A Catalytic First | March 17, 2008 Issue - Vol. 86 Issue 11 | Chemical & Engineering News
Volume 86 Issue 11 | p. 12 | News of The Week
Issue Date: March 17, 2008

A Catalytic First

Bacteria master reaction by making the substrate a radical
Department: Science & Technology

A COMMON ANAEROBIC MICROBE in the human gut has been caught doing some curious biochemistry that had been previously postulated but never proven. Clostridium difficile has an enzyme that pulls off a difficult reaction needed for energy metabolism by turning its substrate directly into a radical, a new report shows (Nature, DOI: 10.38/nature06637).

Radicalized
Credit: © 2008 Nature

Typically, substrate radicals involved in enzyme-catalyzed reactions are generated through radical organic cofactors or active-site amino acids. C. difficile provides the first case in which an enzyme radicalizes its substrate directly via simple electron transfer, comments Joseph T. Jarrett, a chemist at the University of Hawaii, Manoa, in an associated commentary in Nature.

The team of researchers, led by Antonio J. Pierik, a biochemist at Philipps University in Marburg, Germany, also shows that the substrate radical is produced through a reduction reaction rather than an oxidation, contrary to standard textbook redox activation. "Most enzymes that are known to generate radicals do so by removing a hydrogen atom from the substrate," Jarrett notes.

The unusual C. difficile reaction is undertaken by an enzyme called 2-hydroxyisocaproyl-CoA dehydratase, which converts leucine into short-chain fatty acids.

Metabolizing leucine in the absence of oxygen is difficult, partially because midway through the process a stalwart 2-hydroxyacyl-CoA intermediate is created. This 2-hydroxyacyl-CoA cannot be reduced further until it can shake off a water molecule. That's when the dehydratase steps in.

Using an electron from the iron-sulfur clusters in its active site, the enzyme turns the 2-hydroxyacyl-CoA into a ketyl radical that can shed the crucial water. The radical product is oxidized to give an isocaprenoyl derivative that can then be further reduced.

"Time will tell whether this newly discovered radical mechanism is used by other enzymes," Jarrett notes. "But the authors have shown that even in the relatively mature field of enzymology, there is still much to learn."

 
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