Studying the Signaling Role of 2-Oxoglutaric Acid Using Analogs that Mimic the Ketone and Ketal Forms of 2-Oxoglutaric Acid Original Research Article

2-Oxoglutaric acid (2-OG), a Krebs cycle intermediate, is a signaling molecule in many organisms. To determine which form of 2-OG, the ketone or the ketal form, is responsible for its signaling function, we have synthesized and characterized various 2-OG analogs. Only 2-methylenepentanedioic acid (2-MPA), which resembles closely the ketone form of 2-OG, is able to elicit cell responses in the cyanobacterium Anabaena by inducing nitrogen-fixing cells called heterocysts. None of the analogs mimicking the ketal form of 2-OG are able to induce heterocysts because none of them are able to interact with NtcA, a 2-OG sensor. NtcA interacts with 2-MPA and 2-OG in a similar manner, and it is necessary for heterocyst differentiation induced by 2-MPA. Therefore, it is primarily the ketone form that is responsible for the signaling role of 2-OG in Anabaena.