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(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate
(Z)-but-1-ene-1,2,4-tricarboxylate + H2O
(R)-homocitrate
?
-
-
-
-
?
(Z)-but-1-ene-1,2,4-tricarboxylate + H2O
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate
-
i.e. cis-homoaconitate, three different stereoisomeric substrate types, cis-homo1-aconitate, cis-homo2-aconitate, and cis-homo3-aconitate, in the reaction, overview
i.e. homoisocitrate, Arg26 of MJ1271 plays a key role in homoaconitate substrate recognition, while discriminating against the hydrophobic methyl or isopropyl gamma-chains of citraconate and 3-isopropylmalate. Catalytic Ser67 and Arg69 residues in the IMPI small subunit MJ1277 model are equivalent to Ser65 and Arg67 in MJ1271, but residues Val28-Tyr29 replace the polar Arg26-Thr27 residues in the flexible loop region between alpha2 and alpha3
-
r
(Z)-but-1-ene-1,2,4-tricarboxylic acid
?
-
-
-
-
?
(Z)-hex-1-ene-1,2,6-tricarboxylate
?
-
-
-
-
?
(Z)-pent-1-ene-1,2,5-tricarboxylate
?
-
-
-
-
?
2-Hydroxy-3-carboxyadipate
?
2-hydroxybutane-1,2,4-tricarboxylate
but-1-ene-1,2,4-tricarboxylate + H2O
cis-homoaconitate
homoisocitrate + H2O
cis-homoaconitate + H2O
(2R,3S)-homoisocitrate
-
-
-
-
?
additional information
?
-
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate
(Z)-but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate
(Z)-but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
-
r
2-Hydroxy-3-carboxyadipate
?
-
enzyme is involved in the L-Lys biosynthesis via 2-aminoadipate pathway
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
evaluation of the possible evolutionary scenario for the origin of the Lys biosynthetic pathway by comparison of similarity of homoaconitate hydratase to isopropylmalate isomerase and iron-responsive element binding proteins from fungi and other eukaryotes, eubacteria, and archaea
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
evaluation of the possible evolutionary scenario for the origin of the Lys biosynthetic pathway by comparison of similarity of homoaconitate hydratase to isopropylmalate isomerase and iron-responsive element binding proteins from fungi and other eukaryotes, eubacteria, and archaea
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
enzyme is involved in the L-Lys biosynthesis via 2-aminoadipate pathway
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
enzyme of the homocitrate pathway
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
evaluation of the possible evolutionary scenario for the origin of the Lys biosynthetic pathway by comparison of similarity of homoaconitate hydratase to isopropylmalate isomerase and iron-responsive element binding proteins from fungi and other eukaryotes, eubacteria, and archaea
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
enzyme of the lysine biosynthetic pathway
-
-
?
2-hydroxybutane-1,2,4-tricarboxylate
but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
?
2-hydroxybutane-1,2,4-tricarboxylate
but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
?
2-hydroxybutane-1,2,4-tricarboxylate
but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
?
2-hydroxybutane-1,2,4-tricarboxylate
but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
?
2-hydroxybutane-1,2,4-tricarboxylate
but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
?
2-hydroxybutane-1,2,4-tricarboxylate
but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
?
2-hydroxybutane-1,2,4-tricarboxylate
but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
?
2-hydroxybutane-1,2,4-tricarboxylate
but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
?
cis-homoaconitate
homoisocitrate + H2O
-
-
-
?
cis-homoaconitate
homoisocitrate + H2O
-
-
-
-
?
additional information
?
-
-
HACNMj is specific for cis-unsaturated tricarboxylates, while isopropylmalate isomerase, IPMIMj, recognizes cis-unsaturated dicarboxylates, substrate specificity determinants of homologous IPMI and HACN proteins from Methanocaldococcus jannaschii from a structural model show characteristic residues in a flexible loop region between R2 and R3 that distinguish HACN from IPMI and aconitase proteins, overview
-
-
?
additional information
?
-
-
no activity with cis-aconitate
-
-
?
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(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate
(Z)-but-1-ene-1,2,4-tricarboxylate + H2O
2-Hydroxy-3-carboxyadipate
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate
(Z)-but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate
(Z)-but-1-ene-1,2,4-tricarboxylate + H2O
-
-
-
-
r
2-Hydroxy-3-carboxyadipate
?
-
enzyme is involved in the L-Lys biosynthesis via 2-aminoadipate pathway
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
evaluation of the possible evolutionary scenario for the origin of the Lys biosynthetic pathway by comparison of similarity of homoaconitate hydratase to isopropylmalate isomerase and iron-responsive element binding proteins from fungi and other eukaryotes, eubacteria, and archaea
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
evaluation of the possible evolutionary scenario for the origin of the Lys biosynthetic pathway by comparison of similarity of homoaconitate hydratase to isopropylmalate isomerase and iron-responsive element binding proteins from fungi and other eukaryotes, eubacteria, and archaea
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
enzyme is involved in the L-Lys biosynthesis via 2-aminoadipate pathway
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
enzyme of the homocitrate pathway
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
evaluation of the possible evolutionary scenario for the origin of the Lys biosynthetic pathway by comparison of similarity of homoaconitate hydratase to isopropylmalate isomerase and iron-responsive element binding proteins from fungi and other eukaryotes, eubacteria, and archaea
-
-
?
2-Hydroxy-3-carboxyadipate
?
-
enzyme of the lysine biosynthetic pathway
-
-
?
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1.5
(R)-homocitrate
-
in 50 mM Tris-HCl (pH 8.5), 50 mM KCl, 5 mM MgCl2, 20 mM dithiothreitol, at 20°C
0.022 - 0.46
(Z)-but-1-ene-1,2,4-tricarboxylate
0.036 - 0.66
(Z)-hex-1-ene-1,2,6-tricarboxylate
0.03 - 1.6
(Z)-pent-1-ene-1,2,5-tricarboxylate
1.1
2-hydroxy-3-carboxyadipate
-
-
0.022
(Z)-but-1-ene-1,2,4-tricarboxylate
-
wild-type HACNMj, pH 7.0, temperature not specified in the publication
0.135
(Z)-but-1-ene-1,2,4-tricarboxylate
-
mutant R26K, pH 7.0, temperature not specified in the publication
0.22
(Z)-but-1-ene-1,2,4-tricarboxylate
-
mutant R26V, pH 7.0, temperature not specified in the publication
0.22
(Z)-but-1-ene-1,2,4-tricarboxylate
-
mutant T27A, pH 7.0, temperature not specified in the publication
0.3
(Z)-but-1-ene-1,2,4-tricarboxylate
-
pH 7.0, temperature not specified in the publication
0.46
(Z)-but-1-ene-1,2,4-tricarboxylate
-
mutant R26V/T27Y, pH 7.0, temperature not specified in the publication
0.036
(Z)-hex-1-ene-1,2,6-tricarboxylate
-
wild-type HACNMj, pH 7.0, temperature not specified in the publication
0.64
(Z)-hex-1-ene-1,2,6-tricarboxylate
-
mutant R26V/T27Y, pH 7.0, temperature not specified in the publication
0.65
(Z)-hex-1-ene-1,2,6-tricarboxylate
-
mutant T27A, pH 7.0, temperature not specified in the publication
0.66
(Z)-hex-1-ene-1,2,6-tricarboxylate
-
mutant R26V, pH 7.0, temperature not specified in the publication
0.03
(Z)-pent-1-ene-1,2,5-tricarboxylate
-
wild-type HACNMj, pH 7.0, temperature not specified in the publication
0.269
(Z)-pent-1-ene-1,2,5-tricarboxylate
-
mutant T27A, pH 7.0, temperature not specified in the publication
0.87
(Z)-pent-1-ene-1,2,5-tricarboxylate
-
mutant R26V, pH 7.0, temperature not specified in the publication
1.6
(Z)-pent-1-ene-1,2,5-tricarboxylate
-
mutant R26V/T27Y, pH 7.0, temperature not specified in the publication
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0.48 - 2.5
(Z)-but-1-ene-1,2,4-tricarboxylate
1.9 - 4.1
(Z)-hex-1-ene-1,2,6-tricarboxylate
0.66 - 6.6
(Z)-pent-1-ene-1,2,5-tricarboxylate
0.48
(Z)-but-1-ene-1,2,4-tricarboxylate
-
mutant R26V, pH 7.0, temperature not specified in the publication
0.75
(Z)-but-1-ene-1,2,4-tricarboxylate
-
wild-type HACNMj, pH 7.0, temperature not specified in the publication
1.43
(Z)-but-1-ene-1,2,4-tricarboxylate
-
mutant R26K, pH 7.0, temperature not specified in the publication
1.7
(Z)-but-1-ene-1,2,4-tricarboxylate
-
mutant R26V/T27Y, pH 7.0, temperature not specified in the publication
2.5
(Z)-but-1-ene-1,2,4-tricarboxylate
-
mutant T27A, pH 7.0, temperature not specified in the publication
1.9
(Z)-hex-1-ene-1,2,6-tricarboxylate
-
mutant R26V/T27Y, pH 7.0, temperature not specified in the publication
2.5
(Z)-hex-1-ene-1,2,6-tricarboxylate
-
wild-type HACNMj, pH 7.0, temperature not specified in the publication
2.8
(Z)-hex-1-ene-1,2,6-tricarboxylate
-
mutant R26V, pH 7.0, temperature not specified in the publication
4.1
(Z)-hex-1-ene-1,2,6-tricarboxylate
-
mutant T27A, pH 7.0, temperature not specified in the publication
0.66
(Z)-pent-1-ene-1,2,5-tricarboxylate
-
wild-type HACNMj, pH 7.0, temperature not specified in the publication
2.2
(Z)-pent-1-ene-1,2,5-tricarboxylate
-
mutant T27A, pH 7.0, temperature not specified in the publication
5.8
(Z)-pent-1-ene-1,2,5-tricarboxylate
-
mutant R26V, pH 7.0, temperature not specified in the publication
6.6
(Z)-pent-1-ene-1,2,5-tricarboxylate
-
mutant R26V/T27Y, pH 7.0, temperature not specified in the publication
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evolution
-
the mutations of the small-subunit HACN protein MJ1271 loop-region may reverse the evolution of HACN activity from an ancestral IPMI gene, demonstrating the evolutionary potential for promiscuity in hydro-lyase enzymes. Understanding these specificity determinants enables the functional reannotation of paralogous HACN and isopropylmalate isomerase, IPMI, genes in numerous genome sequences
metabolism
-
the enzyme is involved in the lysine biosynthetic pathway
additional information
-
the enzymes' stereospecific hydrolyase activity make it an attractive catalyst to produce diastereomers from unsaturated precursors
malfunction
L2 mutant is deficient in homoaconitase activity since it is complemented by the Aspergillus nidulans lysF gene. Wis 54-1255 gene lys3 complements the L2 mutation. Accumulation of homocitric acid in the L2 strain, resulting from the mutation in the lys3 (homoaconitase) gene, is required for the upregulation of the lysine biosynthetic genes. The mutant Lys3 protein is altered in a region required to bind the [4Fe-4S] cluster
malfunction
-
deletion of the LYS4 gene results in lysine auxotrophy. The mutant shows increased sensitivity to oxidative stress, agents that challenge cell wall/membrane integrity, and azole antifungal drugs
physiological function
lysF gene can complement the Penicillium chrysogenum L2 mutant deficient in homoaconitase activity
physiological function
-
homoaconitase proteins catalyze the isomerization of tricarboxylates with variable chain length gamma-carboxylate groups
physiological function
-
Lys4 plays an important role in mitochondrial iron metabolism, and is required for proper mitochondrial function in Cryptococcus neoformans. LYS4 is required for full virulence in Cryptococcus neoformans
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R26K
-
site-directed mutagenesis of small-subunit HACN protein MJ1271, the mutant variant forms a relatively efficient IPMI enzyme
R26V
-
site-directed mutagenesis of small-subunit HACN protein MJ1271, the mutant variant forms a relatively efficient IPMI enzyme. The R26V variant shows detectable dehydratase activity with 3-isopropylmalate
R26V/T27Y
-
site-directed mutagenesis of small-subunit HACN protein MJ1271, the mutant variant resembles the MJ1277 IPMI small subunit in its flexible loop sequence but demonstrates the broad substrate specificity of theR26V variant
T27A
-
site-directed mutagenesis of small-subunit HACN protein MJ1271, the mutant variant has uniformly lower specificity constants for both IPMI and HACN substrates compared to the wild-type enzyme. In a holoenzyme complex, the T27A variant catalyzes the hydration of citraconate and maleate substrates with a 10fold higher KM than wild-type IPMIMj, and the KM values for cis-homoaconitate substrates increase 10-20fold relative to the wild-type HACNMj. The T27A variant has no detectable dehydratase activity with 3-isopropylmalate
additional information
-
deletion of enzyme gene, results in almost avirulent mutant cells using a low dose intranasal mouse infection model
additional information
-
site-directed mutagenesis of small-subunit HACN protein MJ1271 produces loop-region variant proteins that are reconstituted with wild-type MJ1003 large-subunit protein. The heteromers form promiscuous hydro-lyases with reduced activity but broader substrate specificity, overview
additional information
-
small subunit of enzyme, expression in Thermus thermophilus. Gene product functions by forming a heterodimer with LysT subunit of Thermus thermophilus
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Broquist, H.P.
cis-Homoaconitase
Methods Enzymol.
17B
114-118
1971
Saccharomyces cerevisiae
-
brenda
Betterton, H.; Fjellstedt, T.; Matsuda, M.; Ogur, M.; Tate, R.
Localization of the homocitrate pathway
Biochim. Biophys. Acta
170
459-461
1968
Saccharomyces cerevisiae
brenda
Strassman, M.; Ceci, L.N.
Enzymatic formation of cis-homoaconitic acid, an intermediate in lysine biosynthesis in yeast
J. Biol. Chem.
241
5401-5407
1966
Saccharomyces cerevisiae
brenda
Irvin, S.D.; Bhattacharjee, J.K.
A unique fungal lysine biosynthesis enzyme shares a common ancestor with tricarboxylic acid cycle and leucine biosynthetic enzymes found in diverse organisms
J. Mol. Evol.
46
401-408
1998
Aspergillus nidulans, Saccharomyces cerevisiae, Methanocaldococcus jannaschii
brenda
Weidner, G.; Steffan, B.; Brakhage, A.A.
The Aspergillus nidulans lysF gene encodes homoaconitase, an enzyme involved in the fungus-specific lysine pathway
Mol. Gen. Genet.
255
237-247
1997
Aspergillus nidulans
brenda
Ye, Z.H.; Bhattacharjee, J.K.
Lysine biosynthesis pathway and biochemical blocks of lysine auxotrophs of Schizosaccharomyces pombe
J. Bacteriol.
170
5968-5970
1988
Schizosaccharomyces pombe
brenda
Liebmann, B.; Muhleisen, T.W.; Muller, M.; Hecht, M.; Weidner, G.; Braun, A.; Brock, M.; Brakhage, A.A.
Deletion of the Aspergillus fumigatus lysine biosynthesis gene lysF encoding homoaconitase leads to attenuated virulence in a low-dose mouse infection model of invasive aspergillosis
Arch. Microbiol.
181
378-383
2004
Aspergillus fumigatus
brenda
Lombo, T.; Takaya, N.; Miyazaki, J.; Gotoh, K.; Nishiyama, M.; Kosuge, T.; Nakamura, A.; Hoshino, T.
Functional analysis of the small subunit of the putative homoaconitase from Pyrococcus horikoshii in the Thermus lysine biosynthetic pathway
FEMS Microbiol. Lett.
233
315-324
2004
Pyrococcus horikoshii
brenda
Jia, Y.; Tomita, T.; Yamauchi, K.; Nishiyama, M.; Palmer, D.R.
Kinetics and product analysis of the reaction catalysed by recombinant homoaconitase from Thermus thermophilus
Biochem. J.
396
479-485
2006
Thermus thermophilus
brenda
Drevland, R.M.; Waheed, A.; Graham, D.E.
Enzymology and evolution of the pyruvate pathway to 2-oxobutyrate in Methanocaldococcus jannaschii
J. Bacteriol.
189
4391-4400
2007
Methanocaldococcus jannaschii
brenda
Jeyakanthan, J.; Drevland, R.M.; Gayathri, D.R.; Velmurugan, D.; Shinkai, A.; Kuramitsu, S.; Yokoyama, S.; Graham, D.E.
Substrate specificity determinants of the methanogen homoaconitase enzyme: structure and function of the small subunit
Biochemistry
49
2687-2696
2010
Methanocaldococcus jannaschii
brenda
Teves, F.; Lamas-Maceiras, M.; Garcia-Estrada, C.; Casqueiro, J.; Naranjo, L.; Ullan, R.V.; Scervino, J.M.; Wu, X.; Velasco-Conde, T.; Martin, J.F.
Transcriptional upregulation of four genes of the lysine biosynthetic pathway by homocitrate accumulation in Penicillium chrysogenum: homocitrate as a sensor of lysine-pathway distress
Microbiology
155
3881-3892
2009
Aspergillus nidulans (Q92412), Aspergillus nidulans, Penicillium chrysogenum (B1P2N4), Penicillium chrysogenum
brenda
Lee, E.H.; Lee, K.; Hwang, K.Y.
Structural characterization and comparison of the large subunits of IPM isomerase and homoaconitase from Methanococcus jannaschii
Acta Crystallogr. Sect. D
70
922-931
2014
Methanocaldococcus jannaschii (P81291), Methanocaldococcus jannaschii
brenda
Milewska, M.; Prokop, M.; Gabriel, I.; MilewskiWojciechowski, M.; Milewski, S.
Antifungal activity of homoaconitate and homoisocitrate analogs
Molecules
17
14022-14036
2012
Candida albicans
brenda
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 (P49367), Saccharomyces cerevisiae, Saccharomyces cerevisiae ATCC 204508 (P49367)
brenda
Do, E.; Park, M.; Hu, G.; Caza, M.; Kronstad, J.W.; Jung, W.H.
The lysine biosynthetic enzyme Lys4 influences iron metabolism, mitochondrial function and virulence in Cryptococcus neoformans
Biochem. Biophys. Res. Commun.
477
706-711
2016
Cryptococcus neoformans var. grubii
brenda