Cereulide is a

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

produced by some strains of ''

Bacillus cereus ''Bacillus cereus'' is a Gram-positive rod-shaped bacterium commonly found in soil, food, and marine sponges. The specific name, ''cereus'', meaning "waxy" in Latin, refers to the appearance of colonies grown on blood agar. Some strains are ...

''. It is a potent

cytotoxin Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cell ...

that destroys mitochondria. It also causes

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

and

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

. Cereulide acts as

ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as ...

with a high affinity to

potassium Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosp ...

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

s. Exposure to cereulide causes loss of the

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charge ...

and uncoupling of

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine t ...

in the mitochondria.News on cereulide, the emetic toxin of ''Bacillus Cereus''
/ref> The nausea and vomiting is believed to be caused by cereulide's binding and activation of 5-HT₃ receptors, leading to increased

afferent Afferent may refer to: Anatomical structures Meaning "conveying towards a center": * Afferent arterioles, blood vessels that supply the nephrons * Afferent lymphatic vessels, lymph vessels that carry lymph to a lymph node * Afferent nerve fiber ...

vagus nerve The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and rig ...

stimulation. Cereulide is a cyclic dodecadepsipeptide resembling

valinomycin Valinomycin is a naturally occurring dodecadepsipeptide used in the transport of potassium and as an antibiotic. Valinomycin is obtained from the cells of several ''Streptomyces'' species, '' S. fulvissimus'' being a notable one. It is a member o ...

; it contains three repeats of four amino acids: D-

Oxy Oxy may refer to: Arts, entertainment, and media * Oxy, a fictional character from the Molecularium Project * Oxy, abbreviation for the Oxyrhynchus Papyri Brands and enterprises * Oxy, a line of skin care products from Mentholatum * OXY, Ticker s ...

- Leu—D- Ala—L-Oxy-

Val Val may refer to: Val-a Film * ''Val'' (film), an American documentary about Val Kilmer, directed by Leo Scott and Ting Poo Military equipment * Aichi D3A, a Japanese World War II dive bomber codenamed "Val" by the Allies * AS Val, a Sov ...

—L-Val. It is produced by a dedicated

non-ribosomal peptide synthesis Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacter ...

(NRPS) system in ''B. cereus''. The

spores In biology, a spore is a unit of sexual or asexual reproduction that may be adapted for dispersal and for survival, often for extended periods of time, in unfavourable conditions. Spores form part of the life cycles of many plants, algae, ...

of cereulide-producing strains of ''B. cereus'' are manyfold more heat resistant than spores of cereulide non-producers. The toxin has no loss of activity upon

autoclaving An autoclave is a machine used to carry out industrial and scientific processes requiring elevated temperature and pressure in relation to ambient pressure and/or temperature. Autoclaves are used before surgical procedures to perform steriliz ...

, cooking, or baking.

Biosynthesis

In ''Bacillus cereus'', cereulide biosynthesis occurs by the non-ribosomal peptide synthetase of the heterodimer proteins CesA and CesB. In non-ribosomal peptide synthetase, individual amino acids are added, modified, and linked. Addition is facilitated by the adenylation (A) domain. Modification is accomplished by the ketoreductase (KR) and epimerization (E) domains. Finally, the growing peptides are linked by condensation domains. The transportation between domains is facilitated by a peptide carrier protein or thiolation (T) domain, which houses the growing peptide chain. Additionally, a thioesterase (TE) domain is used by the final module to cleave and cyclize the final peptide product. The peptides produced from both CesA and CesB are linked with an ester rather than amide bond; given the cyclic structure of cereulide, this cyclic ester (or lactone) linkage makes cereulide a depsipeptide. CesA is a 387 kDa heterodimer protein composed of CesA1 and CesA2 modules. CesA1 adds ketoisocaproic acid to the adenylation domain. The thiolation domain will then move the ketoisocaproic acid along the ketoreductase domain, which reduces ketoisocaproic acid into D-α-hydroxyisocaproic acid with the cofactor NADPH. In module CesA2, L-alanine is added to the adenylation domain. The condensation domain will facilitate a nucleophilic attack by the free amine on L-alanine onto the thioester of D-α-hydroxyisocaproic acid (D-HIC) on the CesA1 module. This event links the peptides and situates the growing peptide molecule on the thiolation domain of CesA2. Next, an epimerization domain changes the stereochemistry of L-alanine (L-Ala) into D-alanine (D-Ala). CesB is a 305 kDa heterodimer protein composed of CesB1 and CesB2 modules. CesB1 behaves almost identically to CesA1, where ketoisocaproic acid was added and reduced; however, the substrate α-ketoisovaleric acid is reduced to L- α-hydroxyisovaleric acid (L-HIV). Additionally, a condensation domain at the end of CesA (beyond CesA2) facilitates the ester formation between L-HIV and the D-HIC-D-Ala peptide. Next, CesB2 adds L-valine (L-Val) to the adenylation domain, and the condensation domain facilitates the nucleophilic attack of the amine on L-Val onto the D-HIC-D-Ala-L-HIV thioester, which creates a D-HIC-D-Ala-L-HIV-L-Val tetrapeptide on the thiolation domain of CesB2. Finally, the final thioesterase domain combines three units of the aforementioned tetrapeptide between the α-hydroxyl group of D-HIC and the thioester of a L-Val of another tetrapeptide. Ultimately, three esters are formed during this cyclization of 3 tetrapeptides. The resulting cyclic depsipeptide, which contains alternating units of esters and amides, is cereulide. Cereulide biosynthesis

References

External links

* *{{cite journal, url=http://proteomics.embl.de/Cereulide.pdf , title=Molecular diversity of cereulide , author1=S. Pitchayawasin , author2=M. Isobe , author3=M. Kuse , author4=T. Franz , author5=N. Agata , author6=M. Ohta , date=May 19, 2004 , url-status=dead, archiveurl=https://web.archive.org/web/20050313113550/http://proteomics.embl.de/Cereulide.pdf , archivedate=March 13, 2005 Archive.org Cyclic peptides Ionophores Depsipeptides Bacterial toxins Emetics 5-HT3 agonists