Free-Radical Enzyme Chemistry Thrives In Confined Spaces

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.