scholarly journals Enzymology of extracellular NAD metabolism

2021 ◽  
Author(s):  
Massimiliano Gasparrini ◽  
Leonardo Sorci ◽  
Nadia Raffaelli
Keyword(s):  
Current Knowledge ◽  
Biochemical Properties ◽  
Extracellular Proteins ◽  
Membrane Receptors ◽  
Intracellular Regeneration ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nad Metabolism ◽  
Nucleotide Pyrophosphatase ◽  
Nicotinic Acid Phosphoribosyltransferase ◽  
Extracellular Environment

AbstractExtracellular NAD represents a key signaling molecule in different physiological and pathological conditions. It exerts such function both directly, through the activation of specific purinergic receptors, or indirectly, serving as substrate of ectoenzymes, such as CD73, nucleotide pyrophosphatase/phosphodiesterase 1, CD38 and its paralog CD157, and ecto ADP ribosyltransferases. By hydrolyzing NAD, these enzymes dictate extracellular NAD availability, thus regulating its direct signaling role. In addition, they can generate from NAD smaller signaling molecules, like the immunomodulator adenosine, or they can use NAD to ADP-ribosylate various extracellular proteins and membrane receptors, with significant impact on the control of immunity, inflammatory response, tumorigenesis, and other diseases. Besides, they release from NAD several pyridine metabolites that can be taken up by the cell for the intracellular regeneration of NAD itself. The extracellular environment also hosts nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase, which inside the cell catalyze key reactions in NAD salvaging pathways. The extracellular forms of these enzymes behave as cytokines, with pro-inflammatory functions. This review summarizes the current knowledge on the extracellular NAD metabolome and describes the major biochemical properties of the enzymes involved in extracellular NAD metabolism, focusing on the contribution of their catalytic activities to the biological function. By uncovering the controversies and gaps in their characterization, further research directions are suggested, also to better exploit the great potential of these enzymes as therapeutic targets in various human diseases.

scholarly journals Increased nicotinamide adenine dinucleotide content and synthesis in Plasmodium falciparum-infected human erythrocytes

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1705-1710 ◽  
Author(s):  
CR Zerez ◽  
EF Jr Roth ◽  
S Schulman ◽  
KR Tanaka
Keyword(s):  
Plasmodium Falciparum ◽  
Nicotinic Acid ◽  
Nicotinamide Adenine Dinucleotide ◽  
Biosynthetic Pathway ◽  
Pentose Phosphate ◽  
Nicotinamide Adenine ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nad Synthesis ◽  
Infected Rbcs ◽  
Nicotinic Acid Phosphoribosyltransferase

Abstract Plasmodium falciparum-infected red blood cells (RBCs) are characterized by increases in the activity of glycolytic enzymes. Because nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP) are cofactors in the reactions of glycolysis and pentose phosphate shunt, we have examined NAD and NADP content in P. falciparum-infected RBCs. Although NADP content was not significantly altered, NAD content was increased approximately 10-fold in infected RBCs (66% parasitemia) compared with uninfected control RBCs. To determine the mechanism for the increase in NAD content, we examined the activity of several NAD biosynthetic enzymes. It is known that normal human RBCs make NAD exclusively from nicotinic acid and lack the capacity to make NAD from nicotinamide. We demonstrate that infected RBCs have readily detectable nicotinamide phosphoribosyltransferase (NPRT), the first enzyme in the NAD biosynthetic pathway that uses nicotinamide, and abundant nicotinamide deamidase, the enzyme that converts nicotinamide to nicotinic acid, thereby indicating that infected RBCs can make NAD from nicotinamide. In addition, infected RBCs have a threefold increase in nicotinic acid phosphoribosyltransferase (NAPRT), the first enzyme in the NAD biosynthetic pathway that uses nicotinic acid. Thus, the increase in NAD content in P falciparum-infected RBCs appears to be mediated by increases in NAD synthesis from both nicotinic acid and nicotinamide.

scholarly journals The Biochemical Properties of Manganese in Plants

Plants ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 381 ◽  
Author(s):  
Schmidt ◽  
Husted
Keyword(s):  
Metal Ions ◽  
Oxidation State ◽  
Metal Binding ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Biochemical Properties ◽  
Oxygen Evolving Complex ◽  
Functional Roles ◽  
Catalyzed Reactions ◽  
Enzyme Catalyzed Reactions

Manganese (Mn) is an essential micronutrient with many functional roles in plant metabolism. Manganese acts as an activator and co-factor of hundreds of metalloenzymes in plants. Because of its ability to readily change oxidation state in biological systems, Mn plays and important role in a broad range of enzyme-catalyzed reactions, including redox reactions, phosphorylation, decarboxylation, and hydrolysis. Manganese(II) is the prevalent oxidation state of Mn in plants and exhibits fast ligand exchange kinetics, which means that Mn can often be substituted by other metal ions, such as Mg(II), which has similar ion characteristics and requirements to the ligand environment of the metal binding sites. Knowledge of the molecular mechanisms catalyzed by Mn and regulation of Mn insertion into the active site of Mn-dependent enzymes, in the presence of other metals, is gradually evolving. This review presents an overview of the chemistry and biochemistry of Mn in plants, including an updated list of known Mn-dependent enzymes, together with enzymes where Mn has been shown to exchange with other metal ions. Furthermore, the current knowledge of the structure and functional role of the three most well characterized Mn-containing metalloenzymes in plants; the oxygen evolving complex of photosystem II, Mn superoxide dismutase, and oxalate oxidase is summarized.

scholarly journals Molecular Properties and New Potentials of Plant Nepenthesins

Plants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 570
Author(s):  
Zelalem Eshetu Bekalu ◽  
Giuseppe Dionisio ◽  
Henrik Brinch-Pedersen
Keyword(s):  
Current Knowledge ◽  
Industrial Applications ◽  
Biochemical Properties ◽  
Carnivorous Plant ◽  
Current Data ◽  
Fungal Resistance ◽  
Limited Attention ◽  
Specific Sequence ◽  
Aspartic Proteases ◽  
Trait Improvement

Nepenthesins are aspartic proteases (APs) categorized under the A1B subfamily. Due to nepenthesin-specific sequence features, the A1B subfamily is also named nepenthesin-type aspartic proteases (NEPs). Nepenthesins are mostly known from the pitcher fluid of the carnivorous plant Nepenthes, where they are availed for the hydrolyzation of insect protein required for the assimilation of insect nitrogen resources. However, nepenthesins are widely distributed within the plant kingdom and play significant roles in plant species other than Nepenthes. Although they have received limited attention when compared to other members of the subfamily, current data indicates that they have exceptional molecular and biochemical properties and new potentials as fungal-resistance genes. In the current review, we provide insights into the current knowledge on the molecular and biochemical properties of plant nepenthesins and highlights that future focus on them may have strong potentials for industrial applications and crop trait improvement.

scholarly journals Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

2020 ◽  
Vol 17 (18) ◽  
pp. 6811
Author(s):  
Henrieta Hlisníková ◽  
Ida Petrovičová ◽  
Branislav Kolena ◽  
Miroslava Šidlovská ◽  
Alexander Sirotkin
Keyword(s):  
Reproductive Health ◽  
Human Health ◽  
Intracellular Signaling ◽  
Current Knowledge ◽  
Membrane Receptors ◽  
Reproductive Disorders ◽  
Testicular Dysgenesis Syndrome ◽  
Fertility Disorders ◽  
Reproductive Processes ◽  
Cancer And Fertility

The production of plastic products, which requires phthalate plasticizers, has resulted in the problems for human health, especially that of reproductive health. Phthalate exposure can induce reproductive disorders at various regulatory levels. The aim of this review was to compile the evidence concerning the association between phthalates and reproductive diseases, phthalates-induced reproductive disorders, and their possible endocrine and intracellular mechanisms. Phthalates may induce alterations in puberty, the development of testicular dysgenesis syndrome, cancer, and fertility disorders in both males and females. At the hormonal level, phthalates can modify the release of hypothalamic, pituitary, and peripheral hormones. At the intracellular level, phthalates can interfere with nuclear receptors, membrane receptors, intracellular signaling pathways, and modulate gene expression associated with reproduction. To understand and to treat the adverse effects of phthalates on human health, it is essential to expand the current knowledge concerning their mechanism of action in the organism.

scholarly journals The Biological Axis of Protein Arginine Methylation and Asymmetric Dimethylarginine

2019 ◽  
Vol 20 (13) ◽  
pp. 3322 ◽  
Author(s):  
Melody D. Fulton ◽  
Tyler Brown ◽  
Y. George Zheng
Keyword(s):  
Asymmetric Dimethylarginine ◽  
Current Knowledge ◽  
Arginine Methylation ◽  
Biochemical Properties ◽  
Acid Product ◽  
Protein Protein Interaction ◽  
Protein Arginine Methylation ◽  
Protein Nucleic Acid ◽  
Eukaryotic Organisms ◽  
Substrate Proteins

Protein post-translational modifications (PTMs) in eukaryotic cells play important roles in the regulation of functionalities of the proteome and in the tempo-spatial control of cellular processes. Most PTMs enact their regulatory functions by affecting the biochemical properties of substrate proteins such as altering structural conformation, protein–protein interaction, and protein–nucleic acid interaction. Amid various PTMs, arginine methylation is widespread in all eukaryotic organisms, from yeasts to humans. Arginine methylation in many situations can drastically or subtly affect the interactions of substrate proteins with their partnering proteins or nucleic acids, thus impacting major cellular programs. Recently, arginine methylation has become an important regulator of the formation of membrane-less organelles inside cells, a phenomenon of liquid–liquid phase separation (LLPS), through altering π-cation interactions. Another unique feature of arginine methylation lies in its impact on cellular physiology through its downstream amino acid product, asymmetric dimethylarginine (ADMA). Accumulation of ADMA in cells and in the circulating bloodstream is connected with endothelial dysfunction and a variety of syndromes of cardiovascular diseases. Herein, we review the current knowledge and understanding of protein arginine methylation in regards to its canonical function in direct protein regulation, as well as the biological axis of protein arginine methylation and ADMA biology.

Ecto-nucleotide pyrophosphatase/phosphodiesterase as part of a multiple system for nucleotide hydrolysis by platelets from rats: Kinetic characterization and biochemical properties

Platelets ◽  
2006 ◽  
Vol 17 (2) ◽  
pp. 84-91 ◽  
Author(s):  
Cristina Ribas Fürstenau ◽  
Danielle Da Silva Trentin ◽  
Maria Luiza Morais Barreto-Chaves ◽  
João José Freitas Sarkis
Keyword(s):  
Biochemical Properties ◽  
Kinetic Characterization ◽  
Nucleotide Hydrolysis ◽  
Nucleotide Pyrophosphatase

scholarly journals NAD metabolism fuels human and mouse intestinal inflammation

Gut ◽  
2017 ◽  
Vol 67 (10) ◽  
pp. 1813-1823 ◽  
Author(s):  
Romana R Gerner ◽  
Victoria Klepsch ◽  
Sophie Macheiner ◽  
Kathrin Arnhard ◽  
Timon E Adolph ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Intestinal Inflammation ◽  
Activated T Cells ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nad Metabolism ◽  
Macrophage Polarisation ◽  
Inflammatory Monocytes ◽  
Promising Therapeutic Approach ◽  
The Impact

ObjectiveNicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism.DesignWe investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD.ResultsFK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1−⁄− mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10.ConclusionOur data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

Structure and properties of the Ca2+-binding CUB domain, a widespread ligand-recognition unit involved in major biological functions

2011 ◽  
Vol 439 (2) ◽  
pp. 185-193 ◽  
Author(s):  
Christine Gaboriaud ◽  
Lynn Gregory-Pauron ◽  
Florence Teillet ◽  
Nicole M. Thielens ◽  
Isabelle Bally ◽  
...  
Keyword(s):  
Binding Site ◽  
Protein Interactions ◽  
Current Knowledge ◽  
Density Lipoprotein ◽  
Extracellular Proteins ◽  
Present Review ◽  
Biological Functions ◽  
Protein Motifs ◽  
Wide Range ◽  
Cub Domain

CUB domains are 110-residue protein motifs exhibiting a β-sandwich fold and mediating protein–protein interactions in various extracellular proteins. Recent X-ray structural and mutagenesis studies have led to the identification of a particular CUB domain subset, cbCUB (Ca2+-binding CUB domain). Unlike other CUB domains, these harbour a homologous Ca2+-binding site that underlies a conserved binding site mediating ionic interaction between two of the three conserved acidic Ca2+ ligands and a basic (lysine or arginine) residue of a protein ligand, similar to the interactions mediated by the low-density lipoprotein receptor family. cbCUB-mediated protein–ligand interactions usually involve multipoint attachment through several cbCUBs, resulting in high-affinity binding through avidity, despite the low affinity of individual interactions. The aim of the present review is to summarize our current knowledge about the structure and functions of cbCUBs, which represent the majority of the known CUB repertoire and are involved in a variety of major biological functions, including immunity and development, as well as in various cancer types. Examples discussed in the present review include a wide range of soluble and membrane-associated human proteins, as well as some archaeal and invertebrate proteins. The fact that these otherwise unrelated proteins share a common Ca2+-dependent ligand-binding ability suggests a mechanism inheri-ted from very primitive ancestors. The information provided in the present review should stimulate further investigations on the crucial interactions mediated by cbCUB-containing proteins.

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