Acetyl CoA-synthase

Central to acetogenesis [94], acetyl CoA synthase (ACS) effectively catalyzes the formation of acetyl CoA from CO and a cobalamin-like methyl carrier called the corrinoid iron sulfur protein (CoFeSP) (Eq. 12.8). 

CoFeSP obtains its methyl groups from an N-methylated heterocycle, the identity of which differs for bacteria and archaea [95]. 

ACS-CODH usually exists as an a,jfi2 heterotetramer of 310 kDa. The A clusters, the site of the ACS activity, occupy the a subunits (82 kDa each) and the C clusters, site of the CODH activity, occupy the 3 subunits (73 kDa) [96]. Three [4Fe-4S] clusters also are located in the P subunits. The a and p subunits are interconnected by a hydrophobic channel that allows transport of CO between all four catalytic clusters. While ACS is usually found as part of the bifunctional enzyme ACS-CODH, it can be obtained as a monomer [96]. 

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In contrast to the abundance of Fe-proteins, there are only six known nickel-containing enzymes hydrogenase, CO dehydrogenase (CODA), acetyl-CoA synthase (ACS), superoxide dismutase, urease, and S-methyl-CoM methylreductase. Among these enzymes, it exists in very diverse environments, including a dinickel site (urease), a Ni-Fe heterobinuclear site (hydrogenase), a Ni-Fe4S4 heterometallic... 

The most important physiological role of CODH in the metabolism of acetogenic bacteria was unknown until 1985, when it was shown that the enzyme is bifunctional and has acetyl-CoA synthase activity (121). It was previously thought that acetyl-CoA was synthesized at the cobalt center of a vitamin-Bi2-containing protein. In the same paper, it was proposed that nickel is the active site of CO oxidation and acetyl-CoA synthesis. 

The properties of CODH/acetyl-CoA synthase are summarized in Table II. The enzyme has been isolated from eight species. There exist three types of CODH. One, which lacks nickel and acetyl-CoA synthase activity, contains a molybdopterin active site and will not be... 

Fig. 11. Active sites and reactions of the bifunctional CODH/ACS. For synthesis of acetyl-CoA, two electrons are transferred from external electron donors to Cluster B of the CODH subunit. Electrons are relayed to Cluster C which reduces CO2 to CO. The CO is proposed to be channeled to Cluster A of the ACS subunit to form a metal-CO adduct that combines with the methyl group of the CFeSP and CoA to form acetyl-CoA. For utilization of acetyl-CoA, these reactions are reversed. The abbreviations are CODH, CO dehydrogenase ACS, acetyl-CoA synthase CFeSP, the corrinoid iron-sulfur protein CoA, Coenzyme A.

Figure 2 Structures of the actrive sites of metalloenzymes containing metal-sulfur cluster units, (a) Fe only hydrogenase, H-cluster (Hoxfarm) (b) Sulfite reductase (c) NiFe carbon monoxide dehydrogenase, C-cluster and (d) NiFe carbon monoxide dehydrogenase, A-cluster, which functions as acetyl-CoA synthase...

Drennan, C.L., Doukov, T.I. and Ragsdale, S.W. (2004) The metalloclusters of carbon monoxide dehydrogenase/acetyl-CoA synthase a story in pictures, J. Biol. Inorg. Client.. 9, 511-515. 

Svetlitchnyi, V., Dobbek, H., Meyer-Klauke, W., Meins, T., Thiele, B., Romer, P., Huber, R. and Meyer, O. (2004) A functional Ni-Ni-[4Fe-4S] cluster in the monomeric acetyl-CoA synthase from Carboxydothermus hydrogenoformans, Proc. Natl. Acad. Sci. U.S.A., 101, 446-451. 

Fig. 9. Pathway duplication the methyl citrate cycle and the glyoxylate shunt. A pathway for acetate metabolism in E. coli that uses the glyoxylate shunt is depicted on the right. Part of the methyl citrate cycle, a pathway for propionate metabolism, is depicted on the left. The pathways are analogous furthermore, three of the four steps are catalyzed by homologous enzymes. PrpE (propionyl-CoA synthase) is homologous to AcsA (acetyl-CoA synthase). PrpC (2-methyl-citrate synthase) is homologous to GltA (citrate synthase). PrpB (2-methyl-isocitrate lyase) is homologous to AceA (isocitrate lyase). The third step in the methyl citrate cycle has been suggested to be catalyzed by PrpD the second half of the reaction (the hydration) can be catalyzed by aconitase.

The CO dehydrogenase/acetyl-CoA synthase (Cdh) complex cleaves the C-C and C-S bonds in the acetyl moiety of acetyl-CoA, oxidizes the car-... 

Murakami E, Ragsdale SW. 2000. Evidence for intersnbnnit communication during acetyl-CoA cleavage by the multienzyme CO dehydrogenase/acetyl-CoA synthase complex from Methanosarcina thermophila. Evidence that the beta subunit catalyzes C-C and C-S bond cleavage. J Biol Chem 275 4699-707. 

Doukov TI, Iverson TM, SeravaUi J, et al. 2002. A Ni-Fe-Cu center in a bifunctional carbon monoxide/acetyl-CoA synthase. Science 298 567-72. 

Ragsdale SW, Kumar M. 1996. Nickel-containing carbon monoxide dehydroge-nase/acetyl-CoA synthase. Chem Rev 96 2515-39. 

It should be noted that HATs and HDACs are not only limited to histones, but rather various nonhistone proteins can be acetylated/deacetylated as well [2, 4]. Many regulators of DNA repair, recombination and replication, viral proteins, classic metabolic enzymes (e.g. bacterial and mammalian acetyl-CoA synthases) and... 

This enzyme [EC 1.2.99.2], also known as acetyl-CoA synthase, catalyzes the reaction of carbon monoxide with water and an acceptor to produce carbon dioxide and the reduced acceptor. The cofactors of this enzyme include nickel and zinc ions as well as non-heme iron. Methyl viologen can act as the acceptor substrate. The enzyme is isolated from Clostridium sp. Interestingly, it also catalyzes an exchange reaction of carbon between Cl of acetyl-CoA and carbon monoxide. The protein participates in the synthesis of acetyl-CoA from carbon dioxide and hydrogen in the organisms. 

The significance of these experimental (metabolic) data might be circumstantial without molecular (DNA sequence) data support (Boxma et al. 2005). Notably, no gene similar to PFO or PFL could be detected. However, genes for all three subunits of a PDH are present and are expressed. In addition, a gene was detected for acetyl-CoA synthase, an enzyme for the produc-... 

Carbon Monoxide Dehydrogenases and Carbon Monoxide Dehydrogenase/Acetyl-CoA Synthase... 

Reductive acetyl-CoA pathway 4-5 3 NAD(P)H, 2-3 ferredoxin, 1 H2 (in methanogens) Acetyl-CoA synthase/ CO dehydrogenase, formate dehydrogenase, pyruvate synthase C02 Acetyl-CoA, pyruvate Acetyl-CoA synthase/CO dehydrogenase, enzymes reducing C02 to methyltetrahydropterin... 

Figure 3.3 Reductive acetyl-CoA pathway. CD, CO dehydrogenase/acetyl-CoA-synthase , pyruvate ferredoxin oxidoreductase.

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