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Biochimica Et Biophysica Acta.... Jan 2021The molybdenum cofactor (Moco) represents an ancient metal‑sulfur cofactor, which participates as catalyst in carbon, nitrogen and sulfur cycles, both on individual... (Review)
Review
The molybdenum cofactor (Moco) represents an ancient metal‑sulfur cofactor, which participates as catalyst in carbon, nitrogen and sulfur cycles, both on individual and global scale. Given the diversity of biological processes dependent on Moco and their evolutionary age, Moco is traced back to the last universal common ancestor (LUCA), while Moco biosynthetic genes underwent significant changes through evolution and acquired additional functions. In this review, focused on eukaryotic Moco biology, we elucidate the benefits of gene fusions on Moco biosynthesis and beyond. While originally the gene fusions were driven by biosynthetic advantages such as coordinated expression of functionally related proteins and product/substrate channeling, they also served as origin for the development of novel functions. Today, Moco biosynthetic genes are involved in a multitude of cellular processes and loss of the according gene products result in severe disorders, both related to Moco biosynthesis and secondary enzyme functions.
Topics: Coenzymes; Eukaryota; Gene Fusion; Humans; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Substrate Specificity
PubMed: 33017596
DOI: 10.1016/j.bbamcr.2020.118883 -
Archives of Biochemistry and Biophysics Jul 2013Vitamin B2 (riboflavin) is an essential dietary compound used for the enzymatic biosynthesis of FMN and FAD. The human genome contains 90 genes encoding for... (Review)
Review
Vitamin B2 (riboflavin) is an essential dietary compound used for the enzymatic biosynthesis of FMN and FAD. The human genome contains 90 genes encoding for flavin-dependent proteins, six for riboflavin uptake and transformation into the active coenzymes FMN and FAD as well as two for the reduction to the dihydroflavin form. Flavoproteins utilize either FMN (16%) or FAD (84%) while five human flavoenzymes have a requirement for both FMN and FAD. The majority of flavin-dependent enzymes catalyze oxidation-reduction processes in primary metabolic pathways such as the citric acid cycle, β-oxidation and degradation of amino acids. Ten flavoproteins occur as isozymes and assume special functions in the human organism. Two thirds of flavin-dependent proteins are associated with disorders caused by allelic variants affecting protein function. Flavin-dependent proteins also play an important role in the biosynthesis of other essential cofactors and hormones such as coenzyme A, coenzyme Q, heme, pyridoxal 5'-phosphate, steroids and thyroxine. Moreover, they are important for the regulation of folate metabolites by using tetrahydrofolate as cosubstrate in choline degradation, reduction of N-5.10-methylenetetrahydrofolate to N-5-methyltetrahydrofolate and maintenance of the catalytically competent form of methionine synthase. These flavoenzymes are discussed in detail to highlight their role in health and disease.
Topics: Coenzymes; Disease; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Flavoproteins; Folic Acid; Genome, Human; Humans; Mutation; Oxidation-Reduction; Proteome; Vitamin B 12
PubMed: 23500531
DOI: 10.1016/j.abb.2013.02.015 -
IUBMB Life May 2019Nucleotide coenzymes dot the map of metabolic pathways providing energy to drive the reactions of the pathway and play an important role in regulating and controlling... (Review)
Review
Nucleotide coenzymes dot the map of metabolic pathways providing energy to drive the reactions of the pathway and play an important role in regulating and controlling energy metabolism through their shared potential energy, which is widely unobserved due to the paradox that the energy in the coenzyme pools cannot be determined from the concentration of the coenzyme couples. The potential energy of the nucleotide couples in the mitochondria or the cytoplasm is expressed in the enzyme reactions in which they take part. The energy in these couples, [NAD+]/[NADH], [NADP+]/[NADPH], [acetyl CoA]/[CoA], and [ATP]/[ADP]x[Pi], regulates energy metabolism. The energy contained in the couples can be altered by suppling energy equivalents in the form of ketones, such as, D-β-hydroxybutyrate to overcome insulin resistance, to restore antioxidants capacity, to form potential treatments for Alzheimer's and Parkinson's diseases, to enhance life span, and to increase physiological performance. © 2019 IUBMB Life, 71(5):565-579, 2019.
Topics: Animals; Antioxidants; Coenzymes; Energy Metabolism; Humans; Metabolic Networks and Pathways; Mitochondria; Nucleotides
PubMed: 30624851
DOI: 10.1002/iub.1997 -
Angewandte Chemie (International Ed. in... Mar 2021The evolution of coenzymes, or their impact on the origin of life, is fundamental for understanding our own existence. Having established reasonable hypotheses about the... (Review)
Review
The evolution of coenzymes, or their impact on the origin of life, is fundamental for understanding our own existence. Having established reasonable hypotheses about the emergence of prebiotic chemical building blocks, which were probably created under palaeogeochemical conditions, and surmising that these smaller compounds must have become integrated to afford complex macromolecules such as RNA, the question of coenzyme origin and its relation to the evolution of functional biochemistry should gain new impetus. Many coenzymes have a simple chemical structure and are often nucleotide-derived, which suggests that they may have coexisted with the emergence of RNA and may have played a pivotal role in early metabolism. Based on current theories of prebiotic evolution, which attempt to explain the emergence of privileged organic building blocks, this Review discusses plausible hypotheses on the prebiotic formation of key elements within selected extant coenzymes. In combination with prebiotic RNA, coenzymes may have dramatically broadened early protometabolic networks and the catalytic scope of RNA during the evolution of life.
Topics: Coenzymes; Evolution, Molecular; Origin of Life; RNA
PubMed: 31945250
DOI: 10.1002/anie.201914786 -
Metabolic Engineering Jul 2016Saccharomyces cerevisiae is an important industrial cell factory and an attractive experimental model for evaluating novel metabolic engineering strategies. Many current... (Review)
Review
Saccharomyces cerevisiae is an important industrial cell factory and an attractive experimental model for evaluating novel metabolic engineering strategies. Many current and potential products of this yeast require acetyl coenzyme A (acetyl-CoA) as a precursor and pathways towards these products are generally expressed in its cytosol. The native S. cerevisiae pathway for production of cytosolic acetyl-CoA consumes 2 ATP equivalents in the acetyl-CoA synthetase reaction. Catabolism of additional sugar substrate, which may be required to generate this ATP, negatively affects product yields. Here, we review alternative pathways that can be engineered into yeast to optimize supply of cytosolic acetyl-CoA as a precursor for product formation. Particular attention is paid to reaction stoichiometry, free-energy conservation and redox-cofactor balancing of alternative pathways for acetyl-CoA synthesis from glucose. A theoretical analysis of maximally attainable yields on glucose of four compounds (n-butanol, citric acid, palmitic acid and farnesene) showed a strong product dependency of the optimal pathway configuration for acetyl-CoA synthesis. Moreover, this analysis showed that combination of different acetyl-CoA production pathways may be required to achieve optimal product yields. This review underlines that an integral analysis of energy coupling and redox-cofactor balancing in precursor-supply and product-formation pathways is crucial for the design of efficient cell factories.
Topics: Acetyl Coenzyme A; Biosynthetic Pathways; Coenzymes; Cytosol; Energy Metabolism; Genetic Enhancement; Metabolic Engineering; Metabolic Flux Analysis; Metabolic Networks and Pathways; Oxidation-Reduction; Reactive Oxygen Species; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 27016336
DOI: 10.1016/j.ymben.2016.03.006 -
The Journal of Biological Chemistry Oct 2021In most organisms, transition metal ions are necessary cofactors of ribonucleotide reductase (RNR), the enzyme responsible for biosynthesis of the 2'-deoxynucleotide... (Review)
Review
In most organisms, transition metal ions are necessary cofactors of ribonucleotide reductase (RNR), the enzyme responsible for biosynthesis of the 2'-deoxynucleotide building blocks of DNA. The metal ion generates an oxidant for an active site cysteine (Cys), yielding a thiyl radical that is necessary for initiation of catalysis in all RNRs. Class I enzymes, widespread in eukaryotes and aerobic microbes, share a common requirement for dioxygen in assembly of the active Cys oxidant and a unique quaternary structure, in which the metallo- or radical-cofactor is found in a separate subunit, β, from the catalytic α subunit. The first class I RNRs, the class Ia enzymes, discovered and characterized more than 30 years ago, were found to use a diiron(III)-tyrosyl-radical Cys oxidant. Although class Ia RNRs have historically served as the model for understanding enzyme mechanism and function, more recently, remarkably diverse bioinorganic and radical cofactors have been discovered in class I RNRs from pathogenic microbes. These enzymes use alternative transition metal ions, such as manganese, or posttranslationally installed tyrosyl radicals for initiation of ribonucleotide reduction. Here we summarize the recent progress in discovery and characterization of novel class I RNR radical-initiating cofactors, their mechanisms of assembly, and how they might function in the context of the active class I holoenzyme complex.
Topics: Animals; Catalysis; Catalytic Domain; Coenzymes; Humans; Metals; Oxidation-Reduction; Ribonucleotide Reductases
PubMed: 34461093
DOI: 10.1016/j.jbc.2021.101137 -
Journal of the American Chemical Society Jun 2023Coenzymes are involved in ≥30% of enzymatic reactions and likely predate enzymes, going back to prebiotic chemistry. However, they are considered poor organocatalysts,...
Coenzymes are involved in ≥30% of enzymatic reactions and likely predate enzymes, going back to prebiotic chemistry. However, they are considered poor organocatalysts, and thus their pre-enzymatic function remains unclear. Since metal ions are known to catalyze metabolic reactions in the absence of enzymes, here we explore the influence of metal ions on coenzyme catalysis under conditions relevant to the origin of life (20-75 °C, pH 5-7.5). Specifically, Fe or Al, the two most abundant metals in the Earth's crust, were found to exhibit substantial cooperative effects in transamination reactions catalyzed by pyridoxal (PL), a coenzyme scaffold used by roughly 4% of all enzymes. At 75 °C and 7.5 mol % loading of PL/metal ion, Fe-PL was found to be 90-fold faster at catalyzing transamination than PL alone and 174-fold faster than Fe alone, whereas Al-PL was 85-fold faster than PL alone and 38-fold faster than Al alone. Under milder conditions, reactions catalyzed by Al-PL were >1000 times faster than those catalyzed by PL alone. Pyridoxal phosphate (PLP) exhibited similar behavior to PL. Experimental and theoretical mechanistic studies indicate that the rate-determining step in the PL-metal-catalyzed transamination is different from metal-free and biological PL-based catalysis. Metal coordination to PL lowers the p of the PL-metal complex by several units and slows the hydrolysis of imine intermediates by up to 259-fold. Coenzymes, specifically pyridoxal derivatives, could have exhibited useful catalytic function even before enzymes.
Topics: Pyridoxal; Pyridoxal Phosphate; Metals; Coenzymes; Amination; Catalysis
PubMed: 37278531
DOI: 10.1021/jacs.3c03542 -
Proceedings of the National Academy of... Nov 2022Nucleobase-containing coenzymes are hypothesized to be relics of an early RNA-based world that preceded the emergence of proteins. Despite the importance of...
Nucleobase-containing coenzymes are hypothesized to be relics of an early RNA-based world that preceded the emergence of proteins. Despite the importance of coenzyme-protein synergisms, their emergence and evolution remain understudied. An excellent target to address this issue is the Rossmann fold, the most catalytically diverse and abundant protein architecture in nature. We investigated two main Rossmann lineages: the nicotinamide adenine dinucleotide phosphate (NAD(P)) and the S-adenosyl methionine (SAM)- binding superfamilies. To identify the evolutionary changes that lead to a coenzyme specificity switch on these superfamilies, we performed structural and sequence-based Hidden Markov model analysis to systematically search for key motifs in their coenzyme-binding pockets. Our analyses revealed that through insertions and deletions (InDels) and a residue substitution, the ancient β1-loop-α1 coenzyme-binding structure of NAD(P) could be reshaped into the SAM-binding β1-loop-α1 structure. To experimentally prove this obsevation, we removed three amino acids from the NAD(P)-binding pocket and solved the structure of the resulting mutant, revealing the characteristic loop features of the SAM-binding pocket. To confirm the binding to SAM, we performed isothermal titration calorimetry measurements. Molecular dynamics simulations also corroborated the role of InDels in abolishing NAD binding and acquiring SAM binding. Our results uncovered how nature may have utilized insertions and deletions to optimize the different coenzyme-binding pockets and the distinct functionalities observed for Rossmann superfamilies. This work also proposes a general mechanism by which protein templates could have been recycled through the course of evolution to adopt different coenzymes and confer distinct chemistries.
Topics: NAD; Coenzymes; Proteins; NADP; S-Adenosylmethionine
PubMed: 36417431
DOI: 10.1073/pnas.2207965119 -
International Journal of Molecular... Jul 2023Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic... (Review)
Review
Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic thiamine prodrug, the thioester benfotiamine (BFT), has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has no known adverse effects and improves cognitive outcomes in patients with mild Alzheimer's disease. In cell culture and animal models, BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. Recent in vitro studies show that another thiamine thioester, O,S-dibenzoylthiamine (DBT), is even more efficient than BFT, especially with respect to its anti-inflammatory potency, and is effective at lower concentrations. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified open thiazole ring derivatives. The identification of the active neuroprotective metabolites and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental, and psychiatric conditions. The present review aims to summarize existing data on the neuroprotective effects of thiamine thioesters and give a comprehensive account.
Topics: Animals; Humans; Neurodegenerative Diseases; Thiamine; Thiamine Pyrophosphate; Coenzymes
PubMed: 37511056
DOI: 10.3390/ijms241411296 -
Current Opinion in Plant Biology Apr 2022In plants, primary and specialized metabolism have classically been distinguished as either essential for growth or required for survival in a particular environment.... (Review)
Review
In plants, primary and specialized metabolism have classically been distinguished as either essential for growth or required for survival in a particular environment. Coenzymes (organic cofactors) are essential for growth but their importance to specialized metabolism is often not considered. In line with the recent proposal of viewing primary and specialized metabolism as an integrated whole rather than segregated lots with a defined interface, we highlight here the importance of collating information on the regulation of coenzyme supply with metabolic demands using examples of vitamin B derived coenzymes. We emphasize that coenzymes can have enormous influence on the outcome of metabolic as well as engineered pathways and should be taken into account in the era of synthetic biology.
Topics: Coenzymes; Plants; Vitamin B Complex
PubMed: 35063913
DOI: 10.1016/j.pbi.2021.102170