Cyanobacteria provide a new paradigm in the regulation of cofactor dependence.

Competition for resources is a decisive driver for success. Entire civilizations have collapsed when food scarcity leads to conflict. Competition for nutrients has also shaped evolution, with modern-day species descending from the victors. While archeological digs and historical accounts yield insight into how resource competition impacted human history, whole-genome sequencing is needed to understand the inherited adaptations that passed the filter of natural selection. Leveraging comparative genomics, Garcia-Canas et al. (1) report their discovery of how cyanobacteria won the arms race when confronted with resource limitation caused by copper deficiency. Cyanobacteria are an ancient group of bacteria credited with the evolution of oxygen-producing photosynthesis, a process with an absolute requirement for metal cofactors, including iron, manganese, and copper. Garcia-Canas et al. (1) find that a BlaI-family transcription factor and BlaR1-family protease evolved to regulate the transcription-mediated swap of copper-dependent plastocyanin (PC) for iron-dependent cytochrome c 6 (Cyt c 6) (1). Over 40 y ago, researchers studying green algae (2) and cyanobacteria (3) proposed that replacement of PC with Cyt c 6 provides a strategy to maintain photosynthesis with a “back-up” protein when PC becomes inactivated due to copper insufficiency, but how this interchange is regulated in cyanobacteria remained unknown until now. PC and Cyt c 6 are functionally identical, small, soluble, electron-transfer proteins that transfer one electron at a time from the cytochrome b 6 f complex to photosystem I during oxygenic photosynthesis. However, that is where their similarities end. The two proteins are evolutionarily unrelated, differing in both primary sequence and tertiary structure. The most striking difference between these two isofunctional proteins is their cofactors. Cyt c 6 contains a tetrapyrrole-bound iron atom (i.e., heme) that switches between Fe3+ and Fe2+ … [↵][1]1Email: cblaby{at}bnl.gov. [1]: #xref-corresp-1-1