Латрункулин: актин полимеризациясын тежеуші және оның биоло­гиялық әсері

The latrunculins are a family of natural products and toxins produced by certain sponges, including genus Latrunculia and Negombata, whence the name is derived. It binds actin monomers near the nucleotide binding cleft with 1:1 stoichiometry and prevents them from polymerizing. Administered in vivo, this effect results in disruption of the actin filaments of the cytoskeleton, and allows visualization of the corresponding changes made to the cellular processes. This property is similar to that of cytochalasin, but has a narrow effective concentration range. Latrunculin has been used to great effect in the discovery of cadherin distribution regulation and has potential medical applications. Latrunculin A, a type of the toxin, was found to be able to make reversible morphological changes to mammalian cells by disrupting the actin network. Latrunculin A:
Molecular Formula:C22H31NO5SMolecular Weight:421.552 g/molMolecular Weight:395.514 g/mol
Target and Function

Actin Latrunculin B makes up the structure of the actin fibers. Protein spire homolog 2 needed for cell division, vesicle transport within the actin filament and is essential for the formation of the cleavage formation during cell division.

Latrunculin is a toxin that is produced by sponges. The red coloured Latrunculia magnifica Keller is an abundant sponge in the gulf of Eilat and the gulf of Suez in the red sea, where it lives at a depth of 6–30 meters. The toxin was discovered around 1970. Researchers observed that the red coloured sponges, Latrunculia magnifica Keller, were never damaged or eaten by fishes, while others were. Furthermore, when researchers squeezed the sponges in the sea, they observed that a red fluid came out. Fishes nearby immediately fled the surrounding area when the sponge secreted the fluid. These were the first indications that these sponges produced a toxin. Later this hypothesis was confirmed by squeezing the sponge in an aquarium with fish, whereupon the fish showed a loss of balance and severe bleeding, dying within only 4–6 minutes.

Latrunculin A and latrunculin B affect polymerization of actin. Latrunculin binds actin monomers near the nucleotide binding cleft with 1:1 stoichiometry and prevents them from polymerizing. Experimental evidence shows that latruculin A is biologically active in the solvent DMSO, but not in aqueous solutions, as demonstrated in cell culture and in brain tissue probably due to cellular permeation. When actin is impaired due to latrunculin, Shiga toxins have a better chance of infiltrating the intestinal epithelial monolayer in E. coli, which may cause a higher chance of generating gastrointestinal illnesses. It seems that actin monomers are more sensitive to bind latrunculin A than to bind Latrunculin B. In other words, latrunculin A is a more potent toxin. Latrunculin B is inactivated faster than latrunculin A. The prevention of polymerizing of the actin filaments causes reversible changes in the morphology of mammalian cells. Lantranculin interferes with the structure of the cytoskeleton in rats. After latrunculin B exposure, mouse fibroblasts grow bigger and PtK2 kidney cells from a potoroo stem produced long, branched extensions. The extensions seem to be an accumulation of actin monomers.

Yeast cells in absence of the proteins osh3 or osh5 demonstrated hypersensitivity to latrunculin B. The osh proteins are homologous to OSBP generated enzymes that appear in mammals, indicating that these might play a role in the toxicokinetics of latrunculins. Yeast mutants that are resistant to latrunculin show a mutation, D157E, that initiates a hydrogen bond with latrunculin. Adding latrunculin B to solutions of pollen F actin produced a rapid decrease in the total amount of polymer, the extent of depolymerization increasing with the concentrations of the toxic. The concentration of latrunculin B required for half maximal inhibition of pollen germination is 40 to 50 nM, whereas pollen tube extension is much more sensitive, requiring only 5 to 7 nM LATB for half maximal inhibition. The disruption of germination and pollen tube growth by latrunculin B is partially reversible at low concentrations. (<30 nM). Latrunculin A has been used as acrosome reaction inhibitor of guinea pig in laboratory conditions.

In nature, latrunculins are used by the sponges themselves as a defense mechanism, and for the same purpose are also sequestered by certain nudibranchs. Latrunculins are produced for fundamental research and have potential medical applications as latrunculins and their derivatives show antiangionic, antiproliferative, antimicrobial and antimetastatic activities. The sponges themselves are not damaged by latrunculin. As a measure against self toxination, they keep the latrunculin in membrane bound vacuoles, that also function as secretory and storage vesicles. These vacuoles are free of actin and prevent the latrunculin from entering the cytosol where it would damage actin. In the field of Neuroscience, latrunculin has been used to demonstrate the role of actin in regulating voltage gated ion channels in different nerve cells, showing that latrunculin treatment can alter the electrical activity of nerve cells. Latrunculin shows a dose dependent inhibition of K+ currents and acute application can induce the firing of multiple action potentials , which could underlie a mechanism of defense via nociceptors. The potential use of latrunculin as growth inhibitors of tumor cells has already been investigated for certain forms of gastric cancer, In lower doses, latrunculin can be used to decrease disaggregation and cell migration, thereby preventing invasive activities of tumor cells. By cellular relaxation and loosened cell cell junctions, latrunculin can increase humor outflow facility. The first human trial of lantruculin B as treatment of ocular hypertension and glaucoma showed significantly lower intraocular pressure in patients.