Dinuclear nickel complexes modeling the structure and function of the acetyl CoA synthase active site

Abstract

acetylthioester formation ͉ dinuclear nickel-site model ͉ N2S2 ligand ͉ nickel acyl complex A cetyl-CoA synthase/CO dehydrogenase (ACS/CODH), a bifunctional metalloenzyme found in acetogenic, methanogenic, and sulfate-reducing bacteria, has the important function of fixing CO and CO 2 in the global carbon cycle (1-3). Whereas CODH catalyzes the reversible conversion of CO 2 to CO, ACS assembles acetyl-CoA from CO, CoA, and a methyl moiety that is derived from the methylcobalamin of the corrinoid iron-sulfur protein (CFeSP). Recently, the crystal structures of the ACS/ CODH system from the bacteria Moorella thermoacetica and Carboxydothermus hydrogenoformans have been elucidated (4-6); the ACS active site denoted as the A-cluster contains a [Fe 4 S 4 ] cubane cluster and a Ni d -Ni p dinuclear site as shown in Fig. 1, where the 2 nickels designated as Ni d and Ni p occupy distal and proximal positions, respectively, to the [Fe 4 S 4 ] cluster. The geometry around Ni d is square planar, composed of 2 cysteine sulfurs and 2 carboxyamide nitrogens of the tripeptide Cys-GlyCys from the protein backbone. Ni p carries an unidentified ligand X and 3 bridging cysteine sulfurs, 2 from the aforementioned tripeptide, and 1 from the [Fe 4 S 4 ] cluster.Biological investigations suggest that the oxidized state of the cluster A ox should be formulated as {Ni d 2ϩ -Ni p 2ϩ -[Fe 4 S 4 ] 2ϩ } (7-9). However, the electronic configuration of the active reduced state, probably reduced by 2 electrons from A ox , which is proposed to be {Ni d 2ϩ -Ni p 1ϩ -[Fe 4 S 4 ] 1ϩ }, has not yet been firmly established (10-11). The order of the addition of the substrates, Me, CO, and CoA, to the active site is also controversial, and several mechanisms have been proposed on the basis of biological and computational studies (12)(13)(14). On the other hand, synthetic studies that probe the reaction mechanisms are limited in number, although various thiolato-bridged dinuclear nickel complexes have been reported as A-cluster models (15-23).Proposed ACS mechanisms commonly involve the following steps: (i) methyl transfer from methylcobalamin to the reduced Ni p (0) [or Ni p (I)] site, (ii) CO insertion into the Ni p -Me bond, and (iii) formation of acetyl-CoA via the reductive elimination at the Ni p site (1-3, 7-14). These reactions had been studied by using mononuclear nickel complexes. CO insertion into the Ni-Me bonds of Ni(NS 3 R )Me [NS 3 R is N(CH 2 CH 2 SR) 3 ; R is i-Pr, t-Bu], investigated by Stavropoulos et al. (24) , resulted in the formation of acetylthioesters CH 3 C(O)SR and Ni(0) species in high yield upon treatment with CO. Likewise, the reaction of [Ni(bpy)(SR)(Me)] with Ͼ3 equiv of CO was found to yield [Ni(bpy)(CO) 2 ] and acetylthioesters (25). Before these reports, Kim et al. (26) had shown that the reaction of Ni(dppe-)(SAr)(Me) with CO generated CH 3 C(O)SAr. Recently, Rampersad et al. (27) demonstrated the acetylthioester formation in the reaction of Ni-Pd dinuclear complex, Ni(bme-daco)Pd(CO-)(COMe), with NaSMe. Eckert ...

Metal–metal bonds in biology

“…Where these electrons reside on the A-cluster is uncertain; indeed the location of these two electrons has been a decade-old puzzle that has not been resolved. One possibility is that both electrons localize on Ni p II to afford a d 10 Ni p 0 species [56 - 59]. Alternatively, one electron may localize on Ni p II and the other on the [Fe 4 S 4 ] 2+ cluster to afford a {Ni p I :[Fe 4 S 4 ] 1+ } spin-coupled structure.…”

“…Tatsumi, Rauchfuss, Riordan and others have synthesized A-cluster model complexes with two Ni ions and bridging dithiolates [59, 63 - 66], reminiscent of the Hase model compounds (Figure 6, top). These [Ni 0 Ni II ] compounds show flexible Ni-S 2 -Ni hinge angles, ranging from ca .…”

Metal centers in the anaerobic microbial metabolism of CO and CO2

“…5e, that can be methylated by methyl-cobaloxime, and that can further react with CO to form an acetylthioester compound similar to acetyl-CoA. 51,52 In these studies, the compound Ni(dadt Et )Ni(Me)(SDmp), where dadt Et stands for N , N ′-diethyl-3,7-diazanonane-1,9-dithiolate and Dmp for 2,6-dimesitylphenyl, was synthesized as a Ni II –Ni I complex. It had a S = 1/2 EPR signal ( g x , y , z = 2.62, 2.12, 2.00), could be methylated and then react with CO.…”

Tight Coupling of Partial Reactions in the Acetyl-CoA Decarbonylase/Synthase (ACDS) Multienzyme Complex from Methanosarcina thermophila

“…It has been shown that the presence of a CO ligand in the Ni(0) compound (bis(2-diphenylphosphinoethyl)phenylphosphine)-NiCO prevents methylation by methylcobaloxime (55). And, in recent studies on a binuclear Ni(II)-Ni(II) complex bearing methyl and thiol ligands, it was found that thioester formation, initiated by addition of CO, takes place as a single turnover process because of the concomitant formation of an inactive Ni(0)-carbonyl complex that does not react further with methylcobaloxime (56). This was interpreted to indicate that CO addition to Ni p in ACS must be strictly regulated to prevent the formation of such inactive Ni(0)-CO species.…”