This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Amino Acids Biosynthesis → Proteinogenic Amino Acids Biosynthesis → L-methionine Biosynthesis → L-methionine Salvage → S-methyl-5-thio-alpha-D-ribose 1-phosphate degradation|
|Degradation/Utilization/Assimilation → Nucleosides and Nucleotides Degradation → S-methyl-5-thio-alpha-D-ribose 1-phosphate degradation|
Some taxa known to possess this pathway include : Arabidopsis thaliana col, Bacillus subtilis, Bacillus subtilis subtilis 168, Homo sapiens, Klebsiella oxytoca, Klebsiella pneumoniae, Lupinus luteus, Mus musculus, Oryza sativa, Solanum lycopersicum
The biosynthesis of several important metabolites involves the consumption of L-methionine through the utilization of S-adenosyl-L-methionine (SAM), in a reaction that releases S-methyl-5'-thioadenosine (MTA). These metabilites include polyamines (see spermine biosynthesis, spermidine biosynthesis I and aminopropylcadaverine biosynthesis), ethylene (see ethylene biosynthesis I (plants)), and bacterial auto-inducers (see autoinducer AI-1 biosynthesis).
MTA is a strong inhibitor of polyamine biosynthesis and transmethylation reactions, and its concentration is tightly regulated through the methionine salvage cycle, where MTA is recycled through a series of reactions back to L-methionine.
The methionine salvage pathway is present with some variations in all types of organisms [Albers09]. It has been partially characterized from a number of organisms, including bacteria [Myers93, Wray95, Cornell96a, Dai99a, Dai01], plants [Baur72, Murr75, Kushad83, Miyazaki87a], yeast [Marchitto85], protozoal parasites [Sufrin95, Berger01a] and rat [Backlund81, Backlund82, Wray95]. The pathway was best studied in the Gram-negative bacterium Klebsiella pneumoniae.
While most of the pathway is conserved among all organisms, several variants exist that differ in the initial steps of the pathway, between S-methyl-5'-thioadenosine (MTA) and 5-methylthioribulose 1-phosphate (MTRP). These variants, describing bacteria and plants, higher eukaryotes, and protozoa, are described by several pathways under S-methyl-5'-thioadenosine Degradation. This metabolic differences in the early steps of the methionine salvage pathway are being exploited for developing new drugs targeted against pathogenic microorganisms that utilize the MTA nucleosidase-MTR kinase pathway [Riscoe88, Gianotti90, Tower91].
About This Pathway
This pathway describes the conserved part of the methionine salvage cycle, starting with S-methyl-5-thio-α-D-ribose 1-phosphate. In 6 steps, comprising an isomerase, a dehydratase, an enolase, a phosphatase, an oxygenase, and a transaminase, S-methyl-5-thio-α-D-ribose 1-phosphate is converted to L-methionine [Albers09]. The last enzyme, a glutamine-dependent transaminase, produces the byproduct 2-oxoglutaramate, which is believed to be toxic. Thus an additional enzyme, an ω-amidase that converts the latter to 2-oxoglutarate, is also considered a part of the pathway [Ellens14].
A few notes of interest about the enzymes of this pathway
At least in some strains, such as Bacillus subtilis, EC 220.127.116.11, 2,3-diketo-5-methylthiopentyl-1-phosphate enolase, is a member of the RubisCO protein family [Imker07].
The reaction catalyzed by EC 18.104.22.168, acireductone dioxygenase [iron(II)-requiring], can occur non-enzymatically in the presence of air [Wray95]. It is yet unknown whether the non-enzymatic reaction occurs in vivo [Wray95].
If the enzyme that usually catalyzes EC 22.214.171.124, acireductone dioxygenase [iron(II)-requiring] binds a Ni2+ instead of Fe2+, it catalyzes a different reaction ( EC 126.96.36.199, acireductone dioxygenase (Ni2+-requiring)), forming a shunt of the methionine salvage pathway (see 3-methylthiopropanoate biosynthesis) [Dai01, Dai99a, Wray95]. The purpose of this off-pathway reaction is yet unknown; it may, however, provide a mechanism for regulating L-methionine levels in vivo [Dai01].
In some organisms the reactions catalyzed by EC 188.8.131.52, 2,3-diketo-5-methylthiopentyl-1-phosphate enolase and EC 184.108.40.206, 2-hydroxy-3-keto-5-methylthiopentenyl-1-phosphate phosphatase are catalyzed by a single enzyme, EC 220.127.116.11, acireductone synthase (MtnC).
Albers09: Albers E (2009). "Metabolic characteristics and importance of the universal methionine salvage pathway recycling methionine from 5'-methylthioadenosine." IUBMB Life 61(12);1132-42. PMID: 19946895
Backlund82: Backlund PS, Chang CP, Smith RA (1982). "Identification of 2-keto-4-methylthiobutyrate as an intermediate compound in methionine synthesis from 5'-methylthioadenosine." J Biol Chem 1982;257(8);4196-202. PMID: 7068632
Cornell96a: Cornell KA, Winter RW, Tower PA, Riscoe MK (1996). "Affinity purification of 5-methylthioribose kinase and 5-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Klebsiella pneumoniae." Biochem J 1996;317 ( Pt 1);285-90. PMID: 8694776
Ellens14: Ellens KW, Richardson LG, Frelin O, Collins J, Ribeiro CL, Hsieh YF, Mullen RT, Hanson AD (2014). "Evidence that glutamine transaminase and omega-amidase potentially act in tandem to close the methionine salvage cycle in bacteria and plants." Phytochemistry. PMID: 24837359
Gianotti90: Gianotti AJ, Tower PA, Sheley JH, Conte PA, Spiro C, Ferro AJ, Fitchen JH, Riscoe MK (1990). "Selective killing of Klebsiella pneumoniae by 5-trifluoromethylthioribose. Chemotherapeutic exploitation of the enzyme 5-methylthioribose kinase." J Biol Chem 1990;265(2);831-7. PMID: 2153115
Imker07: Imker HJ, Fedorov AA, Fedorov EV, Almo SC, Gerlt JA (2007). "Mechanistic diversity in the RuBisCO superfamily: the "enolase" in the methionine salvage pathway in Geobacillus kaustophilus." Biochemistry 46(13);4077-89. PMID: 17352497
Marchitto85: Marchitto KS, Ferro AJ (1985). "The metabolism of 5'-methylthioadenosine and 5-methylthioribose 1-phosphate in Saccharomyces cerevisiae." J Gen Microbiol 1985;131 ( Pt 9);2153-64. PMID: 3906034
Myers93: Myers RW, Wray JW, Fish S, Abeles RH (1993). "Purification and characterization of an enzyme involved in oxidative carbon-carbon bond cleavage reactions in the methionine salvage pathway of Klebsiella pneumoniae." J Biol Chem 1993;268(33);24785-91. PMID: 8227039
Sufrin95: Sufrin JR, Meshnick SR, Spiess AJ, Garofalo-Hannan J, Pan XQ, Bacchi CJ (1995). "Methionine recycling pathways and antimalarial drug design." Antimicrob Agents Chemother 1995;39(11);2511-5. PMID: 8585735
Tower91: Tower PA, Johnson LL, Ferro AJ, Fitchen JH, Riscoe MK (1991). "Synergistic activity of 5-trifluoromethylthioribose and inhibitors of methionine synthesis against Klebsiella pneumoniae." Antimicrob Agents Chemother 1991;35(8);1557-61. PMID: 1929327
Wray95: Wray JW, Abeles RH (1995). "The methionine salvage pathway in Klebsiella pneumoniae and rat liver. Identification and characterization of two novel dioxygenases." J Biol Chem 1995;270(7);3147-53. PMID: 7852397
Ashida03: Ashida H, Saito Y, Kojima C, Kobayashi K, Ogasawara N, Yokota A (2003). "A functional link between RuBisCO-like protein of Bacillus and photosynthetic RuBisCO." Science 302(5643);286-90. PMID: 14551435
Ashida08: Ashida H, Saito Y, Kojima C, Yokota A (2008). "Enzymatic characterization of 5-methylthioribulose-1-phosphate dehydratase of the methionine salvage pathway in Bacillus subtilis." Biosci Biotechnol Biochem 72(4);959-67. PMID: 18391471
Balakrishnan93: Balakrishnan R, Frohlich M, Rahaim PT, Backman K, Yocum RR (1993). "Appendix. Cloning and sequence of the gene encoding enzyme E-1 from the methionine salvage pathway of Klebsiella oxytoca." J Biol Chem 1993;268(33);24792-5. PMID: 8227040
Berger03: Berger BJ, English S, Chan G, Knodel MH (2003). "Methionine regeneration and aminotransferases in Bacillus subtilis, Bacillus cereus, and Bacillus anthracis." J Bacteriol 185(8);2418-31. PMID: 12670965
Chae11: Chae, Lee (2011). "The functional annotation of protein sequences was performed by the in-house Ensemble Enzyme Prediction Pipeline (E2P2, version 1.0). E2P2 systematically integrates results from three molecular function annotation algorithms using an ensemble classification scheme. For a given genome, all protein sequences are submitted as individual queries against the base-level annotation methods. The individual methods rely on homology transfer to annotate protein sequences, using single sequence (BLAST, E-value cutoff <= 1e-30, subset of SwissProt 15.3) and multiple sequence (Priam, November 2010; CatFam, version 2.0, 1% FDR profile library) models of enzymatic functions. The base-level predictions are then integrated into a final set of annotations using an average weighted integration algorithm, where the weight of each prediction from each individual method was determined via a 0.632 bootstrap process over 1000 rounds of testing. The training and testing data for E2P2 and the BLAST reference database were drawn from protein sequences with experimental support of existence, compiled from SwissProt release 15.3."
Cobzaru11: Cobzaru C, Ganas P, Mihasan M, Schleberger P, Brandsch R (2011). "Homologous gene clusters of nicotine catabolism, including a new ω-amidase for α-ketoglutaramate, in species of three genera of Gram-positive bacteria." Res Microbiol 162(3);285-91. PMID: 21288482
Erb12: Erb TJ, Evans BS, Cho K, Warlick BP, Sriram J, Wood BM, Imker HJ, Sweedler JV, Tabita FR, Gerlt JA (2012). "A RubisCO-like protein links SAM metabolism with isoprenoid biosynthesis." Nat Chem Biol 8(11);926-32. PMID: 23042035
Fouts08: Fouts DE, Tyler HL, DeBoy RT, Daugherty S, Ren Q, Badger JH, Durkin AS, Huot H, Shrivastava S, Kothari S, Dodson RJ, Mohamoud Y, Khouri H, Roesch LF, Krogfelt KA, Struve C, Triplett EW, Methe BA (2008). "Complete genome sequence of the N2-fixing broad host range endophyte Klebsiella pneumoniae 342 and virulence predictions verified in mice." PLoS Genet 4(7);e1000141. PMID: 18654632
Han09: Han Q, Robinson H, Cai T, Tagle DA, Li J (2009). "Structural insight into the inhibition of human kynurenine aminotransferase I/glutamine transaminase K." J Med Chem 52(9);2786-93. PMID: 19338303
Jaisson09: Jaisson S, Veiga-da-Cunha M, Van Schaftingen E (2009). "Molecular identification of omega-amidase, the enzyme that is functionally coupled with glutamine transaminases, as the putative tumor suppressor Nit2." Biochimie 91(9);1066-71. PMID: 19596042
Kunst97: Kunst F, Ogasawara N, Moszer I, Albertini AM, Alloni G, Azevedo V, Bertero MG, Bessieres P, Bolotin A, Borchert S, Borriss R, Boursier L, Brans A, Braun M, Brignell SC, Bron S, Brouillet S, Bruschi CV, Caldwell B, Capuano V, Carter NM, Choi SK, Codani JJ, Connerton IF, Danchin A (1997). "The complete genome sequence of the gram-positive bacterium Bacillus subtilis." Nature 390(6657);249-56. PMID: 9384377
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