If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
Synonyms: activated methyl cycle, SAM cycle
|Superclasses:||Biosynthesis → Amino Acids Biosynthesis → Proteinogenic Amino Acids Biosynthesis → L-methionine Biosynthesis → L-methionine Salvage → S-adenosyl-L-methionine cycle|
Pathway Summary from MetaCyc:
About 20% of the L-methionine pool is used as a building block of proteins. The rest is converted to S-adenosyl-L-methionine (SAM), the major methyl donor in the cell. When SAM donates its methyl group, it is converted to S-adenosyl-L-homocysteine. This molecule can be recycled back to SAM via the S-adenosyl-L-methionine cycle, also known as the activated methyl cycle (AMC).
There are two main variations of this pathway, one found mostly in prokaryotes, while the other is found predominantly, but not exclusively, in eukaryotes (for example, it operates in Mycobacterium tuberculosis [Reddy08]. The main difference between the variants is the processing of S-adenosyl-L-homocysteine (SAH), the immediate product of the methylation reactions.
In the first pathway (described in S-adenosyl-L-methionine cycle I) SAH is first hydrolyzed to S-ribosyl-L-homocysteine by the MTA/SAH nucleosidase, followed by conversion to L-homocysteine by S-ribosylhomocysteine lyase. In the second pathway, which is described in S-adenosyl-L-methionine cycle II, SAH is hydrolyzed to L-homocysteine in a single step, catalyzed by S-adenosylhomocysteine hydrolase.
The cycle continues with the methylation of L-homocysteine to L-methionine using a methyl group from a methylated folate. In some organisms, including Homo sapiens, this reaction is catalyzed by a cobalamin-dependent methionine synthase (EC 188.8.131.52). In other organisms, such as Bacillus subtilis, the reaction is catalyzed by a cobalamin-independent methionine synthase (EC 184.108.40.206). Yet some organisms, such as Escherichia coli and Corynebacterium glutamicum, have both enzymes, as described in the pathway L-methionine biosynthesis III. In Escherichia coli the reaction catalyzed by the B12-dependent enzyme is more than 100-fold faster than the reaction catalyzed by the B12-independent isoenzyme [Rodionov04].
Finally, the cycle is completed with the regeneration of SAM by S-adenosylmethionine synthetase.
About S-adenosylhomocysteine hydrolase: While the reaction catalyzed by this enzyme is reversible, the equilibrium favors the synthesis of S-adenosyl-L-homocysteine. Thus the removal of the hydrolysis product L-homocysteine is critical for the continuous operation of the cycle. This is achieved by the efficient conversion of L-homocysteine to L-methionine via methionine synthase.
Variants: S-adenosyl-L-methionine cycle I
Pathway Evidence Glyph:
Key to pathway glyph edge colors:
An enzyme catalyzing this reaction is present in this organism
No enzyme catalyzing this reaction has been identified in this organism
The reaction and any enzyme that catalyzes it (if one has been identified) is unique to this pathway
Reddy08: Reddy MC, Kuppan G, Shetty ND, Owen JL, Ioerger TR, Sacchettini JC (2008). "Crystal structures of Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase in ternary complex with substrate and inhibitors." Protein Sci 17(12);2134-44. PMID: 18815415
Rodionov04: Rodionov DA, Vitreschak AG, Mironov AA, Gelfand MS (2004). "Comparative genomics of the methionine metabolism in Gram-positive bacteria: a variety of regulatory systems." Nucleic Acids Res 32(11);3340-53. PMID: 15215334
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