MetaCyc Pathway: S-methyl-5-thio-α-D-ribose 1-phosphate degradation
Traceable author statement to experimental supportInferred from experiment

Enzyme View:

Pathway diagram: S-methyl-5-thio-alpha-D-ribose 1-phosphate degradation

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: BiosynthesisAmino Acids BiosynthesisProteinogenic Amino Acids BiosynthesisL-methionine BiosynthesisL-methionine SalvageS-methyl-5-thio-alpha-D-ribose 1-phosphate degradation
Degradation/Utilization/AssimilationNucleosides and Nucleotides DegradationS-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

Expected Taxonomic Range: Archaea, Bacteria , Embryophyta, Metazoa

General Background

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, Cornell96, Dai99a, Dai01], plants [Baur72, Murr75, Kushad83, Miyazaki87], 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, 2,3-diketo-5-methylthiopentyl-1-phosphate enolase, is a member of the RubisCO protein family [Imker07].

The reaction catalyzed by EC, 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, acireductone dioxygenase [iron(II)-requiring] binds a Ni2+ instead of Fe2+, it catalyzes a different reaction ( EC, 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, 2,3-diketo-5-methylthiopentyl-1-phosphate enolase and EC, 2-hydroxy-3-keto-5-methylthiopentenyl-1-phosphate phosphatase are catalyzed by a single enzyme, EC, acireductone synthase (MtnC).

Superpathways: L-methionine salvage cycle I (bacteria and plants), L-methionine salvage cycle II (plants), L-methionine salvage cycle III

Variants: S-methyl-5-thio-α-D-ribose 1-phosphate degradation II

Created 16-Mar-2011 by Caspi R, SRI International
Revised 01-Jul-2014 by Caspi R, SRI International


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

Backlund81: Backlund PS, Smith RA (1981). "Methionine synthesis from 5'-methylthioadenosine in rat liver." J Biol Chem 1981;256(4);1533-5. PMID: 7007366

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

Baur72: Baur A.H., Yang S.F. "Methionine metabolism in apple tissue in relation to ethylene biosynthesis." Phytochemistry (1972) 11 : 3207-3214.

Berger01a: Berger LC, Wilson J, Wood P, Berger BJ (2001). "Methionine regeneration and aspartate aminotransferase in parasitic protozoa." J Bacteriol 2001;183(15);4421-34. PMID: 11443076

Cornell96: 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

Dai01: Dai Y, Pochapsky TC, Abeles RH (2001). "Mechanistic studies of two dioxygenases in the methionine salvage pathway of Klebsiella pneumoniae." Biochemistry 2001;40(21);6379-87. PMID: 11371200

Dai99a: Dai Y, Wensink PC, Abeles RH (1999). "One protein, two enzymes." J Biol Chem 1999;274(3);1193-5. PMID: 9880484

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

Kushad83: Kushad M.M., Richardson D.G., Ferro A.J. "Intermediates in the recycling of 5-methylthioribose to methionine in fruits." Plant Physiol. (1983) 73 : 257-261.

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

Miyazaki87: Miyazaki J.H., Yang S.F. "The methionine salvage pathway in relation to ethylene and polyamine biosynthesis." Physiol. Plantarum (1987) 69 : 366-370.

Murr75: Murr D.P., Yang S.F. "Conversion of 5'-methylthioadenosine to methionine by apple tissue." Phytochemistry (1975) 14 : 1291-1292.

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

Riscoe88: Riscoe MK, Ferro AJ, Fitchen JH (1988). "Analogs of 5-methylthioribose, a novel class of antiprotozoal agents." Antimicrob Agents Chemother 1988;32(12);1904-6. PMID: 2854458

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

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

AlMjeni02: Al-Mjeni F, Ju T, Pochapsky TC, Maroney MJ (2002). "XAS investigation of the structure and function of Ni in acireductone dioxygenase." Biochemistry 41(21);6761-9. PMID: 12022880

Ambler87: Ambler RP, Auffret AD, Clarke PH (1987). "The amino acid sequence of the aliphatic amidase from Pseudomonas aeruginosa." FEBS Lett 215(2);285-90. PMID: 3108029

Anastasatu: Anastasatu C, Bercea O "[30 years of activity at the Institute of Phthisiology]." Rev Ig Bacteriol Virusol Parazitol Epidemiol Pneumoftiziol Pneumoftiziol 28(2);65-6. PMID: 227040

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

Furfine88: Furfine ES, Abeles RH (1988). "Intermediates in the conversion of 5'-S-methylthioadenosine to methionine in Klebsiella pneumoniae." J Biol Chem 1988;263(20);9598-606. PMID: 2838472

Gaudet10: Gaudet P, Livstone M, Thomas P (2010). "Annotation inferences using phylogenetic trees." PMID: 19578431

GOA01a: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

GOA06: GOA, SIB (2006). "Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins."

Han04: Han Q, Li J (2004). "pH dependence, substrate specificity and inhibition of human kynurenine aminotransferase I." Eur J Biochem 271(23-24);4804-14. PMID: 15606768

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

Hersh71: Hersh LB (1971). "Rat liver omega-amidase. Purification and properties." Biochemistry 10(15);2884-91. PMID: 5114531

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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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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