Vitamin B
, cobalamin, is a cobalt-containing ring-contracted modified tetrapyrrole that represents one of the most complex small molecules made by nature. In prokaryotes it is utilised as a ...cofactor, coenzyme, light sensor and gene regulator yet has a restricted role in assisting only two enzymes within specific eukaryotes including mammals. This deployment disparity is reflected in another unique attribute of vitamin B
in that its biosynthesis is limited to only certain prokaryotes, with synthesisers pivotal in establishing mutualistic microbial communities. The core component of cobalamin is the corrin macrocycle that acts as the main ligand for the cobalt. Within this review we investigate why cobalt is paired specifically with the corrin ring, how cobalt is inserted during the biosynthetic process, how cobalt is made available within the cell and explore the cellular control of cobalt and cobalamin levels. The partitioning of cobalt for cobalamin biosynthesis exemplifies how cells assist metalation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hydrogenases catalyze the formation of hydrogen. The cofactor ('H-cluster') of FeFe-hydrogenases consists of a 4Fe-4S cluster bridged to a unique 2Fe subcluster whose biosynthesis in vivo requires ...hydrogenase-specific maturases. Here we show that a chemical mimic of the 2Fe subcluster can reconstitute apo-hydrogenase to full activity, independent of helper proteins. The assembled H-cluster is virtually indistinguishable from the native cofactor. This procedure will be a powerful tool for developing new artificial H₂-producing catalysts.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cytochrome P450 enzymes primarily catalyze mixed-function oxidation reactions, plus some reductions and rearrangements of oxygenated species, e.g. prostaglandins. Most of these reactions can be ...rationalized in a paradigm involving Compound I, a high-valent iron-oxygen complex (FeO3+), to explain seemingly unusual reactions, including ring couplings, ring expansion and contraction, and fusion of substrates. Most P450s interact with flavoenzymes or iron-sulfur proteins to receive electrons from NAD(P)H. In some cases, P450s are fused to protein partners. Other P450s catalyze non-redox isomerization reactions. A number of permutations on the P450 theme reveal the diversity of cytochrome P450 form and function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
SUMMARY
Cofactors are fundamental to the catalytic activity of enzymes. Additionally, because plants are a critical source of several cofactors (i.e., including their vitamin precursors) within the ...context of human nutrition, there have been several studies aiming to understand the metabolism of coenzymes and vitamins in plants in detail. For example, compelling evidence has been brought forth regarding the role of cofactors in plants; specifically, it is becoming increasingly clear that an adequate supply of cofactors in plants directly affects their development, metabolism, and stress responses. Here, we review the state‐of‐the‐art knowledge on the significance of coenzymes and their precursors with regard to general plant physiology and discuss the emerging functions attributed to them. Furthermore, we discuss how our understanding of the complex relationship between cofactors and plant metabolism can be used for crop improvement.
Significance Statement
An adequate supply of cofactors in plants has a direct impact on their metabolism, development, and stress responses. Therefore, exploring the roles of coenzymes and cofactors, as well as their precursors, in the regulation of metabolism and physiological processes may offer new possibilities to improve plant yield and stress tolerance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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•I propose that life originated from simple catalytically active self-reproducing molecules, similar to coenzymes.•These molecules colonized the surface of oil droplets in water and ...changed surface properties to enable self-reproduction.•Evolvability of primordial systems was based on cooperation of multiple kinds of self-reproducing molecules.•Later events included emergence of template-based replication and transformation of oil droplets into cell membrane.
The origin of life means the emergence of heritable and evolvable self-reproduction. However the mechanisms of primordial heredity were different from those in contemporary cells. Here I argue that primordial life had no nucleic acids; instead heritable signs were represented by isolated catalytically active self-reproducing molecules, similar to extant coenzymes, which presumably colonized surfaces of oil droplets in water. The model further assumes that coenzyme-like molecules (CLMs) changed surface properties of oil droplets (e.g., by oxidizing terminal carbons), and in this way created and sustained favorable conditions for their own self-reproduction. Such niche-dependent self-reproduction is a necessary condition for cooperation between different kinds of CLMs because they have to coexist in the same oil droplets and either succeed or perish together. Additional kinds of hereditary molecules were acquired via coalescence of oil droplets carrying different kinds of CLMs or via modification of already existing CLMs. Eventually, polymerization of CLMs became controlled by other polymers used as templates; and this kind of template-based synthesis eventually resulted in the emergence of RNA-like replicons. Apparently, oil droplets transformed into the outer membrane of cells via engulfing water, stabilization of the surface, and osmoregulation. In result, the metabolism was internalized allowing cells to accumulate free-floating resources (e.g., animoacids, ATP), which was a necessary condition for the development of protein synthesis. Thus, life originated from simple but already functional molecules, and its gradual evolution towards higher complexity was driven by cooperation and natural selection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A protein-derived cofactor is a catalytic or redox-active site in a protein that is formed by post-translational modification of one or more amino acid residues. These post-translational ...modifications are irreversible and endow the modified amino acid residues with new functional properties. This Perspective focuses on the following advances in this area that have occurred during recent years. The biosynthesis of the tryptophan tryptophylquinone cofactor is catalyzed by a diheme enzyme, MauG. A bis-FeIV redox state of the hemes performs three two-electron oxidations of specific Trp residues via long-range electron transfer. In contrast, a flavoenzyme catalyzes the biosynthesis of the cysteine tryptophylquinone (CTQ) cofactor present in a newly discovered family of CTQ-dependent oxidases. Another carbonyl cofactor, the pyruvoyl cofactor found in classes of decarboxylases and reductases, is formed during an apparently autocatalytic cleavage of a precursor protein at the N-terminus of the cleavage product. It has been shown that in at least some cases, the cleavage is facilitated by binding to an accessory protein. Tyrosylquinonine cofactors, topaquinone and lysine tyrosylquinone, are found in copper-containing amine oxidases and lysyl oxidases, respectively. The physiological roles of different families of these enzymes in humans have been more clearly defined and shown to have significant implications with respect to human health. There has also been continued characterization of the roles of covalently cross-linked amino acid side chains that influence the reactivity of redox-active metal centers in proteins. These include Cys-Tyr species in galactose oxidase and cysteine dioxygenase and the Met-Tyr-Trp species in the catalase-peroxidase KatG.
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IJS, KILJ, NUK, PNG, UL, UM
Metal-containing enzyme cofactors achieve their unusual reactivity by stabilizing uncommon metal oxidation states with structurally complex ligands. In particular, the specific cofactor promoting ...both methanogenesis and anaerobic methane oxidation is a porphyrinoid chelated to a nickel(i) atom via a multi-step biosynthetic path, where nickel reduction is achieved through extensive molecular hydrogenation. Here, we demonstrate an alternative route to porphyrin reduction by charge transfer from a selected copper substrate to commercially available 5,10,15,20-tetraphenyl-porphyrin nickel(ii). X-ray absorption measurements at the Ni L3-edge unequivocally show that NiTPP species adsorbed on Cu(100) are stabilized in the highly reactive Ni(i) oxidation state by electron transfer to the molecular orbitals. Our approach highlights how some fundamental properties of synthetically inaccessible biological cofactors may be reproduced by hybridization of simple metalloporphyrins with metal surfaces, with implications towards novel approaches to heterogenous catalysis.
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are currently the most effective medications for reducing low-density lipoprotein cholesterol concentrations. Although generally ...safe, they have been associated with a variety of myopathic complaints. Statins block production of farnesyl pyrophosphate, an intermediate in the synthesis of ubiquinone or coenzyme Q10 (CoQ10). This fact, plus the role of CoQ10 in mitochondrial energy production, has prompted the hypothesis that statin-induced CoQ10 deficiency is involved in the pathogenesis of statin myopathy. We identified English language articles relating statin treatment and CoQ10 levels via a PubMed search through August 2006. Abstracts were reviewed and articles addressing the relationship between statin treatment and CoQ10 levels were examined in detail. Statin treatment reduces circulating levels of CoQ10. The effect of statin therapy on intramuscular levels of CoQ10 is not clear, and data on intramuscular CoQ10 levels in symptomatic patients with statin-associated myopathy are scarce. Mitochondrial function may be impaired by statin therapy, and this effect may be exacerbated by exercise. Supplementation can raise the circulating levels of CoQ10, but data on the effect of CoQ10 supplementation on myopathic symptoms are scarce and contradictory. We conclude that there is insufficient evidence to prove the etiologic role of CoQ10 deficiency in statin-associated myopathy and that large, well-designed clinical trials are required to address this issue. The routine use of CoQ10 cannot be recommended in statin-treated patients. Nevertheless, there are no known risks to this supplement and there is some anecdotal and preliminary trial evidence of its effectiveness. Consequently, CoQ10 can be tested in patients requiring statin treatment, who develop statin myalgia, and who cannot be satisfactorily treated with other agents. Some patients may respond, if only via a placebo effect.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nitrogenase is the only known biological system capable of reducing N2 to NH3, which is a critical component of bioavailable nitrogen fixation. Since the discovery of discrete iron‐sulfur ...metalloclusters within the nitrogenase MoFe protein, synthetic inorganic chemists have sought to reproduce the structural features of these clusters in order to understand how they facilitate the binding, activation and hydrogenation of N2. Through the decades following the initial identification of these clusters, significant progress has been made to synthetically replicate certain compositional and functional aspects of the biogenic clusters. Although much work remains to generate synthetic iron–sulfur clusters that can reduce N2 to NH3, the insights borne from past and recent developments are discussed in this concept article.
Developing a fixation: Synthesizing models that capture both the structure and function of nitrogenase metalloclusters remains a significant challenge for chemists. Developments in the understanding of cofactor assembly and synthetic cluster preparation demonstrate the recent progress made towards achieving these worthwhile biological targets.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To date, there is no information on the effect of TBI on the changes in brain CoQ levels and possible variations in its redox state. In this study, we induced graded TBIs (mild TBI, mTBI and severe ...TBI, sTBI) in male rats, using the weight-drop closed-head impact acceleration model of trauma. At 7 days post-injury, CoQ9, CoQ10 and α-tocopherol were measured by HPLC in brain extracts of the injured rats, as well as in those of a group of control sham-operated rats. In the controls, about the 69% of total CoQ was in the form of CoQ9 and the oxidized/reduced ratios of CoQ9 and CoQ10 were, respectively, 1.05 ± 0.07 and 1.42 ± 0.17. No significant changes in these values were observed in rats experiencing mTBI. Conversely, in the brains of sTBI-injured animals, an increase in reduced and a decrease in oxidized CoQ9 produced an oxidized/reduced ratio of 0.81 ± 0.1 (p < 0.001 compared with both controls and mTBI). A concomitant decrease in both reduced and oxidized CoQ10 generated a corresponding oxidized/reduced ratio of 1.38 ± 0.23 (p < 0.001 compared with both controls and mTBI). An overall decrease in the concentration of the total CoQ pool was also found in sTBI-injured rats (p < 0.001 compared with both controls and mTBI). Concerning α-tocopherol, whilst no differences compared with the controls were found in mTBI animals, a significant decrease was observed in rats experiencing sTBI (p < 0.01 compared with both controls and mTBI). Besides suggesting potentially different functions and intracellular distributions of CoQ9 and CoQ10 in rat brain mitochondria, these results demonstrate, for the first time to the best of knowledge, that sTBI alters the levels and redox states of CoQ9 and CoQ10, thus adding a new explanation to the mitochondrial impairment affecting ETC, OXPHOS, energy supply and antioxidant defenses following sTBI.
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