ExplorEnz: EC 2.1.1.308

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2.1.1.308

Accepted name:

cytidylyl-2-hydroxyethylphosphonate methyltransferase

Reaction:

2 S-adenosyl-L-methionine + cytidine 5′-{[hydroxy(2-hydroxyethyl)phosphonoyl]phosphate} + reduced acceptor = S-adenosyl-L-homocysteine + 5′-deoxyadenosine + L-methionine + cytidine 5′-({hydroxy[(S)-2-hydroxypropyl]phosphonoyl}phosphate) + oxidized acceptor (overall reaction)
(1a) S-adenosyl-L-methionine + cob(I)alamin = S-adenosyl-L-homocysteine + methylcob(III)alamin
(1b) methylcob(III)alamin + cytidine 5′-{[hydroxy(2-hydroxyethyl)phosphonoyl]phosphate} + S-adenosyl-L-methionine = cob(III)alamin + cytidine 5′-({hydroxy[(S)-2-hydroxypropyl]phosphonoyl}phosphate) + 5′-deoxyadenosine + L-methionine
(1c) cob(III)alamin + reduced acceptor = cob(I)alamin + oxidized acceptor

Other name(s):

Fom3; S-adenosyl-L-methionine:methylcob(III)alamin:2-hydroxyethylphosphonate methyltransferase (incorrect); 2-hydroxyethylphosphonate methyltransferase (incorrect); S-adenosyl-L-methionine:cytidine 5′-{[hydroxy(2-hydroxyethyl)phosphonoyl]phosphate} C-methyltransferase

Systematic name:

S-adenosyl-L-methionine:cytidine 5′-{[hydroxy(2-hydroxyethyl)phosphonoyl]phosphate} C²-methyltransferase

Comments:

Requires cobalamin. The enzyme, isolated from the bacterium Streptomyces wedmorensis, is involved in fosfomycin biosynthesis. It is a radical S-adenosyl-L-methionine (SAM) enzyme that contains a [4Fe-4S] center and a methylcob(III)alamin cofactor. The enzyme uses two molecues of SAM for the reaction. One molecule forms a 5′-deoxyadenosyl radical, while the other is used to methylate the cobalamin cofactor. The 5′-deoxyadenosyl radical abstracts a hydrogen from the C₂ position of cytidine 5′-{[(2-hydroxyethyl)phosphonoyl]phosphate} forming a free radical that reacts with the methyl group on methylcob(III)alamin at the opposite side from SAM and the [4Fe-4S] cluster with inversion of configuration to produce the (S)-isomer of the methylated product and cob(III)alamin. Both the [4Fe-4S] cluster and the cob(III)alamin need to be reduced by an unknown factor(s) before the enzyme could catalyse another cycle.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Woodyer, R.D., Li, G., Zhao, H. and van der Donk, W.A. New insight into the mechanism of methyl transfer during the biosynthesis of fosfomycin. Chem. Commun. (Camb.) (2007) 359–361. [DOI] [PMID: 17220970]
2.	Allen, K.D. and Wang, S.C. Initial characterization of Fom3 from Streptomyces wedmorensis: The methyltransferase in fosfomycin biosynthesis. Arch. Biochem. Biophys. 543 (2014) 67–73. [DOI] [PMID: 24370735]
3.	Sato, S., Kudo, F., Kim, S.Y., Kuzuyama, T. and Eguchi, T. Methylcobalamin-dependent radical SAM C-methyltransferase Fom3 recognizes cytidylyl-2-hydroxyethylphosphonate and catalyzes the nonstereoselective C-methylation in fosfomycin biosynthesis. Biochemistry 56 (2017) 3519–3522. [DOI] [PMID: 28678474]
4.	Blaszczyk, A.J. and Booker, S.J. A (re)discovery of the Fom3 substrate. Biochemistry 57 (2018) 891–892. [DOI] [PMID: 29345912]
5.	Sato, S., Kudo, F., Kuzuyama, T., Hammerschmidt, F. and Eguchi, T. C-methylation catalyzed by Fom3, a cobalamin-dependent radical S-adenosyl-L-methionine enzyme in fosfomycin biosynthesis, proceeds with inversion of configuration. Biochemistry 57 (2018) 4963–4966. [DOI] [PMID: 29966085]

[EC 2.1.1.308 created 2014, modified 2019, modified 2024]