An enzymatic activation of formaldehyde for nucleotide methylation

Charles Bou-Nader, Frederick W. Stull, Ludovic Pecqueur, Philippe Simon, Vincent Guérineau, Antoine Royant, Marc Fontecave, Murielle Lombard, Bruce A. Palfey and Djemel Hamdane ()
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Charles Bou-Nader: Université Pierre et Marie Curie
Frederick W. Stull: University of Michigan Medical School
Ludovic Pecqueur: Université Pierre et Marie Curie
Philippe Simon: Université Pierre et Marie Curie
Vincent Guérineau: Université Paris-Saclay
Antoine Royant: Université Grenoble Alpes
Marc Fontecave: Université Pierre et Marie Curie
Murielle Lombard: Université Pierre et Marie Curie
Bruce A. Palfey: University of Michigan Medical School
Djemel Hamdane: Université Pierre et Marie Curie

Nature Communications, 2021, vol. 12, issue 1, 1-8

Abstract: Abstract Folate enzyme cofactors and their derivatives have the unique ability to provide a single carbon unit at different oxidation levels for the de novo synthesis of amino-acids, purines, or thymidylate, an essential DNA nucleotide. How these cofactors mediate methylene transfer is not fully settled yet, particularly with regard to how the methylene is transferred to the methylene acceptor. Here, we uncovered that the bacterial thymidylate synthase ThyX, which relies on both folate and flavin for activity, can also use a formaldehyde-shunt to directly synthesize thymidylate. Combining biochemical, spectroscopic and anaerobic crystallographic analyses, we showed that formaldehyde reacts with the reduced flavin coenzyme to form a carbinolamine intermediate used by ThyX for dUMP methylation. The crystallographic structure of this intermediate reveals how ThyX activates formaldehyde and uses it, with the assistance of active site residues, to methylate dUMP. Our results reveal that carbinolamine species promote methylene transfer and suggest that the use of a CH2O-shunt may be relevant in several other important folate-dependent reactions.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24756-8

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DOI: 10.1038/s41467-021-24756-8

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