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Biological Chemistry

Radical Kind Of Methyl Transfer

ACS Meeting News: Enzyme involved in antibiotic resistance catalyzes radical C-methylation

by Amanda Yarnell
March 29, 2010 | APPEARED IN VOLUME 88, ISSUE 13

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Credit: J. Am. Chem. Soc.
Enzymes RlmN and Cfr each use a radical mechanism to methylate a single adenine (image, orange) in part of the bacterial ribosome where amino acids are stitched together.
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Credit: J. Am. Chem. Soc.
Enzymes RlmN and Cfr each use a radical mechanism to methylate a single adenine (image, orange) in part of the bacterial ribosome where amino acids are stitched together.

Bacteria tap an unexpected mechanism—radical chemistry—to methylate otherwise unreactive C–H bonds in the RNA of their ribosomes, chemists reported at this week's ACS national meeting in San Francisco. Installation of these methyl groups is a key way by which bacteria evade antibiotics, so the team's characterization of the enzymes involved could aid those hunting for ways to quell antibiotic resistance.

Typical methyltransferase enzymes rely on nucleophilic mechanisms to install methyl groups, noted assistant professor Danica Galonić Fujimori of the University of California, San Francisco, in a session sponsored by the Division of Biological Chemistry. She suggested that nature might have reached for "the radical option" in the case of the RlmN and Cfr methyltransferases because both enzymes are tasked with the tall order of appending methyl groups to sp2-hybridized aromatic carbons.

Both enzymes target a single adenine nucleotide in the catalytic center of the bacterial ribosome where proteins are built. The methyl group that RlmN installs is presumed to optimize normal ribosomal function, Fujimori noted. But the one that Cfr appends makes bacteria resistant to antibiotics. Many pathogenic bacteria protect themselves from such drugs by methylating this and other ribosomal nucleotides located in sites where ribosome-targeting antibiotics bind.

Probing the mechanism Cfr uses for methyl transfer could guide those aiming to block this kind of antibiotic evasion, commented enzymologist Marc Fontecave of Joseph Fourier University and the Commission for Atomic Energy, in Grenoble, France.

In San Francisco, Fujimori and postdoc Feng Yan of UC San Francisco described their initial work, done in collaboration with Jacqueline M. LaMarre and Alexander S. Mankin of the University of Illinois, Chicago, and others, on the mechanism of both enzymes (J. Am. Chem. Soc. 2010, 132, 3953). For example, they presented evidence that both enzymes use S-adenosylmethionine—the common biochemical methyl donor known as SAM—not only as a source of methyl but also as a source of radicals. That combination has never been seen before, noted enzymologist Joan B. Broderick of Montana State University.

In addition, both enzymes appear to act as the ribosome is assembled from its constituent proteins and RNAs, Fujimori noted. That timing suggests drug designers might focus on that window of opportunity in trying to outwit Cfr-mediated antibiotic resistance.

The mechanism by which these enzymes methylate aromatic carbon atoms "is of great interest," commented enzymologist Perry A. Frey of the University of Wisconsin. "It will be fascinating to learn more about the chemistry of this process in the future."

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