Insights into the Chemical Reactivity in Acetyl-CoA Synthase

Abstract

The biological synthesis of acetyl-coenzyme A (acetyl-CoA), catalyzed by acetyl-CoA synthase (ACS), is of biological significance and chemical interest acting as a source of energy and carbon. The catalyst contains an unusual hexa-metal cluster with two nickel ions and a [Fe 4 S 4 ] cluster. DFT calculations have been performed to investigate the ACS reaction mechanism starting from three different oxidation states (+2, +1, and 0) of Ni p , the nickel proximal to [Fe 4 S 4 ]. The results indicate that the ACS reaction proceeds first through a methyl radical transfer from cobalamin (Cbl) to Ni p randomly accompanying with the CO binding. After that, CC bond formation occurs between the Ni pbound methyl and CO, forming Ni p -acetyl. The substrate CoA-S − then binds to Ni p , allowing CS bond formation between the Ni pbound acetyl and CoA-S − . Methyl transfer is rate-limiting with a barrier of ∼14 kcal/mol, which does not depend on the presence or absence of CO. Both the Ni p 2+ and Ni p 1+ states are chemically capable of catalyzing the ACS reaction independent of the state (+2 or +1) of the [Fe 4 S 4 ] cluster. The [Fe 4 S 4 ] cluster is not found to affect the steps of methyl transfer and CC bond formation but may be involved in the CS bond formation depending on the detailed mechanism chosen. An ACS active site containing a Ni p (0) state could not be obtained. Optimizations always led to a Ni p 1+ state coupled with [Fe 4 S 4 ] 1+ . The calculations show a comparable activity for Ni p 1+ /[Fe 4 S 4 ] 1+ , Ni p 1+ /[Fe 4 S 4 ] 2+ , and Ni p 2+ /[Fe 4 S 4 ] 2+ . The results here give significant insights into the chemistry of the important ACS reaction.

Mechanistic Investigations of Ruthenium Catalyzed Dehydrogenative Thioester Synthesis and Thioester Hydrogenation

“…Molecules containing the thioester functional group are significant with respect to both synthetic chemistry and biochemistry. In particular, thioesters are utilized as precursors for preparing heterocycles and various materials, and the thioester functional group is prevalent biologically, most notably found in acetyl coenzyme A . Previous methods for the synthesis of thioesters rely on classical acylation of thiols with stoichiometric reagents such as carboxylic anhydrides or acyl chlorides.…”

Modulating Effect of Ligand Charge on the Electronic Properties of 2Ni–2S Structures and Implications for Biological 2M–2S Sites

“…A representative example of the latter case is the bimetallic 2Ni–2S core of CO-methylating acetyl-CoA synthase and respective model compounds. − In the case of the enzyme, the square planar Ni sites are chemically and electronically distinct and substrate conversion is confined to Ni p , , the Ni ion that is located closer (proximal) to the 4Fe–4S cluster that connects to the active site. As depicted in Scheme , the substitution of a chelating diphosphine ligand at Ni p in mixed-valence Ni 2+ Ni p + models , for a combination of monodentate arylthiolate and PPh 3 is reported to change the geometry at Ni p + from square planar to tetrahedral and result in 31 P hyperfine coupling being on the order of or below the cw-EPR line width …”

Biocatalytic One-Carbon Transfer – A Review

“…226 Using the Wood-Ljungdahl metabolic pathway, carbon monoxide can be used as a substrate. The bifunctional enzyme carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS) [55][56][57] is able to catalyze CO 2 reduction, methylation, as well as carbonylation reaction (Scheme 30); for detailed insight see Ragsdale, Hoffman, and co-workers, 227 Chen and Siegbahn, 228 and Drennan and co-workers. 229 Scheme 30 Simplified mechanism of carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS).…”

“…229 Scheme 30 Simplified mechanism of carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS). [227][228][229] The enzymatic reduction of CO 2 by CODH is of particular interest regarding the development of catalysts for CO 2 fixation or degradation. Bioelectric methods are therefore becoming increasingly important.…”