How FocA facilitates fermentation and respiration of formate by .

Formic acid is an important source of reductant and energy for many microorganisms. Formate is also produced as a fermentation product, e.g., by enterobacteria like . As such, formic acid shares many features in common with dihydrogen, explaining perhaps why their metabolism and physiology show considerable overlap. At physiological pH, formic acid is mainly present as the dissociated formate anion and therefore cannot diffuse freely across the cytoplasmic membrane. Specific and bidirectional translocation of formate across the cytoplasmic membrane is, however, achieved in by the homopentameric membrane protein, FocA. Formic acid translocation from the cytoplasm into the periplasm (efflux) serves to maintain a near-neutral cytosolic pH and to deliver formate to the periplasmically-oriented respiratory formate dehydrogenases, Fdh-N and Fdh-O. These enzymes oxidize formate, with the electrons being used to reduce nitrate, oxygen, or other acceptors. In the absence of exogenous electron acceptors, formate is re-imported into the cytoplasm by FocA, where it is sensed by the transcriptional regulator FhlA, resulting in induction of the formate regulon. The genes and operons of the formate regulon encode enzymes necessary to assemble the formate hydrogenlyase complex, which disproportionates formic acid into H and CO. Combined, these mechanisms of dealing with formate help to maintain cellular pH homeostasis and are suggested to maintain the proton gradient during growth and in stationary phase cells. This review highlights our current understanding of how formate metabolism helps balance cellular pH, how it responds to the redox status, and how it helps conserve energy.