2.02012-05-31 14:21:18 -06002015-06-03 17:19:03 -0600ECMDB12249M2MDB000833L-Aspartate-semialdehydeL-Aspartate-semialdehyde is involved in both the lysine biosynthesis and homoserine biosynthesis pathways. AspSAL-aspartate β-semialdehydeL-Aspartate 4-semialdehydeL-aspartate b-semialdehydeL-Aspartate beta-semialdehydeL-Aspartate β-semialdehydeL-Aspartate-4-semialdehydeL-Aspartic 4-semialdehydeL-Aspartic acid β-semialdehydeL-Aspartic acid 4-semialdehydeL-Aspartic acid b-semialdehydeL-Aspartic acid beta-semialdehydeL-Aspartic acid β-semialdehydeL-Aspartic acid-4-semialdehydeL-Aspartic acid-semialdehydeC4H7NO3117.1033117.042593095(2S)-2-amino-4-oxobutanoic acidL-aspartic 4-semialdehyde15106-57-7N[C@@H](CC=O)C(O)=OInChI=1S/C4H7NO3/c5-3(1-2-6)4(7)8/h2-3H,1,5H2,(H,7,8)/t3-/m0/s1HOSWPDPVFBCLSY-VKHMYHEASA-NSolidCytosollogp-2.73logs0.28solubility2.25e+02 g/llogp-3.6pka_strongest_acidic1.95pka_strongest_basic8.98iupac(2S)-2-amino-4-oxobutanoic acidaverage_mass117.1033mono_mass117.042593095smilesN[C@@H](CC=O)C(O)=OformulaC4H7NO3inchiInChI=1S/C4H7NO3/c5-3(1-2-6)4(7)8/h2-3H,1,5H2,(H,7,8)/t3-/m0/s1inchikeyHOSWPDPVFBCLSY-VKHMYHEASA-Npolar_surface_area80.39refractivity25.61polarizability10.51rotatable_bond_count3acceptor_count4donor_count2physiological_charge0formal_charge0Arginine and proline metabolismec00330Cysteine and methionine metabolismec00270Phenylalanine, tyrosine and tryptophan biosynthesisec00400Glycine, serine and threonine metabolismec00260Lysine biosynthesisLysine is biosynthesized from L-aspartic acid. L-aspartic acid can be incorporated into the cell through various methods: C4 dicarboxylate / orotate:H+ symporter ,
glutamate / aspartate : H+ symporter GltP, dicarboxylate transporter , C4 dicarboxylate / C4 monocarboxylate transporter DauA, glutamate / aspartate ABC transporter
L-aspartic acid is phosphorylated by an ATP-driven Aspartate kinase resulting in ADP and L-aspartyl-4-phosphate. L-aspartyl-4-phosphate is then dehydrogenated through an NADPH driven aspartate semialdehyde dehydrogenase resulting in a release of phosphate, NADP and L-aspartic 4-semialdehyde (involved in methionine biosynthesis).
L-aspartic 4-semialdehyde interacts with a pyruvic acid through a 4-hydroxy-tetrahydrodipicolinate synthase resulting in a release of hydrogen ion, water and
(2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate. The latter compound is then reduced by an NADPH driven 4-hydroxy-tetrahydrodipicolinate reductase resulting in a release of water, NADP and (S)-2,3,4,5-tetrahydrodipicolinate, This compound interacts with succinyl-CoA and water through a tetrahydrodipicolinate succinylase resulting in a release of coenzyme A and N-Succinyl-2-amino-6-ketopimelate. This compound interacts with L-glutamic acid through a N-succinyldiaminopimelate aminotransferase resulting in oxoglutaric acid, N-succinyl-L,L-2,6-diaminopimelate. The latter compound is then desuccinylated by reacting with water through a N-succinyl-L-diaminopimelate desuccinylase resulting in a succinic acid and L,L-diaminopimelate. This compound is then isomerized through a diaminopimelate epimerase resulting in a meso-diaminopimelate (involved in peptidoglyccan biosynthesis I). This compound is then decarboxylated by a diaminopimelate decarboxylase resulting in a release of carbon dioxide and L-lysine.
L-lysine is then incorporated into lysine degradation pathway. Lysine also regulate its own biosynthesis by repressing dihydrodipicolinate synthase and also repressing lysine-sensitive aspartokinase 3.
A metabolic connection joins synthesis of an amino acid, lysine, to synthesis of cell wall material. Diaminopimelate is a precursor both for lysine and for cell wall components. The synthesis of lysine, methionine and threonine share two reactions at the start of the three pathways, the reactions converting L-aspartate to L-aspartate semialdehyde. The reaction involving aspartate kinase is carried out by three isozymes, one specific for synthesis of each end product amino acid. Each of the three aspartate kinase isozymes is regulated by its corresponding end product amino acid.PW000771ec00300MetabolicMicrobial metabolism in diverse environmentsec01120Monobactam biosynthesiseco00261Metabolic pathwayseco01100Secondary Metabolites: threonine biosynthesis from aspartateThe biosynthesis of threonine starts with L-aspartic acid being phosphorylated by an ATP driven Aspartate kinase resulting in an a release of an ADP and an L-aspartyl-4-phosphate. This compound interacts with a hydrogen ion through an NADPH driven aspartate semialdehyde dehydrogenase resulting in the release of a phosphate, an NADP and a L-aspartate-semialdehyde.The latter compound interacts with a hydrogen ion through a NADPH driven aspartate kinase / homoserine dehydrogenase resulting in the release of an NADP and a L-homoserine. L-homoserine is phosphorylated through an ATP driven homoserine kinase resulting in the release of an ADP, a hydrogen ion and a O-phosphohomoserine. The latter compound then interacts with a water molecule threonine synthase resulting in the release of a phosphate and an L-threonine. PW000976Metabolicmethionine biosynthesisThe de novo biosynthesis of methionine is an energy-costly process involving inputs from several other pathways. The carbon skeleton of methionine is derived from aspartate. The sulfur is derived from cysteine which derives its sulfur from sulfate assimilation. The methyl group is derived from serine via one-carbon metabolism. Methionine is also converted to S-adenosyl-L-methionine, a methyl group donor, by the product of gene metK .
The synthesis starts with a product of the lysine biosynthesis pathway, L-aspartate-semialdehyde. This compound is dehydrogenated by a NADPH
aspartate kinase / homoserine dehydrogenase resulting in NADP and L-homoserine. Homoserine is activated by O-succinylation in a reaction catalyzed by MetA. The product O-succinyl-L-homoserine combines with cysteine to form cystathionine in a reaction catalyzed by MetB. Lyase cleavage of cystathionine by MetC forms homocysteine. This β-cystathionase activity can also be supplied by MalY as demonstrated in vivo by the ability of constitutive MalY expression to complement metC mutants auxotrophic for methionine . Homocysteine is subsequently methylated by either MetH or MetE to produce methionine. In E. coli MetH can function only in the presence of exogenously supplied vitamin B12 (cobalamin), which represses MetE expression. B12 is likely to be available in the gut. In the absence of exogenously supplied B12, MetE catalyzes this final step of de novo methionine biosynthesis.
L-methionine is then transferred into the periplasmic space through a leucine efflux transporter.
Under stressful conditions there is further regulation of the pathway enzymes. Under heat-shock conditions growth is slowed due to the thermal instability of MetA. Oxidative stress affects MetE which contains an oxidation-sensitive cysteine residue at position 645 near the active site. Oxidation of methionone itself can also occur although the cell contains methionine sufloxide reductases MsrA and MsrB to combat this. Weak organic acids also generate oxidative stress, with more complex effects. Sulfur limitation depletes homocysteine which serves as a coactivator for MetR activation of MetE expression.
Due to the absence of this pathway in mammals, some of the bacterial biosynthetic enzymes are potential drug targets. In addition, although methionine is used as a food additive and a medication, its industrial scale production in microorganisms has not yet been achieved due to the complexity and strong regulation of its biosynthetic pathway.PW000814Metabolicthreonine biosynthesisThe biosynthesis of threonine starts with oxalacetic acid interacting with an L-glutamic acid through an aspartate aminotransferase resulting in a oxoglutaric acid and an L-aspartic acid. The latter compound is then phosphorylated by an ATP driven Aspartate kinase resulting in an a release of an ADP and an L-aspartyl-4-phosphate. This compound interacts with a hydrogen ion through an NADPH driven aspartate semialdehyde dehydrogenase resulting in the release of a phosphate, an NADP and a L-aspartate-semialdehyde.The latter compound interacts with a hydrogen ion through a NADPH driven aspartate kinase / homoserine dehydrogenase resulting in the release of an NADP and a L-homoserine. L-homoserine is phosphorylated through an ATP driven homoserine kinase resulting in the release of an ADP, a hydrogen ion and a O-phosphohomoserine. The latter compound then interacts with a water molecule threonine synthase resulting in the release of a phosphate and an L-threonine. PW000817Metaboliclysine biosynthesis IDAPLYSINESYN-PWYhomoserine biosynthesisHOMOSERSYN-PWYSpecdb::CMs2469Specdb::CMs39884Specdb::CMs160410Specdb::NmrOneD96638Specdb::NmrOneD96639Specdb::NmrOneD96640Specdb::NmrOneD96641Specdb::NmrOneD96642Specdb::NmrOneD96643Specdb::NmrOneD96644Specdb::NmrOneD96645Specdb::NmrOneD96646Specdb::NmrOneD96647Specdb::NmrOneD96648Specdb::NmrOneD96649Specdb::NmrOneD96650Specdb::NmrOneD96651Specdb::NmrOneD96652Specdb::NmrOneD96653Specdb::NmrOneD96654Specdb::NmrOneD96655Specdb::NmrOneD96656Specdb::NmrOneD96657Specdb::MsMs25334Specdb::MsMs25335Specdb::MsMs25336Specdb::MsMs31892Specdb::MsMs31893Specdb::MsMs31894Specdb::MsMs2817669Specdb::MsMs2817670Specdb::MsMs2817671Specdb::MsMs2887328Specdb::MsMs2887329Specdb::MsMs2887330HMDB12249439235388372C00441L-ASPARTATE-SEMIALDEHYDEKeseler, I. M., Collado-Vides, J., Santos-Zavaleta, A., Peralta-Gil, M., Gama-Castro, S., Muniz-Rascado, L., Bonavides-Martinez, C., Paley, S., Krummenacker, M., Altman, T., Kaipa, P., Spaulding, A., Pacheco, J., Latendresse, M., Fulcher, C., Sarker, M., Shearer, A. G., Mackie, A., Paulsen, I., Gunsalus, R. P., Karp, P. D. (2011). "EcoCyc: a comprehensive database of Escherichia coli biology." Nucleic Acids Res 39:D583-D590.21097882Kanehisa, M., Goto, S., Sato, Y., Furumichi, M., Tanabe, M. (2012). "KEGG for integration and interpretation of large-scale molecular data sets." Nucleic Acids Res 40:D109-D114.22080510van der Werf, M. J., Overkamp, K. M., Muilwijk, B., Coulier, L., Hankemeier, T. (2007). "Microbial metabolomics: toward a platform with full metabolome coverage." Anal Biochem 370:17-25.17765195Bifunctional aspartokinase/homoserine dehydrogenase 1P00561AK1H_ECOLIthrAhttp://ecmdb.ca/proteins/P00561.xmlBifunctional aspartokinase/homoserine dehydrogenase 2P00562AK2H_ECOLImetLhttp://ecmdb.ca/proteins/P00562.xmlDihydrodipicolinate synthaseP0A6L2DAPA_ECOLIdapAhttp://ecmdb.ca/proteins/P0A6L2.xmlAspartate-semialdehyde dehydrogenaseP0A9Q9DHAS_ECOLIasdhttp://ecmdb.ca/proteins/P0A9Q9.xmlUncharacterized protein yjhHP39359YJHH_ECOLIyjhHhttp://ecmdb.ca/proteins/P39359.xmlUncharacterized protein yagEP75682YAGE_ECOLIyagEhttp://ecmdb.ca/proteins/P75682.xmlL-Homoserine + NADP <> L-Aspartate-semialdehyde + Hydrogen ion + NADPHR01775L-Aspartate-semialdehyde + Pyruvic acid > 2,3-Dihydrodipicolinic acid + Hydrogen ion +2 WaterR02292DIHYDRODIPICSYN-RXNL-Aspartate-semialdehyde + NADP + Phosphate <> L-Aspartyl-4-phosphate + Hydrogen ion + NADPHR02291ASPARTATE-SEMIALDEHYDE-DEHYDROGENASE-RXNL-Homoserine + NAD <> L-Aspartate-semialdehyde + NADH + Hydrogen ionR01773L-Aspartate-semialdehyde + Pyruvic acid <> 2,3-Dihydrodipicolinic acid +2 WaterR02292Pyruvic acid + L-Aspartate-semialdehyde <> Hydrogen ion + Water + 2,3-Dihydrodipicolinic acidDIHYDRODIPICSYN-RXNNAD(P)<sup>+</sup> + L-Homoserine < NAD(P)H + L-Aspartate-semialdehyde + Hydrogen ionHOMOSERDEHYDROG-RXNL-Homoserine + NAD(P)(+) > L-Aspartate-semialdehyde + NAD(P)HL-Aspartate-semialdehyde + Pyruvic acid > (S)-2,3-dihydrodipicolinate +2 WaterL-Aspartate-semialdehyde + Inorganic phosphate + NADP > L-4-aspartyl phosphate + NADPHPyruvic acid + L-Aspartate-semialdehyde <> (2S,4S)-4-Hydroxy-2,3,4,5-tetrahydrodipicolinate + WaterR10147 L-Aspartyl-4-phosphate + NADPH + Hydrogen ion + NADPH > Phosphate + NADP + L-Aspartate-semialdehydePW_R002526L-Aspartate-semialdehyde + Pyruvic acid > Hydrogen ion + Water + (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate + (2S,4S)-4-Hydroxy-2,3,4,5-tetrahydrodipicolinatePW_R002527L-Aspartate-semialdehyde + Hydrogen ion + NADPH + NADPH > NADP + L-Homoserine + L-HomoserinePW_R002918L-Aspartate-semialdehyde + Pyruvic acid >2 2,3-Dihydrodipicolinic acid + Hydrogen ion +2 WaterL-Aspartate-semialdehyde + NADP + Phosphate <> L-Aspartyl-4-phosphate + Hydrogen ion + NADPHL-Aspartate-semialdehyde + Pyruvic acid >2 2,3-Dihydrodipicolinic acid + Hydrogen ion +2 Water