with acetyl-CoA synthase, as has been well characterized in the anaerobic bacteria Moorella thermoacetica. NiCODH Nickel containing CODH (NiCODH) can be further divided into structural clades, dependent on their phylogenetic relationship. Different annotations for the clades are around, a useful annotation, Clade A to G, with further structural sub groups inside each clade, was proposed by Inoue et al. Structure [[Image:CODH M.thermoacetica.jpg|right|thumb|300px|Structure of CODH/ACS in M.thermoacetica." Alpha (ACS) and beta (CODH) subunits are shown. (1)The A-cluster Ni-[4Fe-4S]. (2)C-cluster Ni-[3Fe-4S]. (3) B-Cluster [4Fe-4S]. (4) D-cluster [4Fe-4S]. Designed from ]] Homodimeric Ni-CODH consists of five metal complexes referred to as clusters. Each differing in individual coordination geometry, presence of nickel, and location of the active site in either sub-unit α or β. Multiple research groups have proposed crystal structures for the α2β2 tetrameric enzyme CODH/ACS from the acetogenic bacteria M. thermoacetica, including two recent examples since 2009: . The two β units are the site of CODH activity and form the central core of the enzyme. In total, the 310 kDa enzyme contains seven iron-sulfur [4Fe-4S] clusters. Each α unit contains a single metal cluster. Together, the two β units contains five clusters of three types. CODH catalytic activity occurs at the Ni-[3Fe-4S] C-clusters while the interior [4Fe-4S] B and D clusters transfer electrons away from the C-cluster to external electron carriers such as ferredoxin. The ACS activity occurs in A-cluster located in the outer two α units. A noteworthy feature of the M. thermoacetica CODH/ACS is an internal gas tunnel connecting the multiple active sites. The full role of the gas channel in regulating the rate catalytic activity is still a subject of investigation, but several studies support the notion that molecules of CO do in fact travel directly from the C-cluster to the ACS active site without leaving the enzyme. For instance, the rate of acetyl-CoA synthase activity in the bifunctional enzyme is not affected by the addition of hemoglobin, which would compete for CO in bulk solution, and isotopic labeling studies show that carbon monoxide derived from the C-cluster is preferentially used at the A-cluster over unlabeled CO in solution. Protein engineering of the CODH/ACS in M.thermoacetica revealed that mutating residues, so as to functionally block the tunnel, stopped acety-CoA synthesis when only CO2 was present. The discovery of a functional CO tunnel places CODH on a growing list of enzymes that independently evolved this strategy to transfer reactive