2-hydroxybutane-1,2,4-tricarboxylate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + H2O + 2-oxoglutarate
2-hydroxybutane-1,2,4-tricarboxylate + CoA
show the reaction diagram
in the yeast Saccharomyces cerevisiae, the first committed step of the lysine biosynthetic pathway is catalysed by two homocitrate synthases encoded by LYS20 and LYS21. During growth on ethanol, homocitrate is mainly synthesized through Lys21p, while under fermentative metabolism, Lys20p and Lys21p play redundant roles
-
-
?
acetyl-CoA + H2O + 2-oxoglutarate
2-hydroxybutane-1,2,4-tricarboxylate + CoA
show the reaction diagram
acetyl-CoA + H2O + oxaloacetate
? + CoA
show the reaction diagram
-
oxaloacetate is a substrate with lower affinity than 2-oxoglutarate
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-
?
additional information
?
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-
the enzyme has no activity with core histone substrates or calf thymus histones. However, when histone H4 purified from yeast is used as substrate, histone acetyltransferases activity is observed
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-
?
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
acetyl-CoA + H2O + 2-oxoglutarate
2-hydroxybutane-1,2,4-tricarboxylate + CoA
show the reaction diagram
in the yeast Saccharomyces cerevisiae, the first committed step of the lysine biosynthetic pathway is catalysed by two homocitrate synthases encoded by LYS20 and LYS21. During growth on ethanol, homocitrate is mainly synthesized through Lys21p, while under fermentative metabolism, Lys20p and Lys21p play redundant roles
-
-
?
acetyl-CoA + H2O + 2-oxoglutarate
2-hydroxybutane-1,2,4-tricarboxylate + CoA
show the reaction diagram
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mg2+
-
0.002 mM MgCl2 has no effect
Zinc
-
bound in the active site
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
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0.01 mM, 91% inhibition
2,2'-dipyridyl
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0.01 mM, 82% inhibition
2-oxoglutarate
-
-
2-Oxomalonate
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-
citrate
CoA
-
noncompetitive versus acetyl-CoA
Cu2+
-
0.0001 mM CuSO4, complete inhibition
desulfo-CoA
-
uncompetitive
glyoxylate
-
competitive, analysis of pH-dependence of inhibition
Hg2+
-
0.01 mM HgCl2, complete inhibition
hydroxylysine
iodoacetic acid
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0.01 mM, 71% inhibition
L-Lys
L-lysine
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isoform Lys20 is one order of magnitude less sensitive to L-lysine inhibition than Lys21
L-norleucine
-
-
lysine
strong allosteric inhibitor of Lys21p. Induces positive cooperativity for alpha-ketoglutarate binding
Na2HAsO4
-
0.01 mM, 67% inhibition
NaF
-
0.01 mM, 73% inhibition
oxaloacetate
-
-
oxalylglycine
-
-
p-hydroxymercuribenzoate
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0.0001 mM, complete inhibition
pyridine-2,3-dicarboxylate
-
-
Pyridine-2,4-dicarboxylate
-
-
Pyridine-2,5-dicarboxylate
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-
pyridine-2,6-dicarboxylate
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pyridine-2-carboxylate
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succinyl phosphonate
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thialysine
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5 mM, complete inhibition
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
L-lysine
-
stimulates activity on histone H4
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1.3 - 42
2-oxoglutarate
0.024 - 0.14
acetyl-CoA
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.617
2-oxoglutarate
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-
0.617
acetyl-CoA
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-
additional information
additional information
-
the kcat for E155Q decreases at high pH, similar to the wild type enzyme, but is pH independent at low pH
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
26
2-oxoglutarate
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pH 7.2
10
2-Oxomalonate
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pH 7.2
13.5 - 200
citrate
0.008 - 0.033
CoA
0.014 - 0.18
desulfo-CoA
26
Glutarate
-
pH 7.2
0.4
glyoxylate
-
pH 7.2
1
oxalate
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pH 7.2
4
oxaloacetate
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pH 7.2
7.7
oxalylglycine
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pH 7.2
3
pyridine-2,3-dicarboxylate
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pH 7.2
0.6
Pyridine-2,4-dicarboxylate
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pH 7.2
14
Pyridine-2,5-dicarboxylate
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pH 7.2
0.7
pyridine-2,6-dicarboxylate
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pH 7.2
0.43
pyridine-2-carboxylate
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pH 7.2
46
succinyl phosphonate
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pH 7.2
additional information
additional information
-
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25 - 40
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25°C: about 60% of maximal activity, 40°C: about 50% of maximal activity
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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deletion of the homocitrate synthase gene suppresses htz1D DNA damage sensitivity
metabolism
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the first committed step in the lysine biosynthetic pathway is catalyzed by the Lys20 and Lys21 homocitrate synthase isoforms. The Lys20 isoform exerts high control over L-lysine flux, while isoform Lys21 exerts low control over the alpha-aminoadipate-pathway flux
physiological function
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the enzyme is linked to the key process of DNA damage repair through the essential MYST family histone acetyltransferase Esa1 and the H2A.Z. The enzyme has a role in addition to amino acid synthesis, and functions in nuclear activities involving chromatin regulation that are distinct from its previously established role in lysine biosynthesis
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E155A
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mutant enzyme exhibits 1000fold lower activity than wild-type enzyme. Activity of E155A can be partially rescued by formate
E155Q
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mutant enzyme exhibits 1000fold lower activity than wild-type enzyme. The kcat for E155Q decreases at high pH, similar to the wild-type enzyme, but is pH independent at low pH
H309A
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inactive mutant enzyme. Slight increase in activity is observed for H309A in the presence of 300 mM imidazole, which is still 1000fold lower than that of wild type
H309N
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inactive mutant enzyme
Y320F
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mutant enzyme loses 25fold activity compared to that of the wild-type enzyme
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
the purified enzyme can be stabilized using a combination of guanidine hydrochloride, alpha-cyclodextrin and ammonium sulfate
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
His-tagged enzyme
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli. Introduction of homocitrate synthase, homoaconitase and homoisocitrate dehydrogenase from Saccharomyces cerevisiae into Escherichia coli enables +1 carbon extension from 2-oxoglutarate to 2-oxoadipate, which is subsequently converted into glutarate by a promiscuous 2-oxo acid decarboxylase (KivD) and a succinate semialdehyde dehydrogenase (GabD)
expressed in Escherichia coli B834 DE3 cells
-
expression in Escherichia coli
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
synthesis
novel glutarate biosynthetic pathway by incorporation of a +1 carbon chain extension pathway from 2-oxoglutarate in combination with 2-oxo acid decarboxylation pathway in Escherichia coli. Introduction of homocitrate synthase, homoaconitase and homoisocitrate dehydrogenase from Saccharomyces cerevisiae into Escherichia coli enables +1 carbon extension from 2-oxoglutarate to 2-oxoadipate, which is subsequently converted into glutarate by a promiscuous 2-oxo acid decarboxylase (KivD) and a succinate semialdehyde dehydrogenase (GabD). The recombinant Escherichia coli coexpressing all five genes produces 0.3 g/l glutarate from glucose. To further improve the titers, 2-oxoglutarate is rechanneled into carbon chain extension pathway via the clustered regularly interspersed palindromic repeats system mediated interference (CRISPRi) of essential genes sucA and sucB in tricarboxylic acid cycle. The final strain can produce 0.42 g/l glutarate, which is increased by 40% compared with the parental strain. Glutarate is one of the most potential building blocks for bioplastics
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Strassman, M.; Ceci, L.N.
Enzymatic formation of homocitric acid, an intermediate in lysine biosynthesis
Biochem. Biophys. Res. Commun.
14
262-267
1964
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Tucci, A.F.; Ceci, L.N.
Homocitrate synthase from yeast
Arch. Biochem. Biophys.
153
742-750
1972
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Gray, G.S.; Bhattacharjee, J.K.
Biosynthesis of lysine in Saccharomyces cerevisiae: properties and spectrophotometric determination of homocitrate synthase activity
Can. J. Microbiol.
22
1664-1667
1976
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Gray, G.S.; Bhattacharjee, J.K.
Biosynthesis of lysine in Saccharomyces cerevisiae: Regulation of homocitrate synthase in analogue-resistant mutants
J. Gen. Microbiol.
97
117-120
1976
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Ramos, F.; Verhasselt, P.; Fellers, A.; Peeters, P.; Wach, A.; Dubois, E.; Volckaert, G.
Identification of the gene encoding a homocitrate synthase isoenzyme of Saccharomyces cerevisiae
Yeast
12
1315-1320
1996
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Chen, S.; Brockenbrough, J.S.; Dove, J.E.; Aris, P.
Homocitrate synthase is located in the nucleus in the yeast Saccharomyces cerevisiae
J. Biol. Chem.
272
10839-10846
1997
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Feller, A.; Ramos, F.; Pierard, A.; Dubois, E.
In Saccharomyces cerevisiae, feedback inhibition of homocitrate synthase by lysine modulates the activation of LYS gene expression by Lys14p
Eur. J. Biochem.
261
163-170
1999
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Banuelos, O.; Casqueiro, J.; Steidl, S.; Gutierrez, S.; Brakhage, A.; Martin, J.F.
Subcellular localization of the homocitrate synthase in Penicillium chrysogenum
Mol. Gen. Genet.
266
711-719
2002
Saccharomyces cerevisiae, Penicillium chrysogenum
Manually annotated by BRENDA team
Andi, B.; West, A.H.; Cook, P.F.
Stabilization and characterization of histidine-tagged homocitrate synthase from Saccharomyces cerevisiae
Arch. Biochem. Biophys.
421
243-254
2004
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Andi, B.; West, A.H.; Cook, P.F.
Kinetic mechanism of histidine-tagged homocitrate synthase from Saccharomyces cerevisiae
Biochemistry
43
11790-11795
2004
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Andi, B.; West, A.H.; Cook, P.F.
Regulatory mechanism of Histidine-tagged homocitrate synthase from Saccharomyces cerevisiae: I. KINETIC STUDIES
J. Biol. Chem.
280
31624-31632
2005
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Andi, B.; Cook, P.F.
Regulatory mechanism of Histidine-tagged homocitrate synthase from Saccharomyces cerevisiae: II. THEORY
J. Biol. Chem.
280
31633-31640
2005
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Qian, J.; West, A.H.; Cook, P.F.
Acid-base chemical mechanism of homocitrate synthase from Saccharomyces cerevisiae
Biochemistry
45
12136-12143
2006
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Qian, J.; Khandogin, J.; West, A.H.; Cook, P.F.
Evidence for a catalytic dyad in the active site of homocitrate synthase from Saccharomyces cerevisiae
Biochemistry
47
6851-6858
2008
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Quezada, H.; Aranda, C.; DeLuna, A.; Hernandez, H.; Calcagno, M.L.; Marin-Hernandez, A.; Gonzalez, A.
Specialization of the paralogue LYS21 determines lysine biosynthesis under respiratory metabolism in Saccharomyces cerevisiae
Microbiology
154
1656-1667
2008
Saccharomyces cerevisiae (P48570), Saccharomyces cerevisiae (Q12122), Saccharomyces cerevisiae
Manually annotated by BRENDA team
Scott, E.M.; Pillus, L.
Homocitrate synthase connects amino acid metabolism to chromatin functions through Esa1 and DNA damage
Genes Dev.
24
1903-1913
2010
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Quezada, H.; Marin-Hernandez, A.; Aguilar, D.; Lopez, G.; Gallardo-Perez, J.C.; Jasso-Chavez, R.; Gonzalez, A.; Saavedra, E.; Moreno-Sanchez, R.
The Lys20 homocitrate synthase isoform exerts most of the flux control over the lysine synthesis pathway in Saccharomyces cerevisiae
Mol. Microbiol.
82
578-590
2011
Saccharomyces cerevisiae, Saccharomyces cerevisiae BY4741
Manually annotated by BRENDA team
Wang, J.; Wu, Y.; Sun, X.; Yuan, Q.; Yan, Y.
De novo biosynthesis of glutarate via alpha-keto acid carbon chain extension and decarboxylation pathway in Escherichia coli
ACS Synth. Biol.
6
1922-1930
2017
Saccharomyces cerevisiae (P48570), Saccharomyces cerevisiae, Saccharomyces cerevisiae ATCC 204508 (P48570)
Manually annotated by BRENDA team