Something special about CO‐dependent CO (2) fixation

Carbon dioxide enters metabolism via six known CO (2) fixation pathways, of which only one is linear, exergonic in the direction of CO (2)‐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 CO (2). We identified 415 reactions corresponding to enzyme commission (EC) numbers involving CO (2), 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 CO (2), 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 CO (2) 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.