| C3 exoenzyme | |||||||
|---|---|---|---|---|---|---|---|
 Structure of Clostridium botulinum C3 exoenzyme NAD from PDB entry 2C8C [1] | |||||||
| Identifiers | |||||||
| Symbol | C3 | ||||||
| SCOPe | 2C89 / SUPFAM | ||||||
| |||||||
Clostridium botulinum C3 exoenzyme is a toxin that causes the addition of one or more ADP-ribose moieties to Rho-like proteins. Many bacterial toxins nucleotide-binding modify by ADP-ribosylation proteins involved in essential cell functions, leading to their toxic effects. [2]
The molecular basis of the action of these enzymes consists in binding of nicotinamide adenine dinucleotide (NAD), splitting NAD into its ADP-ribose and nicotinamide components, and transferring the ADP-ribose moiety to a specific residue on to a protein substrate, often of eukaryotic origin. All the toxins of this family share a highly conserved glutamate, which is the catalytic residue critical for the NAD-glycohydrolase activity. ADP-ribosyltransferase toxins have distinct substrate specificities and variable pathophysiological properties and can be subdivided into four subfamilies: diphtheria-like toxins, cholera-like toxins, binary toxins and C3-like exoenzymes.
C3-like exoenzymes unlike other ADP-ribosyltransferase toxins do not require a specific cell-surface binding translocation component for cell entry. Their specificity is for the small GTP-binding proteins RhoA, RhoB, and RhoC, which are ADP-ribosylated on an asparagine residue.
Nicotinamide adenine dinucleotide (NAD) is a cofactor that is central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH respectively.
An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host-pathogen interface.
Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.
Sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase, or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast.
Cholera toxin is AB5 multimeric protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection. It is a member of the Heat-labile enterotoxin family.
Diphtheria toxin is an exotoxin secreted by Corynebacterium, the pathogenic bacterium that causes diphtheria. The toxin gene is encoded by a prophage. The toxin causes the disease in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis.
The AB5 toxins are six-component protein complexes secreted by certain pathogenic bacteria known to cause human diseases such as cholera, dysentery, and hemolytic-uremic syndrome. One component is known as the A subunit, and the remaining five components are B subunits. All of these toxins share a similar structure and mechanism for entering targeted host cells. The B subunit is responsible for binding to receptors to open up a pathway for the A subunit to enter the cell. The A subunit is then able to use its catalytic machinery to take over the host cell's regular functions.
The formyl peptide receptors (FPR) belong to a class of G protein-coupled receptors involved in chemotaxis. In humans, there are three formyl peptide receptor isoforms, each encoded by a separate gene that are named FPR1, FPR2, and FPR3. These receptors were originally identified by their ability to bind N-formyl peptides such as N-formylmethionine produced by the degradation of either bacterial or host cells. Hence formyl peptide receptors are involved in mediating immune cell response to infection. These receptors may also act to suppress the immune system under certain conditions. The close phylogenetic relation of signaling in chemotaxis and olfaction was recently proved by detection formyl peptide receptor like proteins as a distinct family of vomeronasal organ chemosensors in mice.
Ribose-phosphate diphosphokinase is an enzyme that converts ribose 5-phosphate into phosphoribosyl pyrophosphate (PRPP). It is classified under EC 2.7.6.1.
Adenylylation, more commonly known as AMPylation, is a process in which an adenosine monophosphate (AMP) molecule is covalently attached to the amino acid side chain of a protein. This covalent addition of AMP to a hydroxyl side chain of the protein is a posttranslational modification. Adenylylation involves a phosphodiester bond between a hydroxyl group of the molecule undergoing adenylylation, and the phosphate group of the adenosine monophosphate nucleotide. Enzymes that are capable of catalyzing this process are called AMPylators. The known amino acids to be targeted in the protein are tyrosine and threonine, and sometimes serine. When charges on a protein undergo a change, it affects the characteristics of the protein, normally by altering its shape via interactions of the amino acids which make up the protein. AMPylation can have various effects on the protein. These are properties of the protein like, stability, enzymatic activity, co-factor binding, and many other functional capabilities of a protein. The most commonly identified protein to receive AMPylation are GTPases, and glutamine synthetase.
ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.
ADP-ribose diphosphatase (EC 3.6.1.13) is an enzyme that catalyzes a hydrolysis reaction in which water nucleophilically attacks ADP-ribose to produce AMP and D-ribose 5-phosphate. Enzyme hydrolysis occurs by the breakage of a phosphoanhydride bond and is dependent on Mg2+ ions that are held in complex by the enzyme.
In enzymology, a NAD(P)+-protein-arginine ADP-ribosyltransferase (EC 2.4.2.31) is an enzyme that catalyzes the chemical reaction using nicotinamide adenine dinucleotide
In enzymology, a NAD+-diphthamide ADP-ribosyltransferase (EC 2.4.2.36) is an enzyme that catalyzes the chemical reaction
Tankyrase, also known as tankyrase 1, is an enzyme that in humans is encoded by the TNKS gene. It inhibits the binding of TERF1 to telomeric DNA.
Nicotinamide mononucleotide adenylyltransferase 1 is an enzyme that in humans is encoded by the NMNAT1 gene. It is a member of the nicotinamide-nucleotide adenylyltransferases.
Ecto-ADP-ribosyltransferase 3 is an enzyme that in humans is encoded by the ART3 gene.
The AB toxins are two-component protein complexes secreted by a number of pathogenic bacteria. They can be classified as Type III toxins because they interfere with internal cell function. They are named AB toxins due to their components: the "A" component is usually the "active" portion, and the "B" component is usually the "binding" portion. The "A" subunit possesses enzyme activity, and is transferred to the host cell following a conformational change in the membrane-bound transport "B" subunit. These proteins consist of two independent polypeptides, which correspond to the A/B subunit moieties. The enzyme component (A) enters the cell through endosomes produced by the oligomeric binding/translocation protein (B), and prevents actin polymerisation through ADP-ribosylation of monomeric G-actin.
In molecular biology, the Macro domain or A1pp domain is a module of about 180 amino acids which can bind ADP-ribose, an NAD metabolite, or related ligands. Binding to ADP-ribose can be either covalent or non-covalent: in certain cases it is believed to bind non-covalently, while in other cases it appears to bind both non-covalently through a zinc finger motif, and covalently through a separate region of the protein.
Parthanatos is a form of programmed cell death that is distinct from other cell death processes such as necrosis and apoptosis. While necrosis is caused by acute cell injury resulting in traumatic cell death and apoptosis is a highly controlled process signalled by apoptotic intracellular signals, parthanatos is caused by the accumulation of PAR and the nuclear translocation of apoptosis-inducing factor (AIF) from mitochondria. Parthanatos is also known as PARP-1 dependent cell death. PARP-1 mediates parthanatos when it is over-activated in response to extreme genomic stress and synthesizes PAR which causes nuclear translocation of AIF. Parthanatos is involved in diseases that afflict hundreds of millions of people worldwide. Well known diseases involving parthanatos include Parkinson's disease, stroke, heart attack, and diabetes. It also has potential use as a treatment for ameliorating disease and various medical conditions such as diabetes and obesity.