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EC Tree
The enzyme appears in viruses and cellular organisms
Synonyms
aminoadipate semialdehyde-glutamate reductase, aminoadipic semialdehyde-glutamate reductase, aminoadipic semialdehyde-glutamic reductase, dehydrogenase, saccharopine (nicotinamide adenine dinucleotide phosphate, glutamate-forming), epsilon-N-(L-glutaryl-2)-L-lysine:NAD+(P) oxidoreductase (L-2-aminoadipate-semialdehyde forming), saccharopine dehydrogenase, saccharopine dehydrogenase (L-glutamate forming), saccharopine reductase, SR1,
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aminoadipate semialdehyde-glutamate reductase
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aminoadipic semialdehyde-glutamate reductase
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aminoadipic semialdehyde-glutamic reductase
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dehydrogenase, saccharopine (nicotinamide adenine dinucleotide phosphate, glutamate-forming)
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epsilon-N-(L-glutaryl-2)-L-lysine:NAD+(P) oxidoreductase (L-2-aminoadipate-semialdehyde forming)
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saccharopine dehydrogenase
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saccharopine dehydrogenase (L-glutamate forming)
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saccharopine reductase
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saccharopine reductase
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saccharopine reductase
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O = L-glutamate + (S)-2-amino-6-oxohexanoate + NADPH + H+
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O = L-glutamate + (S)-2-amino-6-oxohexanoate + NADPH + H+
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O = L-glutamate + (S)-2-amino-6-oxohexanoate + NADPH + H+
ordered kinetic mechanism, the reduced dinucleotide substrate binds to enzyme first followed by L-alpha-aminoadipate-delta-semialdehyde, which adds in rapid equilibrium prior to L-glutamate, saccharopine is released prior to NADP+, primary deuterium kinetic isotope effects and solvent deuterium kinetic isotope effects, overview. A conformational change to open the site and release products (in the direction of saccharopine formation) is the rate limiting step. Two groups are involved in the acid-base chemistry of the reaction. An enzyme group with a pKa of 5.6 accepts a proton from the alpha-amine of glutamate to generate the neutral amine that can act as a nucleophile. The alpha-amine of glutamate attacks the carbonyl of the semialdehyde to generate the carbinolamine, which is protonated by a second enzyme group with a pKa of about 7.8-8.0. Ionizable residues that might play a role in the acid-base mechanism of the enzyme are D126, C154 and/or Y99
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N6-(L-1,3-dicarboxypropyl)-L-lysine:NADP+ oxidoreductase (L-glutamate-forming)
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
2-aminoadipate 6-semialdehyde + L-glutamate + NADPH + H+
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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L-glutamate + 2-aminoadipate 6-semialdehyde + NADPH + H+
saccharopine + NADP+ + H2O
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piperidine-6-carboxylic acid and alpha-aminoadipate are precursors for synthesis of alpha-aminoadipate 6-semialdehyde via 3 different pathways, penultimate step in L-lysine biosynthesis
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + (S)-2-amino-6-oxohexanoate + NADPH + H+
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + 2-aminoadipate 6-semialdehyde + NADPH + H+
saccharopine + NADP+ + H2O
L-glutamate + 2-aminoadipate 6-semialdehyde + NADPH + H+
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reverse reaction direction used for activity assay, end product is piperidine-6-carboxylic acid in assays using cell extract
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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N6-(L-1,3-dicarboxypropyl)-L-lysine is identical with saccharopine
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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N6-(L-1,3-dicarboxypropyl)-L-lysine is identical with saccharopine
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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N6-(L-1,3-dicarboxypropyl)-L-lysine is identical with saccharopine
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + (S)-2-amino-6-oxohexanoate + NADPH + H+
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + (S)-2-amino-6-oxohexanoate + NADPH + H+
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + 2-aminoadipate 6-semialdehyde + NADPH + H+
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + 2-aminoadipate 6-semialdehyde + NADPH + H+
enzyme catalyzes the penultimate step in lysine biosynthesis
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + 2-aminoadipate 6-semialdehyde + NADPH + H+
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + 2-aminoadipate 6-semialdehyde + NADPH + H+
saccharopine + NADP+ + H2O
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piperidine-6-carboxylic acid and alpha-aminoadipate are precursors for synthesis of alpha-aminoadipate 6-semialdehyde via 3 different pathways, penultimate step in L-lysine biosynthesis
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + (S)-2-amino-6-oxohexanoate + NADPH + H+
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + 2-aminoadipate 6-semialdehyde + NADPH + H+
enzyme catalyzes the penultimate step in lysine biosynthesis
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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2-aminoadipate 6-semialdehyde + L-glutamate + NADPH
N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
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lysine biosynthesis
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + (S)-2-amino-6-oxohexanoate + NADPH + H+
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N6-(L-1,3-dicarboxypropyl)-L-lysine + NADP+ + H2O
L-glutamate + (S)-2-amino-6-oxohexanoate + NADPH + H+
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NAD+
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NAD+ and NADP+ equally effective in 2-aminoadipate 6-semialdehyde formation
NADH
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NADPH far more effective than NADH in saccaropine formation
NADP+
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NAD+ and NADP+ equally effective in 2-aminoadipate 6-semialdehyde formation
NADPH
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NADPH
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far more effective than NADH in saccharopine formation
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2-amino-6-heptenoic acid
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competitive inhibition versus L-alpha-aminoadipate-delta-semialdehyde, uncompetitive inhibition versus NADPH, and noncompetitive inhibtition versus L-glutamate
2-oxoglutarate
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competitive inhibition versus L-glutamate and uncompetitive inhibition versus L-alpha-aminoadipate-delta-semialdehyde and NADPH; competitive inhibition versus saccharopine and uncompetitive inhibition versus NADP+
alpha-AASA
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shows noncompetitive inhibition versus saccharopine and uncompetitive inhibition versus NADP+
glyoxylic acid
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competitive inhibition versus saccharopine and uncompetitive inhibition versus NADP+
L-glutamate
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exhibits noncompetitive inhibition versus NADP+ and saccharopine
L-ornithine
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competitive inhibition versus saccharopine and uncompetitive inhibition versus NADP+
L-pipecolic acid
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competitive inhibition versus saccharopine and uncompetitive inhibition versus NADP+
N-oxalylglycine
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competitive inhibition versus saccharopine and uncompetitive inhibition versus NADP+
NADP+
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competitive inhibition versus NADPH, noncompetitive inhibition versus L-alpha-aminoadipate-delta-semialdehyde and L-glutamate
p-hydroxymercuribenzoate
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saccharopine
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exhibits noncompetitive inhibition against L-alpha-aminoadipate-delta-semialdehyde, L-glutamate, and NADPH
additional information
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not: carbonyl reagents
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L-leucine
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L-leucine
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competitive inhibition versus saccharopine and uncompetitive inhibition versus NADP+
NADPH
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inhibition is competitive versus NADP+ and noncompetitive versus saccharopine
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0.17
NADP+
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0.92
saccharopine
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22
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wild-type strain Wis 54-1255, cell extract
269.4
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after purification
additional information
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additional information
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10
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saccharopine degradation
8.8
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saccharopine degradation
9.5
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saccharopine degradation
7
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saccharopine formation
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formation of L-saccharopin
9
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assay at
9
formation of L-glutamate
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5.5 - 7.8
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pH 5.5: about 45% of activity maximum, pH 7.8: about 35% of activity maximum
8.3 - 10.3
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about 50% of activity maximum at pH 8.3 and 10.3
9 - 10
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about 50% of activity maximum at pH 9 and 10
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low activity
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brenda
serotype A, strain H99, human pathogen, chimeric spermidine synthase-saccharopine dehydrogenase gene (SPE3-LYS9)
SwissProt
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UniProt
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low activity
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fission yeast
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SwissProt
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gene lys7, strain Wis 54-1255
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UniProt
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baker's yeast
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physiological function
saccharopine reductase catalyzes the reductive amination of L-alpha-aminoadipate-delta-semialdehyde with L-glutamate to give saccharopine
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Magnaporthe oryzae (strain 70-15 / ATCC MYA-4617 / FGSC 8958)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Magnaporthe oryzae (strain 70-15 / ATCC MYA-4617 / FGSC 8958)
Magnaporthe oryzae (strain 70-15 / ATCC MYA-4617 / FGSC 8958)
Magnaporthe oryzae (strain 70-15 / ATCC MYA-4617 / FGSC 8958)
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48000
predicted from gene sequence
48900
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alpha2, 2 * 48900, predicted mass from the gene sequence
67000
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gel filtration with Sephadex G-100
73000
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density gradient centrifugation
84000
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gel filtration with Superdex 200
50000
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1 * 50000, SDS-PAGE
50000
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alpha2, 2 * 50000, SDS-PAGE
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dimer
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alpha2, 2 * 48900, predicted mass from the gene sequence; alpha2, 2 * 50000, SDS-PAGE
monomer
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1 * 50000, SDS-PAGE
additional information
comparison of enzyme structures from Saccharomyces cerevisiae and Magnoporthe grisea
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with hanging-drop vapour-diffusion technique
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analysis of the apoenzyme crystal structure determined at 1.7 A resolution
apo form of enzyme. Protein consists of domain I, a variant of the Rossman fold and binding to NADPH, domain II with an alpha/beta structure and binding saccharopine, and domain III with all-helical fold involved in closing the active site of the enzyme once substrates are bound
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C154S
site-directed mutagenesis
C154S/Y99F
site-directed mutagenesis
D126A
site-directed mutagenesis
D126A/C154S
site-directed mutagenesis
D126A/Y99F
site-directed mutagenesis
Y99F
site-directed mutagenesis
additional information
construction of 3 Spe3-Lys9 mutants, with defects in the spe3-part, the lys9-part, or both, which are auxotrophic for lysine and spermidine, spermidine, and lysine, respectively, transcription levels and phenotype overview, the polyamine auxotrophy due to defect spe3 cannot be overcome by spermine addition, while the mutan with lys 9 defect grows slowly at 30°C with lysine addition, but dies upon lysine starvation, the mutant with defects in both gene parts is avirulent and lethal
additional information
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construction of an enzyme-deficient mutant strain: disruption and inactivation of gene lys7 by double-recombination method leads to lysine auxotrophy and accumulation of piperideine-6-carboxylic acid, and with L-lysine as sole N-source and supplementation of DL-alpha-aminoadipic acid, also of pipecolic acid, transformation of the mutant strain with lys7 can restore enzyme activity
additional information
kinetic parameters of the mutants in the reaction direction of glutamate formation exhibit modest decreases. The pH-rate profiles obtained with all mutant enzymes decrease at low and high pH, suggesting acid and base catalytic groups are still present in all enzymes. Solvent kinetic deuterium isotope effects are all larger than those observed for wild-type enzyme
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-70°C, pH 8.0, 10 mM 2-mercaptoethanol, 5 mM EDTA
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Ni-NTA column chromatography
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purification of heterologously expressed enzyme
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cloned in Escherichia coli
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expressed in Escherichia coli
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expressed in Escherichia coli BL21/(DE-3) RIL cells
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gene lys, subcloning in Escherichia coli
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gene LYS9 is organized as a chimeric spermidine synthase-saccharopine dehydrogenase gene (SPE3-LYS9) encoding functional spermidine synthase, EC 2.5.1.16, and saccharopine dehydrogenase, DNA and amino acid sequence determination and analysis, expression of wild-type enzyme in Saccharomyces cerevisiae, the chimeric gene can complement a Saccharomyces cerevisiae lys9 mutant, but not a spe3 mutant
recombinant expression of wild-type and mutant enzymes in Saccharomyces cerevisiae strain LYS 9
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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
Naranjo, L.; Martin de Valmaseda, E.; Banuelos, O.; Lopez, P.; Riano, J.; Casqueiro, J.; Martin, J.F.
Conversion of pipecolic acid into lysine in Penicillium chrysogenum requires pipecolate oxidase and saccharopine reductase: characterization of the lys7 gene encoding saccharopine reductase
J. Bacteriol.
183
7165-7172
2001
Penicillium chrysogenum, Penicillium chrysogenum (Q96TW2)
brenda
Mukhopadhyay, A.; Mungre, S.M.; Desmukh, D.R.
Comparison of lysine and tryptophan catabolizing enzymes in rat and bovine tissues
Experientia
46
874-876
1990
Bos taurus, Rattus norvegicus
brenda
Schmidt, H.; Bode, R.; Birnbaum, D.
Regulation of the lysine biosynthesis in Pichia guilliermondii
Antonie van Leeuwenhoek
56
337-347
1989
Meyerozyma guilliermondii
brenda
Broquist, H.P.
Aminoadipic semialdehyde-glutamate reductase
Methods Enzymol.
17B
121-124
1971
Saccharomyces cerevisiae
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brenda
Jones, E.E.; Broquist, H.P.
Saccharopine, an intermediate of the aminoadipic acid pathway of lysine biosynthesis. 3. Aminoadipic semialdehyde-glutamate reductase
J. Biol. Chem.
241
3430-3434
1966
Saccharomyces cerevisiae
brenda
Storts, D.R.; Bhattacharjee, J.K.
Purification and properties of saccharopine dehydrogenase (glutamate forming) in the Saccharomyces cerevisiae lysine biosynthetic pathway
J. Bacteriol.
169
416-418
1987
Saccharomyces cerevisiae
brenda
Kinzel, J.J.; Bhattacharjee, J.K.
Role of pipecolic acid in the biosynthesis of lysine in Rhodotorula glutinis
J. Bacteriol.
138
410-417
1979
Rhodotorula glutinis
brenda
Johansson, E.; Steffens, J.J.; Emptage, M.; Lindqvist, Y.; Schneider, G.
Cloning, expression, purification and crystallization of saccharopine reductase from Magnaporthe grisea
Acta Crystallogr. Sect. D
56
662-664
2000
Pyricularia grisea
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brenda
Naranjo, L.; Martin de Valmaseda, E.; Casqueiro, J.; Ullan, R.V.; Lamas-Maceiras, M.; Banuelos, O.; Martin, J.F.
Inactivation of the lys7 gene, encoding saccharopine reductase in Penicillium chrysogenum, leads to accumulation of the secondary metabolite precursors piperideine-6-carboxylic acid and pipecolic acid from alpha-aminoadipic acid
Appl. Environ. Microbiol.
70
1031-1039
2004
Penicillium chrysogenum
brenda
Kingsbury, J.M.; Yang, Z.; Ganous, T.M.; Cox, G.M.; McCusker, J.H.
Novel chimeric spermidine synthase-saccharopine dehydrogenase gene (SPE3-LYS9) in the human pathogen Cryptococcus neoformans
Eukaryot. Cell
3
752-763
2004
Cryptococcus neoformans (Q6RXX2)
brenda
Andi, B.; Cook, P.F.; West, A.H.
Crystal structure of the his-tagged saccharopine reductase from Saccharomyces cerevisiae at 1.7-A resolution
Cell Biochem. Biophys.
46
17-26
2006
Saccharomyces cerevisiae
brenda
Vashishtha, A.K.; West, A.H.; Cook, P.F.
Overall kinetic mechanism of saccharopine dehydrogenase (L-glutamate forming) from Saccharomyces cerevisiae
Biochemistry
47
5417-5423
2008
Saccharomyces cerevisiae
brenda
Vashishtha, A.K.; West, A.H.; Cook, P.F.
Chemical mechanism of saccharopine reductase from Saccharomyces cerevisiae
Biochemistry
48
5899-5907
2009
Saccharomyces cerevisiae
brenda
Almasi, J.; Bushnell, E.; Gauld, J.
A QM/MM-based computational investigation on the catalytic mechanism of saccharopine reductase
Molecules
16
8569-8589
2011
Pyricularia oryzae (Q9P4R4)
brenda
Vashishtha, A.K.; West, A.H.; Cook, P.F.
Probing the chemical mechanism of saccharopine reductase from Saccharomyces cerevisiae using site-directed mutagenesis
Arch. Biochem. Biophys.
584
98-106
2015
Saccharomyces cerevisiae (P38999), Saccharomyces cerevisiae
brenda
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1.5.1.10 saccharopine dehydrogenase (NADP+, L-glutamate-forming)
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