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Synthesis

Free-Radical Enzyme Chemistry Thrives In Confined Spaces

Biocatalysis: Enzymes locate S-adenosyl-L-methionine right next to the reaction substrate to avoid side reactions

by Jyllian Kemsley
May 18, 2015 | A version of this story appeared in Volume 93, Issue 20

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Credit: J. Am. Chem. Soc.
The active site of lysine 2,3-aminomutase, in which the yellow arrow points from the C5´ position of SAM to the hydrogen abstraction site on L-α-lysine.
Graphic shows the active site of lysine 2,3-aminomutase, with a yellow arrow pointing from the C5’ of S-adenosyl-L-methionine to the hydrogen abstraction site on L-α-lysine.
Credit: J. Am. Chem. Soc.
The active site of lysine 2,3-aminomutase, in which the yellow arrow points from the C5´ position of SAM to the hydrogen abstraction site on L-α-lysine.

To safely catalyze radical chemistry, a large group of enzymes positions their target substrates immediately adjacent to a radical-generating cofactor, a spectroscopic study indicates (J. Am. Chem. Soc. 2015, DOI: 10.1021/jacs.5b00498). By locating the substrate next to the cofactor, the enzymes help ensure that the radical acts as desired and doesn’t stray to engage in protein-damaging side reactions. The enzymes in question combine a [4Fe-4S] cluster and S-adenosyl-L-methionine (SAM) to generate 5´-deoxyadenosyl radical, which then reacts with a bound substrate. More than 100,000 such enzymes have been identified across all kingdoms of life. A team led by Joan B. Broderick of Montana State University and Brian M. Hoffman of Northwestern University used electron nuclear double resonance spectroscopy to study lysine 2,3-aminomutase, which isomerizes L-α-lysine to L-β-lysine. The researchers used a SAM analog to investigate the interactions between the cofactor radical and lysine substrate. They found that once the radical forms it needs to shift less than 1 Å to abstract a hydrogen from lysine. Comparison of other structurally characterized SAM radical enzymes suggests that they operate similarly. Enzymes that use coenzyme B12 to generate 5´-deoxyadenosyl radicals require greater movement, which may help explain why they are relatively scarce.

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