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April 12, 2010
Volume 88, Number 15
p. 9

Obesity Clue In View

Structural Biology: Close-up of methyl-clipping enzyme might help probe its obesity connection

Carmen Drahl

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Picky Trimmer: In this 
X-ray structure, FTO (ribbon) binds a methyl-containing nucleotide (aqua) and uses several of its amino acid residues (yellow) to coordinate iron (black sphere). FTO’s unusual loop (red) might form the basis of its substrate selectivity. Adapted from Nature View Enlarged Image
Picky Trimmer In this 
X-ray structure, FTO (ribbon) binds a methyl-containing nucleotide (aqua) and uses several of its amino acid residues (yellow) to coordinate iron (black sphere). FTO’s unusual loop (red) might form the basis of its substrate selectivity.

With X-ray crystallography, researchers have determined the structure of FTO (fat-mass and obesity-associated protein), an enzyme that removes methyl groups from DNA and RNA and that has been linked with an increased risk of obesity. The structure suggests an explanation for the enzyme’s choice of substrates and could help researchers develop small molecules to address questions about its activity.

In some groups of people, adults with specific variations in the gene for FTO are heavier than similar people with the normal FTO gene. And inactivating FTO in mice makes the animals leaner. But it’s not clear how the enzyme is connected to metabolism and body mass.

FTO eschews double-stranded nucleic acids in favor of single-stranded substrates. Its exact sites of action in the body remain a mystery.

Now, a team led by Jijie Chai of the National Institute of Biological Sciences and Tsinghua University, both in China, has probed FTO’s specificity (Nature, DOI:10.1038/nature08921). In computer models, a loop in FTO bumps into the nonmethylated strand of double-stranded DNA and RNA, which might explain FTO’s taste for single-stranded substrates, Chai says. Next, the team plans to find molecules that block FTO’s activity.

FTO isn’t ready to be declared a prime obesity drug target, cautions Claude Bouchard, who specializes in the genetics of obesity at Pennington Biomedical Research Center, in Baton Rouge, La. Geneticists cannot rule out that the gene for FTO is a surrogate for or is working with a nearby gene to affect obesity risk, he says. The natural substrates for FTO still haven’t been identified, and it could be tough to design drugs that selectively block demethylation of obesity-relevant ones, he adds.

Whether or not FTO becomes a bona fide drug target, this structure will likely help identify the molecular mechanisms that link nucleic acid methylation and FTO activity with obesity and metabolism, says Christopher J. Schofield of Oxford University, an expert in FTO biochemistry.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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