Something special about CO-dependent CO₂ fixation

Carbon dioxide enters metabolism via six known CO₂ fixation pathways, of which only one is linear, exergonic in the direction of CO₂ -assimilation, and present in both bacterial and archaeal anaerobes - the Wood-Ljungdahl (WL) or reductive acetyl-CoA pathway. Carbon monoxide (CO) plays a central role in the WL pathway as an energy rich intermediate. Here, we scan the major biochemical reaction databases for reactions involving CO and CO₂ . We identified 415 reactions corresponding to enzyme commission (EC) numbers involving CO₂ , which are non-randomly distributed across different biochemical pathways. Their taxonomic distribution, reversibility under physiological conditions, cofactors and prosthetic groups are summarized. In contrast to CO₂ , only 15 reaction classes involving CO were detected. Closer inspection reveals that CO interfaces with metabolism and the carbon cycle at only two enzymes: anaerobic carbon monoxide dehydrogenase (CODH), a Ni- and Fe-containing enzyme that generates CO for CO₂ fixation in the WL pathway, and aerobic CODH, a Mo- and Cu-containing enzyme that oxidizes environmental CO as an electron source. The CO-dependent reaction of the WL pathway involves carbonyl insertion into a methyl carbon-nickel at the Ni-Fe-S A-cluster of acetyl-CoA synthase (ACS). It appears that no alternative mechanisms to the CO-dependent reaction of ACS have evolved in nearly 4 billion years, indicating an ancient and mechanistically essential role for CO at the onset of metabolism.