Closing The Loop

Cyanobacteria have a complete tricarboxylic acid (TCA) cycle after all, Donald A. Bryant and Shuyi Zhang of Pennsylvania State University report (Science, DOI: 10.1126/science.1210858). Their finding corrects a decades-old misconception and could lead to improved models for engineering microbes for biotechnology applications.

The TCA cycle—also known as the citric acid cycle or the Krebs cycle—is one of the central pathways in cellular metabolism. It produces adenosine triphosphate and generates building blocks for biosynthesis. In cyanobacteria, the second role is more important.

For more than 40 years, scientists thought that these microorganisms didn’t have a complete TCA cycle because they lacked one of the pathway’s enzymes: 2-oxoglutarate dehydrogenase, which converts 2-oxoglutarate to succinyl-coenzyme A (CoA).

“It’s a good example of how misinterpreting negative data can have a very long-lasting impact on a field in science,” Bryant says. “This failure to detect the enzyme didn’t mean that the cycle was incomplete. It just didn’t have a complete cycle with that particular enzyme.”

It turns out that many, but not all, cyanobacteria have two other enzymes instead. The enzyme 2-oxoglutarate decarboxylase converts 2-oxoglutarate to succinic semialdehyde, which in turn is transformed into succinate by the enzyme succinic semialdehyde dehydrogenase. The product of the two enzymes then rejoins the cycle beyond succinyl-CoA. The succinic semialdehyde dehydrogenase needs nicotinamide adenine dinucleotide phosphate to work, and that cofactor wasn’t present in earlier experiments, which is probably why the alternative pathway wasn’t found before, Bryant explains.

Bryant and Zhang found the enzymes by analyzing the cyanobacterium’s genome. They realized that the gene for succinyl semialdehyde dehydrogenase was next to an incorrectly identified gene, which turned out to be the decarboxylase.

The work is a “superb contribution to the understanding of cyanobacterial physiology,” says Robert Haselkorn, an expert on cyanobacteria metabolism at the University of Chicago. “It makes possible a much more accurate background for the calculation of metabolic fluxes, which are needed for biotech applications.”