latrunculin

Latrunculin is a toxin that is produced by sponges. The red-coloured Latrunculia Magnifica Keller is an abundant sponge in the Gulf of Aqaba and the Gulf of Suez{{cite journal|last1=Groweiss|first1=Amiram|last2=Shmueli|first2=Uri|last3=Kashman|first3=Yoel | name-list-style = vanc |date=1983-10-01|title=Marine toxins of Latrunculia magnifica | journal=The Journal of Organic Chemistry|volume=48|issue=20|pages=3512–3516|doi=10.1021/jo00168a028}} in the red sea, where it lives at a depth of 6–30 meters.{{cite journal | vauthors = Kashman V, Groweiss A, Shmueli U | title = Latrunculin, a new 2-thiazolidinone macrolide from the marine sponge | journal = Tetrahedron Letters | date = January 1980 | volume = 21 | issue = 37 | pages = 3629–3632 | doi = 10.1016/0040-4039(80)80255-3 }} 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. Similar effects were observed when the toxin was injected in mice.

Latrunculin makes up to 0.35% of the dry weight of the sponge. There are two main forms of the toxin, A and B. Latrunculin A is only present in sponges which live in the Gulf of Suez while latrunculin B only exist in sponges in the Gulf of Aqaba. Why this is the case is still under investigation.

[[File:Activity of latrunculin analogues.gif|thumb|Figure 2 relative activity of Latrunculin analogues

The micro filament disrupting activity (at 10 μM effective concentration). Abbreviations: ± weak effect, + significant effect, ++ strong effect, +++ very strong effect (less than 20% viable cells).

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There are several isomers of latrunculin, A, B, C, D, G, H, M, S and T. The most common structures are latrunculin A and B. Their formulas are respectively C₂₂H₃₁NO₅S and C₂₀H₂₉NO₅S. The macrolactone ring on top that contains double bonds is a structural feature of the latrunculin molecules. The side chain contains an acylthiazolidinone substitute. Besides these natural occurring forms, scientist have made synthetic forms with different toxic strengths. Figure 2 shows some of these forms with their relative ability to disrupt microfilament activity. Semisynthetic forms that contained N-alkylated derivates were inactive.{{cite journal | vauthors = Maier ME | title = Design and synthesis of analogues of natural products | journal = Organic & Biomolecular Chemistry | volume = 13 | issue = 19 | pages = 5302–43 | date = May 2015 | pmid = 25829247 | doi = 10.1039/C5OB00169B | doi-access = free }}

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. The nucleotide monomers are prevented from dissociation from the nucleotide binding cleft, thus preventing polymerizing.{{cite journal | vauthors = Morton WM, Ayscough KR, McLaughlin PJ | title = Latrunculin alters the actin-monomer subunit interface to prevent polymerization | journal = Nature Cell Biology | volume = 2 | issue = 6 | pages = 376–8 | date = June 2000 | pmid = 10854330 | doi = 10.1038/35014075 | hdl = 1842/757 | s2cid = 1803612 | hdl-access = free }}

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{{cite journal | vauthors = Tazerart S, Mitchell DE, Miranda-Rottmann S, Araya R | title = A spike-timing-dependent plasticity rule for dendritic spines | journal = Nature Communications | volume = 11 | issue = 1 | pages = 4276 | date = August 2020 | pmid = 32848151 | pmc = 7449969 | doi = 10.1038/s41467-020-17861-7 | bibcode = 2020NatCo..11.4276T }} 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.{{cite journal | vauthors = Maluykova I, Gutsal O, Laiko M, Kane A, Donowitz M, Kovbasnjuk O | title = Latrunculin B facilitates Shiga toxin 1 transcellular transcytosis across T84 intestinal epithelial cells | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1782 | issue = 6 | pages = 370–7 | date = June 2008 | pmid = 18342638 | pmc = 2509583 | doi = 10.1016/j.bbadis.2008.01.010 }}

It seems that actin monomers are more sensitive to bind latrunculin A than to bind Latrunculin B.{{cite journal | vauthors = Wakatsuki T, Schwab B, Thompson NC, Elson EL | title = Effects of cytochalasin D and latrunculin B on mechanical properties of cells | journal = Journal of Cell Science | volume = 114 | issue = Pt 5 | pages = 1025–36 | date = March 2001 | doi = 10.1242/jcs.114.5.1025 | pmid = 11181185 | doi-access = free }} In other words, latrunculin A is a more potent toxin. Latrunculin B is inactivated faster than latrunculin A.{{cite journal | vauthors = Spector I, Shochet NR, Blasberger D, Kashman Y | title = Latrunculins--novel marine macrolides that disrupt microfilament organization and affect cell growth: I. Comparison with cytochalasin D | journal = Cell Motility and the Cytoskeleton | volume = 13 | issue = 3 | pages = 127–44 | pmid = 2776221 | doi = 10.1002/cm.970130302 | year = 1989 }}

The prevention of polymerizing of the actin filaments causes reversible changes in the morphology of mammalian cells.{{cite journal | vauthors = Pendleton A, Koffer A | title = Effects of latrunculin reveal requirements for the actin cytoskeleton during secretion from mast cells | journal = Cell Motility and the Cytoskeleton | volume = 48 | issue = 1 | pages = 37–51 | date = January 2001 | pmid = 11124709 | doi = 10.1002/1097-0169(200101)48:1<37::aid-cm4>3.0.co;2-0 }} Lantranculin interferes with the structure of the cytoskeleton in rats.{{cite journal | vauthors = Yarmola EG, Somasundaram T, Boring TA, Spector I, Bubb MR | title = Actin-latrunculin A structure and function. Differential modulation of actin-binding protein function by latrunculin A | journal = The Journal of Biological Chemistry | volume = 275 | issue = 36 | pages = 28120–7 | date = September 2000 | pmid = 10859320 | doi = 10.1074/jbc.m004253200 | doi-access = free }}

After latrunculin B exposure, mouse fibroblasts grow bigger and PtK2 kidney cells from a potoroo stem produced long, branched extensions.{{cite journal | vauthors = Gronewold TM, Sasse F, Lünsdorf H, Reichenbach H | title = Effects of rhizopodin and latrunculin B on the morphology and on the actin cytoskeleton of mammalian cells | journal = Cell and Tissue Research | volume = 295 | issue = 1 | pages = 121–9 | date = January 1999 | pmid = 9931358 | doi = 10.1007/s004410051218 | s2cid = 20994479 }} 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.{{cite journal | vauthors = Fairn GD, McMaster CR | title = Emerging roles of the oxysterol-binding protein family in metabolism, transport, and signaling | journal = Cellular and Molecular Life Sciences | volume = 65 | issue = 2 | pages = 228–36 | date = January 2008 | pmid = 17938859 | doi = 10.1007/s00018-007-7325-2 | pmc = 11131761 | s2cid = 5753339 }} 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. Other yeast mutants adjust the binding site, thus making it resistant to latrunculin.

No research has been done to figure out how the biotransformation of latrunculin works in eukaryotic cells. However, research suggests that it is the unaltered form of latrunculin that causes toxic effects.

As latrunculin inhibits actin polymerization and actomyosin contractile ability, exposure to latrunculin may result in cellular relaxation, expansion of drainage tissues and decreased outflow resistance in e.g. the trabecular meshwork.

Latrunculin B causes marked and dose-dependent reductions in pollen germination frequency and pollen tube growth rate.{{cite journal | vauthors = Gibbon BC, Kovar DR, Staiger CJ | title = Latrunculin B has different effects on pollen germination and tube growth | journal = The Plant Cell | volume = 11 | issue = 12 | pages = 2349–63 | date = December 1999 | pmid = 10590163 | pmc = 144132 | doi = 10.1105/tpc.11.12.2349 | bibcode = 1999PlanC..11.2349G }}

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).

Squeezing Latrunculia magnifica into aquarium with fishes causes their almost immediate agitation, followed by hemorrhage, loss of balance and death in 4–6 minutes.{{cite journal | vauthors = Konishi H, Kikuchi S, Ochiai T, Ikoma H, Kubota T, Ichikawa D, Fujiwara H, Okamoto K, Sakakura C, Sonoyama T, Kokuba Y, Sasaki H, Matsui T, Otsuji E | title = Latrunculin a has a strong anticancer effect in a peritoneal dissemination model of human gastric cancer in mice | journal = Anticancer Research | volume = 29 | issue = 6 | pages = 2091–7 | date = June 2009 | pmid = 19528469 }}

Latrunculin A has been used as acrosome reaction inhibitor of guinea pig in laboratory conditions.{{cite journal | vauthors = Roa-Espitia AL, Hernández-Rendón ER, Baltiérrez-Hoyos R, Muñoz-Gotera RJ, Cote-Vélez A, Jiménez I, González-Márquez H, Hernández-González EO | title = Focal adhesion kinase is required for actin polymerization and remodeling of the cytoskeleton during sperm capacitation | journal = Biology Open | volume = 5 | issue = 9 | pages = 1189–99 | date = September 2016 | pmid = 27402964 | pmc = 5051654 | doi = 10.1242/bio.017558 }}

Lat-A-induces reduction of actomyosin contractility. This is associated with trabecular meshwork porous expansion without evidence of reduced structural extracellular matrix protein expression or cellular viability.{{cite journal | vauthors = Spector I, Shochet NR, Kashman Y, Groweiss A | title = Latrunculins: novel marine toxins that disrupt microfilament organization in cultured cells | journal = Science | volume = 219 | issue = 4584 | pages = 493–5 | date = February 1983 | pmid = 6681676 | doi = 10.1126/science.6681676 | bibcode = 1983Sci...219..493S }} In high doses, latrunculin can induce acute cell injury and programmed cell death through activating the caspase-3/7 pathway.

TDLO - Lowest Published Toxic Dose

LD50 – median Lethal Dose{{Cite web|url=https://www.caymanchem.com/msdss/10010630m.pdf|title=SAFETY DATA SHEET Latrunculin A|last=Cayman chemical|date=2017}}{{Better source needed|reason=Only rat LD50 in this reference, numbers don't agree, table appears to use both european and american comma conventions making the values confusing to read.|date=June 2025}}

In nature, latrunculins are used by the sponges themselves as a defense mechanism, and for the same purpose are also sequestered by certain nudibranchs.{{cite journal | vauthors = Cheney KL, White A, Mudianta IW, Winters AE, Quezada M, Capon RJ, Mollo E, Garson MJ | title = Choose Your Weaponry: Selective Storage of a Single Toxic Compound, Latrunculin A, by Closely Related Nudibranch Molluscs | journal = PLOS ONE | volume = 11 | issue = 1 | pages = e0145134 | date = 2016-01-20 | pmid = 26788920 | pmc = 4720420 | doi = 10.1371/journal.pone.0145134 | bibcode = 2016PLoSO..1145134C | doi-access = free }}

Latrunculins are produced for fundamental research and have potential medical applications as latrunculins and their derivatives show antiangionic, antiproliferative, antimicrobial and antimetastatic activities.

Like many other sessile organisms, sponges are rich of secondary metabolites with toxic properties and most of them, including Latrunculin, have a defense role against predators, competitors and epibionts.{{cite journal | vauthors = Gillor O, Carmeli S, Rahamim Y, Fishelson Z, Ilan M | title = Immunolocalization of the Toxin Latrunculin B within the Red Sea Sponge Negombata magnifica (Demospongiae, Latrunculiidae) | journal = Marine Biotechnology | volume = 2 | issue = 3 | pages = 213–23 | date = May 2000 | pmid = 10852799 | doi = 10.1007/s101260000026 | bibcode = 2000MarBt...2..213G | s2cid = 1759699 }}

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. After production in the choanocytes, the latrunculin is transferred via the archeocytes to the vulnerable areas of the sponges where defense is needed, such as injured or regenerating sites.

Sea slugs of the genus Chromodoris sequester different toxics from the sponges that they eat as defensive metabolites, including latrunculin. They selectively transfer and store latrunculin in the sites of the mantle that are most exposed to potential predators. It is thought that the digestive system of the nudibranchs plays an important role in the detoxification.

In 2015, the discovery that five closely related sea slugs of the genus Chromodoris all use latrunculin as defense, indicates that the toxic might be used via Müllerian mimicry.

Category:Actin inhibitors

Category:Heterocyclic compounds with 2 rings

Category:Lactones

Category:Oxygen heterocycles

Category:Thiazolidines