2.02012-05-31 13:56:11 -06002015-09-13 12:56:12 -0600ECMDB02251M2MDB000449L-HomoserineHomoserine 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)-Homoserine2-Amino-4-hydroxy-Butyrate2-Amino-4-hydroxy-Butyric acid2-Amino-4-hydroxy-L-Butyrate2-Amino-4-hydroxy-L-Butyric acid2-Amino-4-hydroxybutanoate2-Amino-4-hydroxybutanoic acid2-Amino-4-hydroxybutyrate2-Amino-4-hydroxybutyric acidHomo-serHomoSerHomoserineL-HomoserineC4H9NO3119.1192119.058243159(2S)-2-amino-4-hydroxybutanoic acidL-homoserine672-15-1N[C@@H](CCO)C(O)=OInChI=1S/C4H9NO3/c5-3(1-2-6)4(7)8/h3,6H,1-2,5H2,(H,7,8)/t3-/m0/s1UKAUYVFTDYCKQA-VKHMYHEASA-NSolidCytosolExtra-organismPeriplasmlogp-3.31logs0.55solubility4.23e+02 g/lmelting_point203 oClogp-3.8pka_strongest_acidic2.22pka_strongest_basic9.16iupac(2S)-2-amino-4-hydroxybutanoic acidaverage_mass119.1192mono_mass119.058243159smilesN[C@@H](CCO)C(O)=OformulaC4H9NO3inchiInChI=1S/C4H9NO3/c5-3(1-2-6)4(7)8/h3,6H,1-2,5H2,(H,7,8)/t3-/m0/s1inchikeyUKAUYVFTDYCKQA-VKHMYHEASA-Npolar_surface_area83.55refractivity26.91polarizability11.44rotatable_bond_count3acceptor_count4donor_count3physiological_charge0formal_charge0Cysteine and methionine metabolismec00270Glycine, 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.PW000771ec00300MetabolicSulfur metabolismThe 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.PW000922ec00920MetabolicMicrobial metabolism in diverse environmentsec01120Metabolic 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. PW000817Metabolicmethionine biosynthesis IHOMOSER-METSYN-PWYthreonine biosynthesis from homoserineHOMOSER-THRESYN-PWYhomoserine biosynthesisHOMOSERSYN-PWYSpecdb::CMs624Specdb::CMs1064Specdb::CMs1142Specdb::CMs2844Specdb::CMs30371Specdb::CMs31210Specdb::CMs31211Specdb::CMs31848Specdb::CMs31849Specdb::CMs31850Specdb::CMs37719Specdb::CMs131567Specdb::CMs139301Specdb::CMs1072734Specdb::CMs1072736Specdb::CMs1072738Specdb::CMs1072740Specdb::CMs1072741Specdb::CMs1072743Specdb::CMs1072745Specdb::CMs1072746Specdb::CMs1072748Specdb::CMs1072750Specdb::CMs1072752Specdb::CMs1072754Specdb::NmrOneD1261Specdb::NmrOneD1498Specdb::NmrOneD3960Specdb::NmrOneD4242Specdb::NmrOneD4766Specdb::NmrOneD4767Specdb::NmrOneD145110Specdb::NmrOneD145111Specdb::NmrOneD145112Specdb::NmrOneD145113Specdb::NmrOneD145114Specdb::NmrOneD145115Specdb::NmrOneD145116Specdb::NmrOneD145117Specdb::NmrOneD145118Specdb::NmrOneD145119Specdb::NmrOneD145120Specdb::NmrOneD145121Specdb::NmrOneD145122Specdb::NmrOneD145123Specdb::NmrOneD145124Specdb::NmrOneD145125Specdb::NmrOneD145126Specdb::NmrOneD145127Specdb::NmrOneD145128Specdb::MsMs1008Specdb::MsMs1009Specdb::MsMs1010Specdb::MsMs4521Specdb::MsMs4522Specdb::MsMs4523Specdb::MsMs4524Specdb::MsMs4525Specdb::MsMs4526Specdb::MsMs4527Specdb::MsMs4528Specdb::MsMs4529Specdb::MsMs4530Specdb::MsMs4531Specdb::MsMs4532Specdb::MsMs4533Specdb::MsMs4534Specdb::MsMs4535Specdb::MsMs4536Specdb::MsMs4537Specdb::MsMs4538Specdb::MsMs4539Specdb::MsMs4540Specdb::MsMs4542Specdb::MsMs4543Specdb::NmrTwoD1033Specdb::NmrTwoD1444HMDB007191264712126C00263HOMO-SERHSEHomoserineKeseler, I. 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Med Hypotheses. 2002 Apr;58(4):279-83.12027520Compagnini 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):967-74.11683513Kokusenya, 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?1358461291Homoserine kinaseP00547KHSE_ECOLIthrBhttp://ecmdb.ca/proteins/P00547.xmlBifunctional aspartokinase/homoserine dehydrogenase 1P00561AK1H_ECOLIthrAhttp://ecmdb.ca/proteins/P00561.xmlBifunctional aspartokinase/homoserine dehydrogenase 2P00562AK2H_ECOLImetLhttp://ecmdb.ca/proteins/P00562.xmlHomoserine O-succinyltransferaseP07623META_ECOLImetAhttp://ecmdb.ca/proteins/P07623.xmlInner membrane transporter rhtAP0AA67RHTA_ECOLIrhtAhttp://ecmdb.ca/proteins/P0AA67.xmlOuter membrane protein NP77747OMPN_ECOLIompNhttp://ecmdb.ca/proteins/P77747.xmlOuter membrane pore protein EP02932PHOE_ECOLIphoEhttp://ecmdb.ca/proteins/P02932.xmlHomoserine/homoserine lactone efflux proteinP0AG34RHTB_ECOLIrhtBhttp://ecmdb.ca/proteins/P0AG34.xmlOuter membrane protein FP02931OMPF_ECOLIompFhttp://ecmdb.ca/proteins/P02931.xmlOuter membrane protein CP06996OMPC_ECOLIompChttp://ecmdb.ca/proteins/P06996.xmlL-Homoserine + NADP <> L-Aspartate-semialdehyde + Hydrogen ion + NADPHR01775Adenosine triphosphate + L-Homoserine <> ADP + Hydrogen ion + O-PhosphohomoserineR01771HOMOSERKIN-RXNL-Homoserine + Succinyl-CoA <> Coenzyme A + O-Succinyl-L-homoserineR01777HOMSUCTRAN-RXNAdenosine triphosphate + L-Homoserine <> ADP + O-PhosphohomoserineR01771HOMOSERKIN-RXNL-Homoserine + NAD <> L-Aspartate-semialdehyde + NADH + Hydrogen ionR01773NAD(P)<sup>+</sup> + L-Homoserine < NAD(P)H + L-Aspartate-semialdehyde + Hydrogen ionHOMOSERDEHYDROG-RXNL-Homoserine + Adenosine triphosphate > Hydrogen ion + O-Phosphohomoserine + ADPHOMOSERKIN-RXNL-Homoserine + Succinyl-CoA > O-Succinyl-L-homoserine + Coenzyme AHOMSUCTRAN-RXNL-Homoserine + NAD(P)(+) > L-Aspartate-semialdehyde + NAD(P)HAdenosine triphosphate + L-Homoserine > ADP + O-PhosphohomoserineSuccinyl-CoA + L-Homoserine > CoA + O-Succinyl-L-homoserineL-Homoserine + Succinyl-CoA + L-Homoserine + Succinyl-CoA > Coenzyme A + O-Succinyl-L-homoserinePW_R002889L-Aspartate-semialdehyde + Hydrogen ion + NADPH + NADPH > NADP + L-Homoserine + L-HomoserinePW_R002918L-Homoserine + Adenosine triphosphate + L-Homoserine > Adenosine diphosphate + Hydrogen ion + O-Phosphohomoserine + ADPPW_R002920Adenosine triphosphate + L-Homoserine <> ADP + Hydrogen ion + O-PhosphohomoserineAdenosine triphosphate + L-Homoserine <> ADP + Hydrogen ion + O-Phosphohomoserine48 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 GlucoBioreactor, pH controlled, O2 and CO2 controlled, dilution rate: 0.2/h16.1uM0.037 oCBW25113Stationary Phase, glucose limited644000Ishii, 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