Closing the loop on a gene regulatory network

Like humans, Escherichia coli—seen in this false-color image—sometimes become set in their dietary ways. When glucose is available, for instance, the bacteria stop producing enzymes used to metabolize alternative carbon sources such as lactose and fructose. That response, termed catabolite repression, is one of the oldest known examples of gene regulation. But despite decades of intensive study, its underlying mechanism remains murky. Now an international collaboration led by Terence Hwa (University of California, San Diego) has shed new light on the behavior. The intracellular processing of nutrients into proteins can be roughly viewed as a kind of assembly line: Enzymes metabolize carbon-based nutrients into molecules known as α-ketoacids; nitrogen and other essential ingredients are used to convert the α-ketoacids into amino acids; and amino acids are then assembled into new proteins. Hwa and company posited that α-ketoacids might be inhibiting the production of cyclic adenosine monophosphate (cAMP), a messenger molecule tasked with promoting the synthesis of certain carbon-metabolizing enzymes. If that’s indeed the case, then whenever carbon metabolism outpaces amino-acid production, α-ketoacids should accumulate and the inhibition should grow stronger. That would explain why glucose triggers catabolite repression—the relatively simple sugar can be quickly metabolized. To test that theory, the team added α-ketoacids directly into the bacteria’s nutrient supply. Sure enough, the microbes immediately stopped synthesizing cAMP-promoted enzymes—regardless of which carbon sources they had been feeding on. (C. You et al., Nature 500, 301, 2013 .)—Ashley G. Smart