The cyanobacteria or "blue-green algae", as they are commonly termed, comprise a diverse group of oxygenic photosynthetic bacteria that inhabit a wide range of aquatic and terrestrial environments, ...and display incredible morphological diversity. Many aquatic, bloom-forming species of cyanobacteria are capable of producing biologically active secondary metabolites, which are highly toxic to humans and other animals. From a toxicological viewpoint, the cyanotoxins span four major classes: the neurotoxins, hepatotoxins, cytotoxins, and dermatoxins (irritant toxins). However, structurally they are quite diverse. Over the past decade, the biosynthesis pathways of the four major cyanotoxins: microcystin, nodularin, saxitoxin and cylindrospermopsin, have been genetically and biochemically elucidated. This review provides an overview of these biosynthesis pathways and additionally summarizes the chemistry and toxicology of these remarkable secondary metabolites.
Several species of Dinophysis produce one or two groups of lipophilic toxins: okadaic acid (OA) and its derivatives; or the dinophysistoxins (DTXs) (also known as diarrhetic shellfish poisons or DSP ...toxins) and pectenotoxins (PTXs). DSP toxins are potent inhibitors of protein phosphatases, causing gastrointestinal intoxication in consumers of contaminated seafood. Forty years after the identification of Dinophysis as the causative agent of DSP in Japan, contamination of filter feeding shellfish exposed to Dinophysis blooms is recognized as a problem worldwide. DSP events affect public health and cause considerable losses to the shellfish industry. Costly monitoring programs are implemented in regions with relevant shellfish production to prevent these socioeconomic impacts. Harvest closures are enforced whenever toxin levels exceed regulatory limits (RLs). Dinophysis species are kleptoplastidic dinoflagellates; they feed on ciliates (Mesodinium genus) that have previously acquired plastids from cryptophycean (genera Teleaulax, Plagioselmis, and Geminigera) nanoflagellates. The interactions of Dinophysis with different prey regulate their growth and toxin production. When Dinophysis cells are ingested by shellfish, their toxins are partially biotransformed and bioaccumulated, rendering the shellfish unsuitable for human consumption. DSP toxins may also affect shellfish metabolism. This book covers diverse aspects of the abovementioned topics—from the laboratory culture of Dinophysis and the kinetics of uptake, transformation, and depuration of DSP toxins in shellfish to Dinophysis population dynamics, the monitoring and regulation of DSP toxins, and their impact on the shellfish industry in some of the aquaculture regions that are traditionally most affected, namely, northeastern Japan, western Europe, southern Chile, and New Zealand.
Clostridium difficile
is the cause of antibiotics-associated diarrhea and pseudomembranous colitis. The pathogen produces three protein toxins:
C. difficile
toxins A (TcdA) and B (TcdB), and
C. ...difficile
transferase toxin (CDT). The single-chain toxins TcdA and TcdB are the main virulence factors. They bind to cell membrane receptors and are internalized. The N-terminal glucosyltransferase and autoprotease domains of the toxins translocate from low-pH endosomes into the cytosol. After activation by inositol hexakisphosphate (InsP6), the autoprotease cleaves and releases the glucosyltransferase domain into the cytosol, where GTP-binding proteins of the Rho Ras family are mono-
O
-glucosylated and, thereby, inactivated. Inactivation of Rho proteins disturbs the organization of the cytoskeleton and affects multiple Rho-dependent cellular processes, including loss of epithelial barrier functions, induction of apoptosis, and inflammation. CDT, the third
C. difficile
toxin, is a binary actin-ADP-ribosylating toxin that causes depolymerization of actin, thereby inducing formation of the microtubule-based protrusions. Recent progress in understanding of the toxins' actions include insights into the toxin structures, their interaction with host cells, and functional consequences of their actions.
Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors
. One such mechanism involves type VI secretion systems, which bacteria can use to inject antibacterial toxins ...directly into neighbouring cells. Many of these toxins target the integrity of the cell envelope, but the full range of growth inhibitory mechanisms remains unknown
. Here we identify a type VI secretion effector, Tas1, in the opportunistic pathogen Pseudomonas aeruginosa. The crystal structure of Tas1 shows that it is similar to enzymes that synthesize (p)ppGpp, a broadly conserved signalling molecule in bacteria that modulates cell growth rate, particularly in response to nutritional stress
. However, Tas1 does not synthesize (p)ppGpp; instead, it pyrophosphorylates adenosine nucleotides to produce (p)ppApp at rates of nearly 180,000 molecules per minute. Consequently, the delivery of Tas1 into competitor cells drives rapid accumulation of (p)ppApp, depletion of ATP, and widespread dysregulation of essential metabolic pathways, thereby resulting in target cell death. Our findings reveal a previously undescribed mechanism for interbacterial antagonism and demonstrate a physiological role for the metabolite (p)ppApp in bacteria.
Abstract
Cyanobacteria produce an unparalleled variety of toxins that can cause severe health problems or even death in humans, and wild or domestic animals. In the last decade, biosynthetic pathways ...have been assigned to the majority of the known toxin families. This review summarizes current knowledge about the enzymatic basis for the production of the hepatotoxins microcystin and nodularin, the cytotoxin cylindrospermopsin, the neurotoxins anatoxin and saxitoxin, and the dermatotoxin lyngbyatoxin. Elucidation of the biosynthetic pathways of the toxins has paved the way for the development of molecular techniques for the detection and quantification of the producing cyanobacteria in different environments. Phylogenetic analyses of related clusters from a large number of strains has also allowed for the reconstruction of the evolutionary scenarios that have led to the emergence, diversification, and loss of such gene clusters in different strains and genera of cyanobacteria. Advances in the understanding of toxin biosynthesis and evolution have provided new methods for drinking-water quality control and may inspire the development of techniques for the management of bloom formation in the future.
We report the biosynthetic pathways of cyanobacterial toxins and describe the evolutionary scenarios that have led to the emergence, diversification and loss of such gene clusters.
Epsilon toxin (ETX) is produced by strains of Clostridium perfringens classified as type B or type D. ETX belongs to the heptameric β‐pore‐forming toxins including aerolysin and Clostridium septicum ...alpha toxin, which are characterized by the formation of a pore through the plasma membrane of eukaryotic cells consisting in a β‐barrel of 14 amphipatic β strands. By contrast to aerolysin and C. septicum alpha toxin, ETX is a much more potent toxin and is responsible for enterotoxemia in animals, mainly sheep. ETX induces perivascular edema in various tissues and accumulates in particular in the kidneys and brain, where it causes edema and necrotic lesions. ETX is able to pass through the blood–brain barrier and stimulate the release of glutamate, which accounts for the symptoms of nervous excitation observed in animal enterotoxemia. At the cellular level, ETX causes rapid swelling followed by cell death involving necrosis. The precise mode of action of ETX remains to be determined. ETX is a powerful toxin, however, it also represents a unique tool with which to vehicle drugs into the central nervous system or target glutamatergic neurons.
Clostridium perfringensε‐toxin is a potent lethal toxin, which is responsible for animal enterotoxemia. It is structurally related to aerolysin and Clostridium septicumα‐toxin. These toxins heptamerize, form pores through the plasma membrane, and induce cell necrosis, ε‐toxin being the most potent. ε‐toxin accumulates in the kidneys, passes the blood brain barrier and stimulates the glutamate release
Abstract
Bacillus thuringiensis bacteria are insect pathogens that produce different Cry and Cyt toxins to kill their hosts. Here we review the group of three-domain Cry (3d-Cry) toxins. Expression ...of these 3d-Cry toxins in transgenic crops has contributed to efficient control of insect pests and a reduction in the use of chemical insecticides. The mode of action of 3d-Cry toxins involves sequential interactions with several insect midgut proteins that facilitate the formation of an oligomeric structure and induce its insertion into the membrane, forming a pore that kills midgut cells. We review recent progress in our understanding of the mechanism of action of these Cry toxins and focus our attention on the different mechanisms of resistance that insects have evolved to counter their action, such as mutations in cadherin, APN and ABC transporter genes. Activity of Cry1AMod toxins, which are able to form toxin oligomers in the absence of receptors, against different resistant populations, including those affected in the ABC transporter and the role of dominant negative mutants as antitoxins, supports the hypothesis that toxin oligomerization is a limiting step in the Cry insecticidal activity. Knowledge of the action of 3d-Cry toxin and the resistance mechanisms to these toxins will set the basis for a rational design of novel toxins to overcome insect resistance, extending the useful lifespan of Cry toxins in insect control programs.
The review examined the similarities and differences of the molecular mechanisms and environmental factors that regulate aflatoxin, fumonisin and trichothecene biosynthesis.
Bacterial toxins represent a vast reservoir of biochemical diversity that can be repurposed for biomedical applications. Such proteins include a group of predicted interbacterial toxins of the ...deaminase superfamily, members of which have found application in gene-editing techniques
. Because previously described cytidine deaminases operate on single-stranded nucleic acids
, their use in base editing requires the unwinding of double-stranded DNA (dsDNA)-for example by a CRISPR-Cas9 system. Base editing within mitochondrial DNA (mtDNA), however, has thus far been hindered by challenges associated with the delivery of guide RNA into the mitochondria
. As a consequence, manipulation of mtDNA to date has been limited to the targeted destruction of the mitochondrial genome by designer nucleases
.Here we describe an interbacterial toxin, which we name DddA, that catalyses the deamination of cytidines within dsDNA. We engineered split-DddA halves that are non-toxic and inactive until brought together on target DNA by adjacently bound programmable DNA-binding proteins. Fusions of the split-DddA halves, transcription activator-like effector array proteins, and a uracil glycosylase inhibitor resulted in RNA-free DddA-derived cytosine base editors (DdCBEs) that catalyse C•G-to-T•A conversions in human mtDNA with high target specificity and product purity. We used DdCBEs to model a disease-associated mtDNA mutation in human cells, resulting in changes in respiration rates and oxidative phosphorylation. CRISPR-free DdCBEs enable the precise manipulation of mtDNA, rather than the elimination of mtDNA copies that results from its cleavage by targeted nucleases, with broad implications for the study and potential treatment of mitochondrial disorders.
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