Carbon Chapter 108 F430

6.3.5.1 Introduction

Similar to the high-valent Ni story, significant impetus for the interest in low-valent Ni chemistry stems from the involvement of NiI species in bioinorganic processes, predominantly from the unique NiI state of the active form of coenzyme F430 of methylcoenzyme M reductase (MCR) and the possible relevance of NiI in [Ni,Fe] hydrogenase. This also contributes to the particular prominence of nitrogen- and sulfur-based ligand systems in studies on NiI complexes. However, not every ligand environment can support NiI, and in many cases Ni0 is produced directly upon reduction of NiII compounds. Hence, most NiI species with simple N and O ligands are thermodynamically and kinetically unstable with respect to disproportionation into Ni0 and NiII. Stabilization of NiI is more easily achieved by soft donor ligation (C, P, As, S donor atoms) or by a macrocyclic environment. The redox chemistry of nickel has been reviewed.63

Biological Ligands for Metal Ions

Robert Crichton, in Biological Inorganic Chemistry (Third Edition), 2019

Porphyrin-Based Cofactors

Tetrapyrroles are organic molecules that contain four five-membered heterocyclic (pyrrole) rings, linked in a cyclic or linear array. Haem, chlorophyll, cobalamin (vitamin B12), siroHaem4 and coenzyme F430 belong to a family of prosthetic groups that are characterized by their tetrapyrrole-derived nature and contain a central, complexed metal ion: Fe2+ in haem and sirohaem, Mg2+ in chlorophyll and bacteriochlorophyll, Co2+ in cobalamin, and Ni2+ in coenzyme F430 They are all derived from a common tetrapyrrole precursor, uroporphyrinogen III (Fig. 4.5). The important and varied functions of haemoproteins in oxygen transport and storage, in oxygen activation and electron transport are discussed in greater detail in Chapter 1, Iron: Essential for Almost All Life. The isomerases, methyl transferases and class II ribonucleotide reductases, which employ cobalamine cofactors, are discussed in Chapter 15, Nickel and Cobalt: Evolutionary Relics, where we also discuss the unusual Ni-corrin coenzyme F430 cofactor involved in the final step of methane production. The verdant colour of chlorophyll, harbinger of spring, as plants, trees and shrubs, recover from the dead of winter, not only visually revitalizes us, but also harnesses the energy of the sun to generate energy and to fix CO2, as we explain in greater detail in Chapter 10, Magnesium-Phosphate Metabolism and Photoreceptors. We first describe the biosynthesis of haem, before briefly examining how metals are incorporated into porphyrins and corrins to form haem and other metallated tetrapyrroles.

Figure 4.5. The relationship between tetrapyrrole biosynthetic pathways. Uroporphyrinogen III is the tetrapyrrole that is common to all tetrapyrrole pathways. 5-Aminolaevulinate (ALA) a precursor of uroporphyrinogen III derives from glycine and succinyl-CoA (in eukaryotes other than plants and the subgroup of the photosynthetic purple bacteria) or glutamate (in plants and most bacteria). Class I, II and III chelatases are shown in blue, purple and yellow, respectively.

Haem biosynthesis can be conveniently divided into three parts: (i) formation of the precursor molecule, 5-aminolaevulinate (ALA) (ii) formation of the cyclic tetrapyrrole uroporphyrinogen III, and (iii) the conversion of uroporphyrinogen III into haem. Uroporphyrinogen III is formed from the 5-aminolevulinic acid in three enzymatic steps via the intermediates porphobilinogen and preuroporphyrinogen (Fig. 4.6). Uroporphyrinogen III, the tetrapyrrole that is common to all tetrapyrrole pathways, is synthesized from ALA. In plants and most bacteria ALA is derived from tRNA-bound glutamate via reduction to glutamate-1-semialdehyde, which is then converted into ALA by glutamate-1-semialdehyde-2,1-aminomutase. However in eukaryotes other than plants and the subgroup of the photosynthetic purple bacteria, ALA is synthesized in the mitochondria by ALA synthase via condensation of succinyl-CoA derived from the citric acid cycle with glycine. Once it has been synthesized, ALA is exported to the cytoplasm where the next steps in the haem biosynthetic pathway take place. Two molecules of ALA then condense to form the pyrrole, porphobilinogen (PBG), oligomerization of four molecules of PBG gives the linear tetrapyrrole preuroporpobiliniogen, followed by ring closure to the first cyclic tetrapyrrole intermediate uroporphyrinogen III. In the next step uroporphyrinogen decarboxylase converts uroporphyrinogen III to coproporphyrinogen III, which is then imported into the mitochondrial intermembrane space. Coproporphyrinogen III then undergoes oxidative decarboxylation to protoporphyrinogen IX. The penultimate step is the oxidation of protoporphyrinogen IX to protoporphyrin IX, catalysed by protoporphyrinogen oxidase. The terminal step of haem synthesis is the insertion of ferrous iron into the protoporphyrin macrocycle to yield the final product, haem, which is discussed in greater detail below. All of the genes involved in haem biosynthesis have been cloned and the crystal structures of all of the enzymes have been determined (Hamza and Dailey, 2012). For reviews of haem biosynthesis see Ajioka et al., 2006; Al-Karadaghi et al., 2006; Layer et al., 2010; Dailey and Meissner, 2013 Chiabrando et al., 2014.

Figure 4.6. Haeme biosynthesis. (A) The first cyclic tetrapyrrole uroporphyrinogen III is formed from the precursor 5-aminolevulinic acid in three enzymatic steps via the intermediates porphobilinogen and preuroporphyrinogen. Depending on the organism, ALA is either synthesized by condensation of glycine with succinyl-CoA or from tRNA-bound glutamate via glutamate-1-semialdehyde. (B) Uroporphyrinogen III is converted into haeme in four consecutive enzymatic steps via the intermediates coproporphyrinogen III, protoporphyrinogen IX, and protoporphyrin IX. Structures of all haeme biosynthesis enzymes have been determined with the exception of oxygen-independent PPO (n.d., structure not determined).

The specific insertion of a number of different metal ions (Fe, Mg, Co or Ni) into tetrapyrroles resulting in the formation of haem, chlorophyll, cobalamine and coenzyme F430 respectively, is carried out by a class of enzymes called chelatases. The most extensively studied of these is ferrochelatase, which catalyses the insertion of ferrous iron into PPIX to form haem. When the three-dimensional structure of ferrochelatase is compared to other known protein structures, it turns out that its overall fold is most similar to that of bacterial periplasmic binding proteins (see Chapter 7, Metal Aassimilation Pathways), with the polypeptide folded into two similar domains each with a four-stranded parallel β-sheet flanked by α-helices (Fig. 4.7).

Figure 4.7. (Top) Structure of B. subtilis ferrochelatase in complex with the transition state inhibitor N-methylmesoporphyrin (N-MeMP) PDB code 1C1H. The structure is composed of two Rossmann-type domains (green and blue), in which a central four-stranded β-sheet is flanked by α-helices. A cleft defined by structural elements (red) from both domains accommodates the porphyrin and metal binding sites. The inhibitor N-MeMP is shown in the cleft (carbon atoms, yellow; oxygen, red; nitrogen, blue). (Bottom) (A) Out-of-plane saddle structure in which two pyrrole rings with unprotonated nitrogens (blue spheres) point upwards, while the other two, protonated (blue and white spheres) point downward. (B) Steps in the mechanism for incorporation of the metal ion (red) into the porphyrin (pyrrole rings in green), described in the text.

Distortion of the porphyrin macrocycle has long been recognized to be a critical step in porphyrin metallation since it facilitates metal chelation by endowing the porphyrin with an appropriate configuration for metal ion complexation. In this configuration, the lone pair orbitals of the pyrrole nitrogen atoms are exposed to the incoming metal ion. The crystal structure of ferrochelatase complexed with N-methylmesoporphyrin (N-MeMP), a potent inhibitor of ferrochelatase which mimics a strained substrate, is shown in Fig. 4.7 (Al-Karadaghi et al., 2006) This has served as the basis for a mechanistic model of ferrochelatases (Al-Karadaghi et al., 2006), which involves as the first step, the distortion of the tetrapyrrole porphyrin upon binding to the enzyme to give a saddled structure (Fig. 4.7A). In this structure, two opposite pyrrole rings are slightly tilted upwards while the other two pyrrole rings are tilted slightly downwards. The two unprotonated nitrogen atoms of the pyrrole rings point upward, while the two protonated nitrogens point downward. Following distortion of the porphyrin ring, the first metal–porphyrin bond is formed (Fig. 4.7B), followed by other ligand exchange steps leading to formation of a complex in which the iron atom is sitting on top of the porphyrin, with two of its nitrogen atoms coordinated to the metal while the other two are still protonated. This is followed by sequential deprotonation of the two pyrrole nitrogen atoms coupled with formation of the metallated porphyrin. Analysis of X-ray structures of bacterial, human and yeast ferrochelatases support the view that ferrochelatase catalysis involves binding of a distorted porphyrin substrate and releasing of a flatter, metalated porphyrin. However, although close to 50 ferrochelatase structures are available, the exact mechanism for iron insertion into porphyrin is still a matter for debate. There is also growing evidence that the mitochondrial iron-binding frataxin delivers iron directly to ferrochelatase.

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Biological Ligands for Metal Ions

Robert R. Crichton, in Biological Inorganic Chemistry (Second Edition), 2012

Chelatase – The Terminal Step in Tetrapyrrole Metallation

Tetrapyrroles are organic molecules that contain four five-membered heterocyclic (pyrrole) rings, linked in a cyclic or linear array. Haem, chlorophyll, cobalamin (vitamin B12), siroHaem,6 and coenzyme F430 belong to a family of prosthetic groups that are characterised by their tetrapyrrole-derived nature and contain a central, complexed metal ion: Fe2+ in haem and siroHaem, Mg2+ in chlorophyll and bacteriochlorophyll, Co2+ in cobalamin, and Ni2+ in coenzyme F430 They are all derived from a common tetrapyrrole precursor, uroporphyrinogen III (Fig. 4.8). The insertion of each of these metal ions involves a group of enzymes called chelatases, of which the best characterised is ferrochelatase, which inserts Fe2+ into protoporphyrin IX in the terminal step of the haem biosynthetic pathway. The different chelatases are thought to have similar mechanisms, which involve as the first step the distortion of the tetrapyrrole porphyrin upon binding to the enzyme to give a saddled structure (Fig. 4.9a) in which two opposite pyrrole rings are slightly tilted upwards while the other two pyrrole rings are tilted slightly downwards. In Fig. 4.9a, the two unprotonated nitrogen atoms of the pyrrole rings point upward, while the two protonated nitrogens point downward with respect to the porphyrin ring. Subsequent to the distortion of the porphyrin ring, the first metal–porphyrin bond is formed (Fig. 4.9b), followed by other ligand exchange steps leading to formation of a complex in which the iron atom is sitting on top of the porphyrin, with two of its nitrogen atoms coordinated to the metal while the other two are still protonated. This is followed by the sequential deprotonation of the two pyrrole nitrogen atoms coupled with formation of the metallated porphyrin. The saddling of the porphyrin is an out-of-plane deformation, which exposes both of the protons and the lone pairs of the nitrogen atoms of the porphyrin molecule in an appropriate arrangement for metal insertion.

FIGURE 4.8. The tetrapyrrole biosynthetic pathways. Chelatases selectively insert Fe2+ to form haem, Mg2+ to form chlorophyll, Co2+ to form cobalamine, and, in methane-producing bacteria, Ni2+ to form coenzyme F430.

FIGURE 4.9. Mechanism of porphyrin metallation. (a) Out-of-plane saddling deformation used to describe a nonplanar distortion of the porphyrin macrocycle in which two opposite pyrrole rings with unprotonated nitrogen atoms (blue spheres) point upwards, and the other two pyrrole rings with protonated nitrogen atoms (blue and white spheres) point downwards. (b) Steps in the reaction mechanism for incorporation of the metal ion (red) into porphyrin (pyrrole rings, green; unprotonated pyrrole nitrogen atoms, blue; protonated pyrrole nitrogen atoms with protons, yellow) include (i) deformation of the porphyrin ring; (ii) formation of the first metal–porphyrin bond, followed by other ligand-exchange steps leading to formation of a 'sitting-atop' complex (in which two pyrrolenine nitrogen atoms coordinate to the metal ion and two protons remain on the pyrrole nitrogen atoms); and (iii) sequential deprotonation of the two pyrrole nitrogen atoms coupled with formation of the metallated porphyrin.

The structure of several ferrochelatases has been determined, and it is clear that the porphyrin rings B, C, and D are held in a very tight grip by conserved amino acids, whereas the A ring is distorted. Two metal-ion-binding sites have been identified, one located at the surface of the molecule, occupied by a fully hydrated Mg2+ ion, and the other located in the porphyrin-binding cleft, close to the distorted porphyrin ring A, with its nitrogen pointing towards His183 and Glu264 (Fig. 4.10). It has been proposed that the metal ion on the outermost site, by ligand exchange with a series of acidic residues arranged along the helical edge of a π-helix,7 would be shuttled to the inner site, there to be exchanged with the pyrrole nitrogens, resulting in insertion of the metal ion into the porphyrin. The two sites, occupied respectively by a Zn2+ ion and a fully hydrated Mg2+ ion, are ~7 Å apart. Two of the ligands to the Zn2+ ion in the outer site, His183 and Glu264, are invariant in all ferrochelatases. The side chains of Glu272, Asp268, and Glu272 are aligned along the π-helix, in a line connecting the two metal sites. Only a π-helix can provide such an alignment of side chains. This is reminiscent of several other metalloproteins, like nitrogenase and the ferritin superfamily, in which residues in π-helices function to coordinate metal ions involved in enzymatic activity.

FIGURE 4.10. Porphyrin and metal-ion-binding sites in ferrochelatase. (a) Structure of B. subtilis ferrochelatase in complex with the transition-state inhibitor N-methylmesoporphyrin (N-MeMP). (b) Interaction of N-MeMP with amino acids in the substrate-binding cleft of B. subtilis ferrochelatase. (c) Two metal-binding sites in B. subtilis ferrochelatase. The two sites are shown with a Zn2+ ion (grey sphere) and a fully hydrated Mg2+ ion (green sphere).

An interesting question is why does a particular chelatase introduce just one particular divalent transition metal ion rather than any one of a number of others? It might be because that particular M2+ is present in that biological compartment (e.g., in the case of haem synthesis, Fe2+) and present at much larger concentrations than any other. Clues have begun to appear, however, from experiments in which site-directed mutagenesis of specific amino acid residues in the proposed metal-ion-binding site of the chelatase has changed the specificity of the metal ion, which is inserted into the porphyrin.

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Radical S-Adenosylmethionine Methylases

Danielle V. Miller, ... Squire J. Booker, in Reference Module in Chemistry, Molecular Sciences and Chemical Engineering, 2020

4.5.6 A new domain architecture for class B RSMTs

Class B radical SAM enzymes have been characterized up until this point by their domain architecture where the Cbl binding domain resides N-terminally to the radical SAM domain.26 However, recently Radle et al. identified a Cbl dependent radical SAM methylating enzyme, Mmp10, that does not have an N-terminal Cbl binding domain (Fig. 28A).129 In fact, the Mmp10 (methanogenesis marker protein 10) from Methanosarcina acetivorans and other methanogenic homologues is not annotated to bind Cbl at all. The Booker laboratories prior experience in working with Class B radical SAM enzymes suggested to them that the slow activity observed for Mmp10 initially was likely due to a missing cofactor, such as Cbl. This intuition was verified when with the addition of Cbl M. acetivorans Mmp10 became catalytic and multiple turnovers was observed.129

Fig. 28. Class B domain architecture (A) and MCR reaction with the methylated CoM, CoB, and F430 cofactors shown (B).

Mmp10 was originally confirmed to be a methylase when a knockout of the gene, mmp10 from M. acetivorans, was shown to be responsible for methylating Arg285 of the M. acetivorans Methyl Coenzyme M Reductase (MCR) alpha subunit of MCR.130 MCR is the terminal enzyme complex made up of three subunits (α, β, and γ) of methanogenesis resulting in the release of methane through the use of three distinct cofactors: coenzyme F430, methyl-2-mecaptoethanesulfonate (CoM), and N-7-mercaptoheptanoylthreonine phosphate (CoB) (Fig. 28B).131–134 The α subunit of MCR contains several post translational modifications all located in the active site.136 However, none of the post translational modifications, 1-N-methylhistidine, S-methylcysteine, 5-C-(S)-methylarginine (MeArg), 2-C-(S)-methylglutamine, thioglycine, 6-hydroxytryptophane, and 7-hydroxytryptophan have been determined to be essential to MCR activity nor completely conserved.135–137 Feeding studies using d3-methionine confirmed that the methylation modifications, such as MeArg, likely originated from SAM, where the MeArg and 2-C-(S)-methylglutamine modifications were likely performed by a RS enzyme due to the methylations being performed on unreactive carbon centers (Fig. 29).

Fig. 29. Mmp10 reaction methylating the Arg residue of MCRα.

MaMmp10 was recombinantly overexpressed in E. coli and characterized for its ability to methylate a 13 amino acid peptide mimic of the MCR α subunit.129 However, the enzymes ability to methylate the MCRα peptide mimic was not observed until Cbl was included in the assay.129 The addition of Cbl to the assay resulted in MaMmp10 to perform multiple turnovers and a kcat of 1.87 min− 1 was observed for the formation of SAH, 5′-dAH, and the methylated arginine peptide product.129 These surprising results led the authors to confirm that MeCbl was the intermediate of the reaction by observing the transfer of the d3-labeled methyl group from d3-SAM to MeCbl as d3-MeCbl and finally to the methylated peptide product (d3-methylargine peptide mimic).129

These results prompted the authors to dig more into the bioinformatics of the Mmp10 and its homologues and found MaMmp10 to be annotated in a single database to contain the domain of unknown function (DUF) 512. DUF512 contains more than 3000 members from all domains of life.138,139 In addition, the DUF512 is located C-terminally to a radical SAM domain and when analyzed for domain organization it clusters with Cbl binding radical SAM enzymes (Class B).138 Taken together the author's suggest that Mmp10 might contain a DUF512 domain, which is supported by the conversation between M. acetivorans Mmp10 and other DUF512 containing proteins, and the DUF512 domain could be a Cbl binding domain.129 Identification of the DUF512 domain as a potential Cbl binding domain is an exciting conclusion and could indicate that there are many more Cbl binding radical SAM enzymes than originally believed, where many of the proteins indicated to be members of the DUF512 are from pathogenic enzymes and contain a peptide binding site, PDZ, signaling domain. It will be of further interest to see if members of the DUF512 do bind Cbl and the types of chemistry they are performing.

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Contemporary Aspects of Boron: Chemistry and Biological Applications

V.M. Dembitsky, ... M. Srebnik, in Studies in Inorganic Chemistry, 2005

8. Synthesis of Substituted Porphyrins

Porphyrin synthesis arouses continuing interests in biological, material and inorganic chemistry. Substitutents at the β-positions of porphyrins exert much larger steric and electronic effects on the porphyrin ring than substiutents at the meso-aryl positions [328]. The β-substitutents also induce the porphyrin ring into a non-planar conformation which may control the biological properties in tetrapyrrole systems like the photosynthetic centers, vitamin B12 [329], coenzyme F430 [330] and the P-450 [331]. In fact, the recent crytallographic studies of iron[IV] oxo cation radical has demonstrated the stabilizing effect of β-halogen substitutents [331].

As was demonstrated [332] that β-bromoporphyrins 437,439,441 undergo Suzuki cross coupling reactions with aryl boronic acids gave corresponding β-arylporpyrins 438a-e, 440a,b, and 442a-c in high yields (Scheme 151).

Scheme 151.

5,10,15,20-Tetrakis(trifluoromethyl)porphyrin zinc complex 443 has been shown to undergo monobromination and regioselective dibromination gave β-bromoporphyrins 443a-c [333]. The free base β-bromoporphyrins 445a,b are converted to aryl porphyrins through Suzuki cross-coupling reaction. The free base porphyrins 445a-c were obtained by acid treatment of 443a-c with 35% HCl and subsequent neutralization (Scheme 152). 445a,b were easily demetallated in high yields of about 90% while 445c was obtained in only 44% yield. The low yield of 445c may be due to its acid lability.

Scheme 152.

Alos investigating the synthesis of dodecaarylporphyrins using the Suzuki coupling reaction of arylboronic acids (Scheme 153) with octabromotetraarylporphyrins 446 was reported [334]. Variable temperature 1H NMR studies of these new porphyrins 447a-g reveal several dynamic processes including the first examples of β-aryl rotation.

Scheme 153.

Among the synthetic molecular architectures based on substituted (β- or meso-positions) porphyrins, the welldefined modular organization of the linear meso-porphyrins offers homogeneous structural motifs useful for the construction of supramolecular assemblies. C2-Symmetric meso-porphyrins have been prepared 449 a-g (Scheme 154) in high yields by a palladium-catalyzed cross-coupling reaction involving dibromoporphyrins 448 and arylboronic acids [335].

Scheme 154.

A new method for the synthesis of meso-substituted porphyrins wass described [336]. Reaction of 5,10,15,20-tetrabromoporphine magnesium complex 450 with aryl or heteroaryl boronic acids in the presence of Pd(PPh3)4 gave meso-substituted porphyrins 451a-c in up to 70% yields (Scheme 155).

Scheme 155.

A method for synthesizing combinatorial libraries of unsymmetrically substituted tetra-meso-phenyl porphyrins on polystyrene based resin was described [337]. Attachment of 5,15-dibromo-10-(4-hydroxyphenyl)-20-(4-nitrophenyl)porphyrin onto brominated Wang resin 452 gave a convenient scaffold for the synthesis of photoactive porphyrin libraries with three points for generating diversity (Scheme 156). An array of nine TPP derivatives 453a-i was prepared by sequential Suzuki coupling/nitro-reduction and acylation protocols.

Scheme 156.

Multiporphyrin arrays 454, Fig. 14 with p-phenylene linkers, aryl groups at the non-linking meso positions, and no β-substituents are attractive constructs for light-harvesting applications. Condensation of a free base porphyrin-benzaldehyde and 5-mesityldipyrromethane in CH2CI2 containing 100 mM TFA at room temperature for 30–40 min followed by oxidation with DDQ afforded a p-phenylene-linked porphyrin trimer in 36% yield [338a]. Suzuki coupling of an iodo-porphyrin and a bis(dioxaborolane)-porphyrin in toluene/DMF containing K2CO3 at 90–95 °C for ∼20 h afforded the same trimer in 66% yield. The former route was used to prepare a diethynyl substituted p-phenylene-linked porphyrin trimer. While the two routes are somewhat complementary in scope, both are convergent and proceed in a rational manner.

Fig. 14. Multiporphyrin arrays 454

The Suzuki cross-coupling methodology provides a facile synthetic approach for the modular preparation of meso-tetraaryl cofacial bisporphyrins anchored by xanthene and dibenzofuran (Scheme 157). This synthetic method furnishes cofacial bisporphyrin templates with enhanced steric and electronic protection 454A and 454B from í-oxo formation and oxidative degradation. The ability of these platforms to support multi-electron oxidation chemistry mediated by proton-coupled electron transfer was demonstrated by their reactivity for the catalytic disproportionation of hydrogen peroxide to oxygen and water, Fig. 15.

Scheme 157.

Fig. 15. Cofacial bisporphyrin templates with enhanced steric and electronic protection 454A and 454B

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Bio-Relevant Chemistry of Nickel

Anna Company, Aidan R. McDonald, in Reference Module in Chemistry, Molecular Sciences and Chemical Engineering, 2020

3.2 Methyl Coenzyme M Reductase (MCR)

MCR is a Ni enzyme involved in the reversible synthesis of CH4 from a methylthioether (Scheme 26, methyl-2-mercaptoethanesulfonate (methyl-SCoM)).72,132–134 This represents the final step in methanogenesis or conversely the first step in anaerobic CH4 oxidation. Given the potential use of CH4 as an energy source and its toxicity as a greenhouse gas, an understanding of the chemistry of MCR could provide a number of important insights into how to generate and activate this important small molecule. MCR contains an unusual tetrahydrocorrin coordinated Ni center in the F430 coenzyme postulated to effect CH4 synthesis and oxidative activation (Scheme 26). MCR is postulated to cycle through a NiI/NiIII classical organometallic pathway, where the Ni protein in its reduced state undergoes oxidative addition with a methylthioether, methyl-SCoM, to yield a NiIII-CH3 moiety which undergoes protonation to form CH4 and NiIII. Successive oxidations of the neighboring thiols, HSCoM and N-7-mercaptoheptanoylthreonine phosphate (CoBSH), facilitates the regeneration of the NiI state and a disulfide product. An alternative mechanistic postulate involving free methyl radical, from the homolysis of the SC bond in methyl-SCoM, which in turn abstracts an H-atom from CoBSH to yield CH4, has limited experimental support.

Scheme 26. Structure of the active site of MCR and postulated catalytic mechanism for reversible CH4 synthesis/oxidation.

Tatsumi has been to the fore in attempting to mimic the structure and function of the MCR enzyme.135–137 Initial work focused on the properties of [NiII(Cl)(TMC)]+ complexes and their reaction with methyl coenzyme-M (MeSCoM, 2-sulfonyl-1-(S-methyl)-mercaptoethane) or the unalkylated derivative thereof (coenzyme-M, HSCoM, 2-sulfonyl-1-mercaptoethane) (Scheme 27). The first identified product showed the sulfonate groups of H/MeSCoM simply replacing the counterion of the starting complex [NiII(Cl)(TMC)]+ in a non-binding fashion, thus not coordinating to the Ni center. Halide abstraction, by addition of silver triflate yielded the desired [NiII(H/MeSCoM)(TMC)]+ complexes 99. Comparable cyclam complexes 100, with an appended axial pyridine ligand, were prepared in a similar fashion from the NiII–Cl precursor. Sodium triflate was used to remove the chloride ligand followed by reaction with tetrabutylammonium-MeSCoM to give the desired model complex 100.

Scheme 27. Tatsumi's functional models of MCR.

The complexes were characterized using X-ray crystallography demonstrating pseudo-square pyramidal and octahedral coordination geometries for the TMC and pyridine-appended cyclam ligands, respectively. Complex 100, containing the appended axial pyridine donor ligand, was identified as the more reliable mimic of the MCR active site, demonstrating octahedral geometry. For both the thiol HSCoM and thioether MeSCoM donors, metal ligation was through the hard sulfonate donor group and not the softer thiol or thioether donors, respectively, which mimics certain trapped states of MCR, although S-atom ligation has also been proposed.72 In a fascinating expansion of this structural work, the same group prepared NiIII adducts 101 from the reaction between [NiIII(Cl)2(cyclam)]+ (cyclam = 1,4,8,11-tetraazacyclotetradecane), silver triflate, and tetrabutylammonium-H/MeSCoM (Scheme 27).136 For MeSCoM, a mononuclear [NiIII(MeSCoM)2(cyclam)]+ was isolated and characterized, demonstrating octahedral geometry and binding to Ni through the sulfonate O-atoms. In contrast, when tetrabutylammonium-HSCoM was reacted with [NiIII(cyclam)]3 +, the NiIII ions were reduced to yield polymeric repeating units of [NiII(cyclam)]2 + linked by disulfide derivatives of HSCoM, with coordination via the sulfonate O-atoms. The corresponding [NiII(H/MeSCoM)2(cyclam)] complexes, analogous to [NiII(H/MeSCoM)(TMC)]+, were also synthesized demonstrating octahedral geometry around the NiII ion and coordination through the sulfonate O-atom.

Further work demonstrated the preparation of methylthioether-functionalized cyclam ligands that formed octahedral complexes with NiII (102, Scheme 27). These NiII complexes could be reduced to a NiI complex 103 using Na/Hg. Under certain conditions, the thioether functionality was observed to coordinate to the NiI ion. The thioether containing NiI complexes decayed to yield the dealkylated NiII-thiolate complex 104 and CH4, amongst other Ni and saturated hydrocarbon products. This observation demonstrated the homolysis of the SC bond in the NiI-bound thioether adduct and concomitant oxidation of the NiI ion to NiII, providing plausible experimental support for the postulate that the NiI state is involved in MCR reactivity.

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Polyketides and Other Secondary Metabolites Including Fatty Acids and Their Derivatives

Ronald J. Parry, in Comprehensive Natural Products Chemistry, 1999

1.29.2.3 Coenzyme M

The methanogenic bacteria are anaerobic organisms that convert CO2 to methane via a sequence of reactions that utilizes several unusual cofactors. One of these cofactors is coenzyme M (17), whose structure was determined in 1974 by Taylor and Wolfe.41 The final stages in the reduction of CO2 to methane involve the transfer of a CO2-derived methyl group from a methylcobamide-containing protein to coenzyme M to give S-methyl coenzyme M (MeCoM, Scheme 6). This is followed by a reaction that utilizes N-(7-mercaptoheptanoyl)threonine phosphate ((18), component B), S-methyl coenzyme M, and a Ni corphin (coenzyme F430)-containing methyl reductase to produce methane and a mixed disulfide between coenzyme M and N-(7-mercaptoheptanoyl)threonine phosphate. The last step of the reaction involves the reduction of the mixed disulfide to (17) and (18) by a heterodisulfide reductase (Scheme 6).42

Scheme 6.

The biosynthesis of coenzyme M has been investigated by White.43–45 Using mass spectrometric analysis, it was found that growth of three different strains of methanogenic bacteria (Methanobacterium formicicum, Methanosarcina strain TM-1, and rumen isolate 10-16B) in the presence of [2H3]acetate led to the formation of coenzyme M with up to two deuterium atoms present at C-1. The extent of labeling was the same as that calculated for the phosphoenolpyruvate in the cells. Using strain 10-16B, [1,2-13C2]acetate was shown to be incorporated into coenzyme M as a unit. Additional experiments revealed that dl-[3-2H2]sulfolactic acid and H34SO−3 also serve as coenzyme M precursors in strain 10-16B (3.2% and 3.1% incorporation, respectively), while labeled forms of sulfate, cysteic acid, sulfoacetic acid, taurine, and isethionate (2-hydroxyethanesulfonic acid) do not. On the basis of these results, the biosynthetic pathway shown in Scheme 7 was proposed. It is postulated that phosphoenolpyruvate (19) reacts with bisulfite anion via conjugate addition to produce sulfolactate which is then oxidized to sulfopyruvate (20). The next stage of the pathway is suggested to proceed by decarboxylation of sulfopyruvate to sulfoacetaldehyde (21) followed by reaction of the latter with l-cysteine to give the thiazolidine derivative (22). The final stages of the pathway are postulated to involve reduction of the thiazolidine (22) to S-(2-sulfoethyl)cysteine (23) which is then converted to coenzyme M and pyruvate by a transformation that presumably requires pyridoxal phosphate. Additional evidence is available that supports several stages of this pathway. Partially purified cell-free extracts of Methanobacterium formicicum were found to produce coenzyme M when incubated with phosphoenolpyruvate, bisulfite, and cysteine. When pyruvate was substituted for phosphoenolpyruvate, no coenzyme M was produced. When extracts incubated with phosphoenolpyruvate, bisulfite, and cysteine were analyzed for the presence of sulfonic acids by GC-MS, three of the proposed intermediates in coenzyme M biosynthesis, sulfolactic acid, sulfopyruvic acid, and sulfoacetaldehyde, were identified. Incubation of the cell-free extracts with sulfopyruvate in the presence or absence of cysteine also produced coenzyme M, sulfolactate, and sulfoacetaldehyde. This clearly suggests that sulfopyruvate lies on the biosynthetic pathway to the coenzyme. Incubation of a cell-free extract of M. formicicum with [2-2H2]sulfoacetaldehyde and l-cysteine under a hydrogen atmosphere led to the formation of coenzyme M in which 78% of the cofactor retained two deuterium atoms. The mass spectral fragmentation pattern demonstrated that the deuterium label was present at C-1 of coenzyme M, as expected. When a similar experiment was carried out with [2-2H2]sulfoacetaldehyde and l-[34S]cysteine, the thiol group of the resulting coenzyme M contained 90 atom % 34S. Incubation of [ethylene-2H4]S-(2-sulfoethyl)-l-cysteine with the cell-free extracts led to the isolation of coenzyme M with 88% of the molecules containing four deuterium atoms. All of these results support the biosynthetic pathway shown in Scheme 7. However, no direct evidence is available for the postulated intermediacy of the thiazolidine (22).

Scheme 7.

The mechanism of formation of the bisulfite required for coenzyme M biosynthesis has not been clearly defined. The only sulfur sources in the growth media for methanogenic bacteria are sulfide and sulfate. Since sulfate does not support the growth of these bacteria46 and is not incorporated into the coenzyme (see above), it appears that bisulfite must be formed by the oxidation of sulfide. It has been suggested that this oxidation could be carried out by a P590 enzyme that has been isolated from Methanosarcina barkeri and shown to possess sulfite reductase activity.

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Fig. 29. Mmp10 reaction methylating the Arg residue of MCRα.

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Scheme 151.

Scheme 152.

Scheme 153.

Scheme 154.

Scheme 155.

Scheme 156.

Fig. 14. Multiporphyrin arrays 454

Scheme 157.

Fig. 15. Cofacial bisporphyrin templates with enhanced steric and electronic protection 454A and 454B

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1.29.2.3 Coenzyme M

Scheme 6.

Scheme 7.

Chapter 108 - F430

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