Literature summary for 1.1.1.39 extracted from

Tronconi, M.A.; Wheeler, M.C.; Martinatto, A.; Zubimendi, J.P.; Andreo, C.S.; Drincovich, M.F.
Allosteric substrate inhibition of Arabidopsis NAD-dependent malic enzyme 1 is released by fumarate (2015), Phytochemistry, 111, 37-47.

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Activating Compound

Activating Compound	Comment	Organism	Structure
fumarate	Arabidopsis NAD-ME1 is strongly stimulated by fumarate. Fumarate binding turns NAD-ME1 into a hyperbolic and high substrate affinity enzyme. This effect is also observed when the allosteric site is either removed or altered. Hence, fumarate is not really an activator, but suppresses the inhibitory effect of L-malate. Binding of L-malate and fumarate at the same allosteric site	Arabidopsis thaliana
fumarate	Arabidopsis NAD-ME1 is strongly stimulated by fumarate. Fumarate binding turns NAD-ME1 into a hyperbolic and high substrate affinity enzyme. This effect is also observed when the allosteric site is either removed or altered. Hence, fumarate is not really an activator, but suppresses the inhibitory effect of L-malate. Binding of L-malate and fumarate at the same allosteric site. Arg84 is essential for fumarate activation	Arabidopsis thaliana

Cloned(Commentary)

Cloned (Comment)	Organism
recombinant expression of His-tagged wild-type and mutant enzymes in Escherichia coli strain BL21(DE3)	Arabidopsis thaliana

Protein Variants

Protein Variants	Comment	Organism
additional information	mutants and chimeric proteins of NAD-ME1 and -2 indicated that the amino-terminal region of NAD-ME1 is implicated in fumarate activation and sigmoidal L-malate responses, structure-function analysis, overview. Generation of chimeric protein NAD-ME1q, which is composed of the first 176 amino acid residues of isozyme NAD-ME2 and the central and C-terminal sequence of isozyme NAD-ME1, exhibits a significantly lower Km L-malate value than the parental isoforms and a hyperbolic behavior that is not modified by fumarate	Arabidopsis thaliana
additional information	mutants and chimeric proteins of NAD-ME1 and -2 indicated that the amino-terminal region of NAD-ME1 is implicated in fumarate activation and sigmoidal L-malate responses, structure-function analysis, overview. Generation of the chimeric protein NAD-ME2q, that possesses the first 176 amino acid residues of NAD-ME1 and the central and C-terminal sequence of NAD-ME2, presents a sigmoidal L-malate response similar to the one for NAD-ME1, but also a higher Km L-malate value and a lower kcat value. NAD-ME2q is activated by fumarate and an increase in its concentration produces a decrease in Km and nH values. At 4 mM fumarate, the Lmalate saturation curve is hyperbolic (nH = 1.1) with an 8fold decrease in Km value. There are no significant changes in kcat value by addition of fumarate, which implies a 9fold increase in NAD-ME2q catalytic efficiency when compared to the enzyme in the absence of fumarate	Arabidopsis thaliana
R50A	site-directed mutagenesis, the mutant does not show altered kinetics after addition of fumarate	Arabidopsis thaliana
R80A	site-directed mutagenesis, the mutant shows altered kinetics after addition of fumarate	Arabidopsis thaliana
R84A	site-directed mutagenesis, the mutant does not show altered kinetics after addition of fumarate	Arabidopsis thaliana

KM Value [mM]

KM Value [mM]	KM Value Maximum [mM]	Substrate	Comment	Organism	Structure
additional information	-	additional information	Arabidopsis NAD-ME1 exhibits a non-hyperbolic behavior for the substrate L-malate and presents a sigmoidal kinetic response for L-malate. Fumarate binding turns NAD-ME1 into a hyperbolic and high substrate affinity enzyme, overview	Arabidopsis thaliana
additional information	-	additional information	NAD-ME2 shows a typical hyperbolic behavior	Arabidopsis thaliana

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
mitochondrion	-	Arabidopsis thaliana	5739	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	a divalent metal ion, Mn+2 or Mg+2+, is essential for the enzyme reaction	Arabidopsis thaliana
Mn2+	a divalent metal ion, Mn+2 or Mg+2+, is essential for the enzyme reaction	Arabidopsis thaliana

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
(S)-malate + NAD+	Arabidopsis thaliana	-	pyruvate + CO2 + NADH	-	r

Organism

Organism	UniProt	Comment	Textmining
Arabidopsis thaliana	Q8L7K9	-	-
Arabidopsis thaliana	Q9SIU0	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
(S)-malate + NAD+	-	Arabidopsis thaliana	pyruvate + CO2 + NADH	-	r
additional information	NAD-ME1 has a regulatory site for L-malate that can also bind fumarate	Arabidopsis thaliana	?	-	?
additional information	NAD-ME1 has a regulatory site for L-malate that can also bind fumarate. L-Malate binding to this site elicits a sigmoidal and low substrate-affinity response, whereas fumarate binding turns NAD-ME1 into a hyperbolic and high substrate affinity enzyme. This effect is also observed when the allosteric site is either removed or altered. Fumarate is not really an activator, but suppresses the inhibitory effect of L-malate. Residues Arg50, Arg80 and Arg84 show different roles in organic acid binding. These residues form a triad, which is the basis of the homo and heterotrophic effects that characterize NAD-ME1	Arabidopsis thaliana	?	-	?

Synonyms

Synonyms	Comment	Organism
AT2g13560	-	Arabidopsis thaliana
At4g00570	-	Arabidopsis thaliana
NAD-dependent malic enzyme 1	-	Arabidopsis thaliana
NAD-dependent malic enzyme 2	-	Arabidopsis thaliana
NAD-ME1	-	Arabidopsis thaliana
NAD-ME2	-	Arabidopsis thaliana

Cofactor

Cofactor	Comment	Organism	Structure
NAD+	-	Arabidopsis thaliana
NADH	-	Arabidopsis thaliana

General Information

General Information	Comment	Organism
additional information	mutants and chimeric proteins of NAD-ME1 and -2 indicated that the amino-terminal region of NAD-ME1 is implicated in fumarate activation and sigmoidal L-malate responses, structure-function analysis, overview	Arabidopsis thaliana
additional information	residues Arg50, Arg80 and Arg84 show different roles in organic acid binding. These residues form a triad, which is the basis of the homo and heterotrophic effects that characterize NAD-ME1. Mutants and chimeric proteins of NAD-ME1 and -2 indicated that the amino-terminal region of NAD-ME1 is implicated in fumarate activation and sigmoidal L-malate responses, structure-function analysis, overview	Arabidopsis thaliana
physiological function	plant mitochondria can use L-malate and fumarate, which accumulate in large levels, as respiratory substrates. In part, this property is due to the presence of NAD-dependent malic enzymes (NAD-ME). Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage	Arabidopsis thaliana
physiological function	Plant mitochondria can use L-malate and fumarate, which accumulate in large levels, as respiratory substrates. In part, this property is due to the presence of NAD-dependent malic enzymes (NAD-ME). Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage. Important role of NAD-ME1 in processes that control flow of C4 organic acids in Arabidopsis mitochondrial metabolism.. NAD-ME1 exhibits a complex homo and heterotrophic allosteric regulation with L-malate wielding an inhibitory effect that is cancelled by competitive fumarate binding	Arabidopsis thaliana

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Release 2023.1 (January 2023)