Beneath the surface: expanding the known repertoire of methylotrophic metabolism

Although the metabolic pathways that allow the utilization of one-carbon compounds as sole sources of carbon and energy (methylotrophy) are well characterized, this understanding has been substantially refined and expanded in recent years. The paradigm-shifting discovery of the lanthanide-dependent methanol dehydrogenase, XoxF, established the biological relevance of rare-earth metals and revealed that methylotrophy required reassessment. We now know that XoxF is broadly distributed among bacteria and may actually constitute an ancestral form by which methylotrophy initially evolved, as well as the predominant form in which it now exists in nature. A new study published in <i>Applied and Environmental Microbiology</i> (C. R. Mineo, J. Jiang, and N. C. Martinez-Gomez, 91:e01304-25, 2025, https://doi.org/10.1128/aem.01304-25) extends this knowledge to characterize a heretofore undemonstrated methylotrophic pathway architecture among nitrogen-fixing plant symbionts of the <i>Sinorhizobium</i> and <i>Bradyrhizobium</i> genera. Their metabolic strategy proceeds via XoxF, complete oxidation to carbon dioxide, and the Calvin-Benson-Bassham cycle to assimilate the oxidized carbon. The authors designate this the "XoxF-CBB pathway," which appears to be well-conserved across these groups of bacteria. Their streamlined pathway represents a unique connection between autotrophy and methylotrophy that, when paired with XoxF, could constitute an underappreciated, but prevalent, variation on methylotrophy. The study highlights the need to remain open-minded about methylotrophic pathway configurations in bacteria, as well as informing the ways in which we should consider seeking to isolate novel methylotrophs. Finally, the pathway's presence in nodule-forming bacteria raises new questions about how methylotrophy shapes their physiology in both free-living soil conditions and plant-symbiotic associations.