Review

Authors: Wolf-Dieter Lienhart, Venugopal Gudipati, Peter Macheroux...

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

Review

Authors: Harmen M van Rossum, Barbara U Kozak, Jack T Pronk...

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

Review

Authors: Simon J Mayr, Ralf-R Mendel, Guenter Schwarz...

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

Review

Authors: Andreas Kirschning

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

Review

Authors: Richard L Veech, Michael Todd King, Robert Pawlosky...

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

Authors: Quentin Dherbassy, Robert J Mayer, Kamila B Muchowska...

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

Authors: Yvonne Kallberg, Udo Oppermann, Hans Jörnvall...

Short-chain dehydrogenases/reductases (SDRs) are enzymes of great functional diversity. Even at sequence identities of typically only 15-30%, specific sequence motifs are detectable, reflecting common folding patterns. We have developed a functional assignment scheme based on these motifs and we find five families. Two of these families were known previously and are called 'classical' and 'extended' families, but they are now distinguished at a further level based on coenzyme specificities. This analysis gives seven subfamilies of classical SDRs and three subfamilies of extended SDRs. We find that NADP(H) is the preferred coenzyme among most classical SDRs, while NAD(H) is that preferred among most extended SDRs. Three families are novel entities, denoted 'intermediate', 'divergent' and 'complex', encompassing short-chain alcohol dehydrogenases, enoyl reductases and multifunctional enzymes, respectively. The assignment scheme was applied to the genomes of human, mouse, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana and Saccharomyces cerevisiae. In the animal genomes, the extended SDRs amount to around one quarter or less of the total number of SDRs, while in the A. thaliana and S. cerevisiae genomes, the extended members constitute about 40% of the SDR forms. The numbers of NAD(H)-dependent and NADP(H)-dependent SDRs are similar in human, mouse and plant, while the proportions of NAD(H)-dependent enzymes are much lower in fruit fly, worm and yeast. We show that, in spite of the great diversity of the SDR superfamily, the primary structure alone can be used for functional assignments and for predictions of coenzyme preference.

Topics: Amino Acid Motifs; Amino Acid Sequence; Animals; Coenzymes; Humans; Markov Chains; Mice; Molecular Sequence Data; Oxidoreductases; Protein Structure, Tertiary; Sequence Alignment; Sequence Analysis, Protein

PubMed: 12230552
DOI: 10.1046/j.1432-1033.2002.03130.x

Review

Authors: Andrea Benzi, Alessia Grozio, Sonia Spinelli...

Nicotinamide adenine dinucleotide (NAD) is a fundamental molecule in the regulation of energy metabolism, representing both a coenzyme and a substrate for different NAD degrading enzymes. Among these enzymes, CD38 can be seen under two perspectives: as the enzyme synthesizing Ca-mobilizing second messenger, starting from NAD, and as the major NAD-consumer, to be inhibited to increase NAD levels. Indeed, the regulation of NAD availability is a key event during different processes. In this review, we examine the recent studies related to the modulation of CD38 expression and activity, and the consequent changes in NAD(P)(H), in adipose tissue, during inflammation and cold-induced thermogenesis.

Topics: ADP-ribosyl Cyclase 1; Adipose Tissue; Animals; Coenzymes; Humans; Models, Biological; NAD; Thermogenesis

PubMed: 34835990
DOI: 10.3390/nu13113734

Review

Authors: Terry B Ruskoski, Amie K Boal

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

Review

Authors: Paula da Fonseca-Pereira, Rita de Cássia Monteiro-Batista, Wagner L Araújo...

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.

Topics: Humans; Coenzymes; Vitamins; Plants; Plant Physiological Phenomena

PubMed: 36861364
DOI: 10.1111/tpj.16167