If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
Synonyms: L-methionine biosynthesis from L-homoserine, L-methionine biosynthesis by transsulfuration
|Superclasses:||Biosynthesis → Amino Acids Biosynthesis → Proteinogenic Amino Acids Biosynthesis → L-methionine Biosynthesis → L-methionine De Novo Biosynthesis|
Methionine can be biosynthesized by microorganisms and plants, although mammals cannot biosynthesize methionone de novo. Methionine is required for many important cellular functions. It is a basic building block of proteins and is required for the initiation of protein synthesis (via N-formyl-L- methionine). Methionine is also used in the synthesis of S-adenosyl-L-methionine which is the major methyl group donor in cellular metabolism. S-adenosyl-L-methionine is also utilized in pathways such as autoinducer AI-2 biosynthesis I and spermidine biosynthesis I.
Some bacteria including Escherichia coli synthesize methionine using organic sulfur through transsulfuration of O-acylated homoserine with cysteine to form cystathionine. Cystathionine is then cleaved to homocysteine, and methylated to methionine as shown in this pathway [Soda87]. Other bacteria, yeast and fungi can use a different route in which they directly assimilate inorganic sulfur by a sulfhydrylation (see MetaCyc pathways sulfate reduction I (assimilatory), L-homocysteine biosynthesis and L-methionine biosynthesis III). While many organisms seem to contain both routes for methionine biosynthesis, in E. coli and other enteric bacteria only the transsulfuration pathway is used. Reviewed in Greene, R.C. (1996) "Biosynthesis of Methionine" in [Neidhardt87] pp. 542-560).
The O-acyl group of homoserine is a succinyl group in enteric bacteria and some other Gram-negative bacteria, such as Pseudomanas aeruginosa and Pseudomonas putida. It is an acetyl group in fungi, yeast, and most Gram-positive bacteria ([Vermeij99, Soda87, Thomas97]). In both routes homocysteine is methylated to methionine via either a cobalamin-independent enzyme, or a cobalamin-dependent enzyme, depending upon the species or growth conditions [Ruckert03, Thomas97].
About This Pathway
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 (see pathway L-homoserine biosynthesis). The sulfur is derived from cysteine (see pathway L-cysteine biosynthesis I) which derives its sulfur from sulfate assimilation (see pathway sulfate reduction I (assimilatory)). The methyl group is derived from serine via one-carbon metabolism (see pathways N10-formyl-tetrahydrofolate biosynthesis and folate polyglutamylation). Methionine is also converted to S-adenosyl-L-methionine, a methyl group donor, by the product of gene metK (see pathway S-adenosyl-L-methionine cycle I). The main steps of methionine biosynthesis from homoserine are shown here.
Homoserine is first 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 [Zdych95]. 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. Although the pathway is largely regulated at the transcriptional level, feedback inhibition of the first enzyme homoserine O-succinyltransferase (MetA) by methionine and S-adenosyl-L-methionine has been shown.
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 [Ejim04]. 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 [Usuda05].
Review: Hondrop, E.R. and R.G. Matthews (2006) "Methionine" EcoSal 22.214.171.124 [ECOSAL]
Superpathways: aspartate superpathway , superpathway of L-lysine, L-threonine and L-methionine biosynthesis I , L-homoserine and L-methionine biosynthesis , superpathway of S-adenosyl-L-methionine biosynthesis
Ejim04: Ejim LJ, D'Costa VM, Elowe NH, Loredo-Osti JC, Malo D, Wright GD (2004). "Cystathionine beta-lyase is important for virulence of Salmonella enterica serovar Typhimurium." Infect Immun 72(6);3310-4. PMID: 15155634
Neidhardt87: Neidhardt FC, Ingraham J, Low KB, Magasanik B, Schaechter M, Umbarger HE "Escherichia coli and Salmonella typhimurium, Cellular and Molecular Biology, Volumes 1 & 2." Microbiology, Washington, D.C., 1987.
Ruckert03: Ruckert C, Puhler A, Kalinowski J (2003). "Genome-wide analysis of the L-methionine biosynthetic pathway in Corynebacterium glutamicum by targeted gene deletion and homologous complementation." J Biotechnol 104(1-3);213-28. PMID: 12948640
Aitken03: Aitken SM, Kim DH, Kirsch JF (2003). "Escherichia coli cystathionine gamma-synthase does not obey ping-pong kinetics. Novel continuous assays for the elimination and substitution reactions." Biochemistry 42(38);11297-306. PMID: 14503880
Arifuzzaman06: Arifuzzaman M, Maeda M, Itoh A, Nishikata K, Takita C, Saito R, Ara T, Nakahigashi K, Huang HC, Hirai A, Tsuzuki K, Nakamura S, Altaf-Ul-Amin M, Oshima T, Baba T, Yamamoto N, Kawamura T, Ioka-Nakamichi T, Kitagawa M, Tomita M, Kanaya S, Wada C, Mori H (2006). "Large-scale identification of protein-protein interaction of Escherichia coli K-12." Genome Res 16(5);686-91. PMID: 16606699
Awano03: Awano N, Wada M, Kohdoh A, Oikawa T, Takagi H, Nakamori S (2003). "Effect of cysteine desulfhydrase gene disruption on L-cysteine overproduction in Escherichia coli." Appl Microbiol Biotechnol 62(2-3);239-43. PMID: 12883870
Awano05: Awano N, Wada M, Mori H, Nakamori S, Takagi H (2005). "Identification and functional analysis of Escherichia coli cysteine desulfhydrases." Appl Environ Microbiol 71(7);4149-52. PMID: 16000837
Banerjee89: Banerjee RV, Johnston NL, Sobeski JK, Datta P, Matthews RG (1989). "Cloning and sequence analysis of the Escherichia coli metH gene encoding cobalamin-dependent methionine synthase and isolation of a tryptic fragment containing the cobalamin-binding domain." J Biol Chem 1989;264(23);13888-95. PMID: 2668277
Banerjee90: Banerjee RV, Frasca V, Ballou DP, Matthews RG (1990). "Participation of cob(I) alamin in the reaction catalyzed by methionine synthase from Escherichia coli: a steady-state and rapid reaction kinetic analysis." Biochemistry 1990;29(50);11101-9. PMID: 2271698
Belfaiza86: Belfaiza J, Parsot C, Martel A, de la Tour CB, Margarita D, Cohen GN, Saint-Girons I (1986). "Evolution in biosynthetic pathways: two enzymes catalyzing consecutive steps in methionine biosynthesis originate from a common ancestor and possess a similar regulatory region." Proc Natl Acad Sci U S A 83(4);867-71. PMID: 3513164
Bertoldi05: Bertoldi M, Cellini B, Laurents DV, Borri Voltattorni C (2005). "Folding pathway of the pyridoxal 5'-phosphate C-S lyase MalY from Escherichia coli." Biochem J 389(Pt 3);885-98. PMID: 15823094
Born99: Born TL, Blanchard JS (1999). "Enzyme-catalyzed acylation of homoserine: mechanistic characterization of the Escherichia coli metA-encoded homoserine transsuccinylase." Biochemistry 1999;38(43);14416-23. PMID: 10572016
Boysen10: Boysen A, Moller-Jensen J, Kallipolitis B, Valentin-Hansen P, Overgaard M (2010). "Translational regulation of gene expression by an anaerobically induced small non-coding RNA in Escherichia coli." J Biol Chem 285(14);10690-702. PMID: 20075074
Brzovic90: Brzovic P, Holbrook EL, Greene RC, Dunn MF (1990). "Reaction mechanism of Escherichia coli cystathionine gamma-synthase: direct evidence for a pyridoxamine derivative of vinylglyoxylate as a key intermediate in pyridoxal phosphate dependent gamma-elimination and gamma-replacement reactions." Biochemistry 1990;29(2);442-51. PMID: 2405904
Chu85: Chu J, Shoeman R, Hart J, Coleman T, Mazaitis A, Kelker N, Brot N, Weissbach H (1985). "Cloning and expression of the metE gene in Escherichia coli." Arch Biochem Biophys 239(2);467-74. PMID: 2988449
Clausen00: Clausen T, Schlegel A, Peist R, Schneider E, Steegborn C, Chang YS, Haase A, Bourenkov GP, Bartunik HD, Boos W (2000). "X-ray structure of MalY from Escherichia coli: a pyridoxal 5'-phosphate-dependent enzyme acting as a modulator in mal gene expression." EMBO J 19(5);831-42. PMID: 10698925
Clausen96: Clausen T, Huber R, Laber B, Pohlenz HD, Messerschmidt A (1996). "Crystal structure of the pyridoxal-5'-phosphate dependent cystathionine beta-lyase from Escherichia coli at 1.83 A." J Mol Biol 262(2);202-24. PMID: 8831789
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