2.0 2012-05-31 13:56:11 -0600 2015-09-13 12:56:12 -0600 ECMDB02251 M2MDB000449 L-Homoserine Homoserine is a more reactive variant of the amino acid serine. In this variant, the hydroxyl side chain contains an additional CH2 group which brings the hydroxyl group closer to its own carboxyl group, allowing it to chemically react to form a five-membered ring. This occurs at the point that amino acids normally join to their neighbours in a peptide bond. (S)-2-amino-4-hydroxy-Butanoate (S)-2-amino-4-hydroxy-Butanoic acid (S)-2-Amino-4-hydroxybutanoate (S)-2-Amino-4-hydroxybutanoic acid (S)-Homoserine 2-Amino-4-hydroxy-Butyrate 2-Amino-4-hydroxy-Butyric acid 2-Amino-4-hydroxy-L-Butyrate 2-Amino-4-hydroxy-L-Butyric acid 2-Amino-4-hydroxybutanoate 2-Amino-4-hydroxybutanoic acid 2-Amino-4-hydroxybutyrate 2-Amino-4-hydroxybutyric acid Homo-ser HomoSer Homoserine L-Homoserine C4H9NO3 119.1192 119.058243159 (2S)-2-amino-4-hydroxybutanoic acid L-homoserine 672-15-1 N[C@@H](CCO)C(O)=O InChI=1S/C4H9NO3/c5-3(1-2-6)4(7)8/h3,6H,1-2,5H2,(H,7,8)/t3-/m0/s1 UKAUYVFTDYCKQA-VKHMYHEASA-N Solid Cytosol Extra-organism Periplasm logp -3.31 ALOGPS logs 0.55 ALOGPS solubility 4.23e+02 g/l ALOGPS melting_point 203 oC logp -3.8 ChemAxon pka_strongest_acidic 2.22 ChemAxon pka_strongest_basic 9.16 ChemAxon iupac (2S)-2-amino-4-hydroxybutanoic acid ChemAxon average_mass 119.1192 ChemAxon mono_mass 119.058243159 ChemAxon smiles N[C@@H](CCO)C(O)=O ChemAxon formula C4H9NO3 ChemAxon inchi InChI=1S/C4H9NO3/c5-3(1-2-6)4(7)8/h3,6H,1-2,5H2,(H,7,8)/t3-/m0/s1 ChemAxon inchikey UKAUYVFTDYCKQA-VKHMYHEASA-N ChemAxon polar_surface_area 83.55 ChemAxon refractivity 26.91 ChemAxon polarizability 11.44 ChemAxon rotatable_bond_count 3 ChemAxon acceptor_count 4 ChemAxon donor_count 3 ChemAxon physiological_charge 0 ChemAxon formal_charge 0 ChemAxon Cysteine and methionine metabolism ec00270 Glycine, serine and threonine metabolism ec00260 Lysine biosynthesis Lysine 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. PW000771 ec00300 Metabolic Sulfur metabolism The sulfur metabolism pathway starts in three possible ways. The first is the uptake of sulfate through an active transport reaction via a sulfate transport system containing an ATP-binding protein which hydrolyses ATP. Sulfate is converted by the sulfate adenylyltransferase enzymatic complex to adenosine phosphosulfate through the addition of adenine from a molecule of ATP, along with one phosphate group. Adenosine phosphosulfate is further converted to phoaphoadenosine phosphosulfate through an ATP hydrolysis and dehydrogenation reaction by the adenylyl-sulfate kinase. Phoaphoadenosine phosphosulfate is finally dehydrogenated and converted to sulfite by phosphoadenosine phosphosulfate reductase. This reaction requires magnesium, and adenosine 3',5'-diphosphate is the bi-product. A thioredoxin is also oxidized. Sulfite can also be produced from the dehydrogenation of cyanide along with the conversion of thiosulfate to thiocyanate by the thiosulfate sulfurtransferase enzymatic complex. Sulfite next undergoes a series of reactions that lead to the production of pyruvic acid, which is a precursor for pathways such as gluconeogenesis. The first reaction in this series is the conversion of sulfite to hydrogen sulfide through hygrogenation and the deoxygenation of sulfite to form a water molecule. The reaction is catalyzed by the sulfite reductase [NADPH] flavoprotein alpha and beta components. Siroheme, 4Fe-4S, flavin mononucleotide, and FAD function as cofactors or prosthetic groups. Hydrogen sulfide next undergoes dehydrogenation in a reversible reaction to form L-Cysteine and acetic acid, via the cysteine synthase complex and the coenzyme pyridoxal 5'-phosphate. L-Cysteine is dehydrogenated and converted to 2-aminoacrylic acid (a bronsted acid) and hydrogen sulfide(which may be reused) by a larger enzymatic complex composed of cysteine synthase A/B, protein malY, cystathionine-β-lyase, and tryptophanase, along with the coenzyme pyridoxal 5'-phosphate. 2-aminoacrylic acid isomerizes to 2-iminopropanoate, which along with a water molecule and a hydrogen ion is lastly converted to pyruvic acid and ammonium in a spontaneous fashion. The second possible initial starting point for sulfur metabolism is the import of taurine(an alternate sulfur source) into the cytoplasm via the taurine ABC transporter complex. Taurine, oxoglutaric acid, and oxygen are converted to sulfite by the alpha-ketoglutarate-dependent taurine dioxygenase. Carbon dioxide, succinic acid, and aminoacetaldehyde are bi-products of this reaction. Sulfite next enters pyruvic acid synthesis as already described. The third variant of sulfur metabolism starts with the import of an alkyl sulfate into the cytoplasm via an aliphatic sulfonate ABC transporter complex which hydrolyses ATP. The alkyl sulfate is dehydrogenated and along with oxygen is converted to sulfite and an aldehyde by the FMNH2-dependent alkanesulfonate monooxygenase enzyme. Water and flavin mononucleotide(which is used in a subsequent reaction as a prosthetic group) are also produced. Sulfite is next converted to pyruvic acid by the process already described. PW000922 ec00920 Metabolic Microbial metabolism in diverse environments ec01120 Metabolic pathways eco01100 Secondary Metabolites: threonine biosynthesis from aspartate The 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. PW000976 Metabolic methionine biosynthesis The 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. PW000814 Metabolic threonine biosynthesis The 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. PW000817 Metabolic methionine biosynthesis I HOMOSER-METSYN-PWY threonine biosynthesis from homoserine HOMOSER-THRESYN-PWY homoserine biosynthesis HOMOSERSYN-PWY Specdb::CMs 624 Specdb::CMs 1064 Specdb::CMs 1142 Specdb::CMs 2844 Specdb::CMs 30371 Specdb::CMs 31210 Specdb::CMs 31211 Specdb::CMs 31848 Specdb::CMs 31849 Specdb::CMs 31850 Specdb::CMs 37719 Specdb::CMs 131567 Specdb::CMs 139301 Specdb::CMs 1072734 Specdb::CMs 1072736 Specdb::CMs 1072738 Specdb::CMs 1072740 Specdb::CMs 1072741 Specdb::CMs 1072743 Specdb::CMs 1072745 Specdb::CMs 1072746 Specdb::CMs 1072748 Specdb::CMs 1072750 Specdb::CMs 1072752 Specdb::CMs 1072754 Specdb::NmrOneD 1261 Specdb::NmrOneD 1498 Specdb::NmrOneD 3960 Specdb::NmrOneD 4242 Specdb::NmrOneD 4766 Specdb::NmrOneD 4767 Specdb::NmrOneD 145110 Specdb::NmrOneD 145111 Specdb::NmrOneD 145112 Specdb::NmrOneD 145113 Specdb::NmrOneD 145114 Specdb::NmrOneD 145115 Specdb::NmrOneD 145116 Specdb::NmrOneD 145117 Specdb::NmrOneD 145118 Specdb::NmrOneD 145119 Specdb::NmrOneD 145120 Specdb::NmrOneD 145121 Specdb::NmrOneD 145122 Specdb::NmrOneD 145123 Specdb::NmrOneD 145124 Specdb::NmrOneD 145125 Specdb::NmrOneD 145126 Specdb::NmrOneD 145127 Specdb::NmrOneD 145128 Specdb::MsMs 1008 Specdb::MsMs 1009 Specdb::MsMs 1010 Specdb::MsMs 4521 Specdb::MsMs 4522 Specdb::MsMs 4523 Specdb::MsMs 4524 Specdb::MsMs 4525 Specdb::MsMs 4526 Specdb::MsMs 4527 Specdb::MsMs 4528 Specdb::MsMs 4529 Specdb::MsMs 4530 Specdb::MsMs 4531 Specdb::MsMs 4532 Specdb::MsMs 4533 Specdb::MsMs 4534 Specdb::MsMs 4535 Specdb::MsMs 4536 Specdb::MsMs 4537 Specdb::MsMs 4538 Specdb::MsMs 4539 Specdb::MsMs 4540 Specdb::MsMs 4542 Specdb::MsMs 4543 Specdb::NmrTwoD 1033 Specdb::NmrTwoD 1444 HMDB00719 12647 12126 C00263 HOMO-SER HSE Homoserine Keseler, 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. 21097882 Kanehisa, 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. 22080510 Vijayendran, C., Barsch, A., Friehs, K., Niehaus, K., Becker, A., Flaschel, E. (2008). "Perceiving molecular evolution processes in Escherichia coli by comprehensive metabolite and gene expression profiling." Genome Biol 9:R72. 18402659 van 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. 17765195 Winder, C. L., Dunn, W. B., Schuler, S., Broadhurst, D., Jarvis, R., Stephens, G. M., Goodacre, R. (2008). "Global metabolic profiling of Escherichia coli cultures: an evaluation of methods for quenching and extraction of intracellular metabolites." Anal Chem 80:2939-2948. 18331064 Ishii, N., Nakahigashi, K., Baba, T., Robert, M., Soga, T., Kanai, A., Hirasawa, T., Naba, M., Hirai, K., Hoque, A., Ho, P. Y., Kakazu, Y., Sugawara, K., Igarashi, S., Harada, S., Masuda, T., Sugiyama, N., Togashi, T., Hasegawa, M., Takai, Y., Yugi, K., Arakawa, K., Iwata, N., Toya, Y., Nakayama, Y., Nishioka, T., Shimizu, K., Mori, H., Tomita, M. (2007). "Multiple high-throughput analyses monitor the response of E. coli to perturbations." Science 316:593-597. 17379776 Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009 Feb 12;457(7231):910-4. 19212411 Shoemaker JD, Elliott WH: Automated screening of urine samples for carbohydrates, organic and amino acids after treatment with urease. J Chromatogr. 1991 Jan 2;562(1-2):125-38. 2026685 Gazarian KG, Gening LV, Gazarian TG: L-Homoserine: a novel excreted metabolic marker of hepatitis B abnormally produced in liver from methionine. Med Hypotheses. 2002 Apr;58(4):279-83. 12027520 Compagnini A, Cunsolo V, Foti S, Saletti R: Improved accuracy in the matrix-assisted laser desorption/ionization-mass spectrometry determination of the molecular mass of cyanogen bromide fragments of proteins by post-cleavage reaction with tris(hydroxymethyl)aminomethane. Proteomics. 2001 Aug;1(8):967-74. 11683513 Kokusenya, Yoshio; Matsuoka, Manabu. Synthesis of amino acids by electrochemical reduction. I. Synthesis of L-homoserine by electrochemical reduction of L-asparagine. Denki Kagaku oyobi Kogyo Butsuri Kagaku (1987), 55(2), 174-5. http://hmdb.ca/system/metabolites/msds/000/000/638/original/HMDB00719.pdf?1358461291 Homoserine kinase P00547 KHSE_ECOLI thrB http://ecmdb.ca/proteins/P00547.xml Bifunctional aspartokinase/homoserine dehydrogenase 1 P00561 AK1H_ECOLI thrA http://ecmdb.ca/proteins/P00561.xml Bifunctional aspartokinase/homoserine dehydrogenase 2 P00562 AK2H_ECOLI metL http://ecmdb.ca/proteins/P00562.xml Homoserine O-succinyltransferase P07623 META_ECOLI metA http://ecmdb.ca/proteins/P07623.xml Inner membrane transporter rhtA P0AA67 RHTA_ECOLI rhtA http://ecmdb.ca/proteins/P0AA67.xml Outer membrane protein N P77747 OMPN_ECOLI ompN http://ecmdb.ca/proteins/P77747.xml Outer membrane pore protein E P02932 PHOE_ECOLI phoE http://ecmdb.ca/proteins/P02932.xml Homoserine/homoserine lactone efflux protein P0AG34 RHTB_ECOLI rhtB http://ecmdb.ca/proteins/P0AG34.xml Outer membrane protein F P02931 OMPF_ECOLI ompF http://ecmdb.ca/proteins/P02931.xml Outer membrane protein C P06996 OMPC_ECOLI ompC http://ecmdb.ca/proteins/P06996.xml L-Homoserine + NADP <> L-Aspartate-semialdehyde + Hydrogen ion + NADPH R01775 Adenosine triphosphate + L-Homoserine <> ADP + Hydrogen ion + O-Phosphohomoserine R01771 HOMOSERKIN-RXN L-Homoserine + Succinyl-CoA <> Coenzyme A + O-Succinyl-L-homoserine R01777 HOMSUCTRAN-RXN Adenosine triphosphate + L-Homoserine <> ADP + O-Phosphohomoserine R01771 HOMOSERKIN-RXN L-Homoserine + NAD <> L-Aspartate-semialdehyde + NADH + Hydrogen ion R01773 NAD(P)⁺ + L-Homoserine < NAD(P)H + L-Aspartate-semialdehyde + Hydrogen ion HOMOSERDEHYDROG-RXN L-Homoserine + Adenosine triphosphate > Hydrogen ion + O-Phosphohomoserine + ADP HOMOSERKIN-RXN L-Homoserine + Succinyl-CoA > O-Succinyl-L-homoserine + Coenzyme A HOMSUCTRAN-RXN L-Homoserine + NAD(P)(+) > L-Aspartate-semialdehyde + NAD(P)H Adenosine triphosphate + L-Homoserine > ADP + O-Phosphohomoserine Succinyl-CoA + L-Homoserine > CoA + O-Succinyl-L-homoserine L-Homoserine + Succinyl-CoA + L-Homoserine + Succinyl-CoA > Coenzyme A + O-Succinyl-L-homoserine PW_R002889 L-Aspartate-semialdehyde + Hydrogen ion + NADPH + NADPH > NADP + L-Homoserine + L-Homoserine PW_R002918 L-Homoserine + Adenosine triphosphate + L-Homoserine > Adenosine diphosphate + Hydrogen ion + O-Phosphohomoserine + ADP PW_R002920 Adenosine triphosphate + L-Homoserine <> ADP + Hydrogen ion + O-Phosphohomoserine Adenosine triphosphate + L-Homoserine <> ADP + Hydrogen ion + O-Phosphohomoserine 48 mM Na2HPO4, 22 mM KH2PO4, 10 mM NaCl, 45 mM (NH4)2SO4, supplemented with 1 mM MgSO4, 1 mg/l thiamine·HCl, 5.6 mg/l CaCl2, 8 mg/l FeCl3, 1 mg/l MnCl2·4H2O, 1.7 mg/l ZnCl2, 0.43 mg/l CuCl2·2H2O, 0.6 mg/l CoCl2·2H2O and 0.6 mg/l Na2MoO4·2H2O. 4 g/L Gluco Bioreactor, pH controlled, O2 and CO2 controlled, dilution rate: 0.2/h 16.1 uM 0.0 37 oC BW25113 Stationary Phase, glucose limited 64400 0 Ishii, N., Nakahigashi, K., Baba, T., Robert, M., Soga, T., Kanai, A., Hirasawa, T., Naba, M., Hirai, K., Hoque, A., Ho, P. Y., Kakazu, Y., Sugawara, K., Igarashi, S., Harada, S., Masuda, T., Sugiyama, N., Togashi, T., Hasegawa, M., Takai, Y., Yugi, K., Arakawa, K., Iwata, N., Toya, Y., Nakayama, Y., Nishioka, T., Shimizu, K., Mori, H., Tomita, M. (2007). "Multiple high-throughput analyses monitor the response of E. coli to perturbations." Science 316:593-597. 17379776