Antimycin A

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Antimycin A
Antimycin A1 Structural Formula V1.svg
Names
Preferred IUPAC name
(2R,3S,6S,7R,8R)-3-(3-Formamido-2-hydroxybenzamido)-8-hexyl-2,6-dimethyl-4,9-dioxo-1,5-dioxonan-7-yl 3-methylbutanoate
Other names
Fintrol
Identifiers
  • 642-15-9 Antimycin A1 Yes check.svgY
  • 1397-94-0 (Antimycin A), 116095-18-2 (Antimycin A1b)
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.162.279 OOjs UI icon edit-ltr-progressive.svg
MeSH Antimycin+A
PubChem CID
UNII
  • InChI=1S/C28H40N2O9/c1-6-7-8-9-11-20-25(39-22(32)14-16(2)3)18(5)38-28(36)23(17(4)37-27(20)35)30-26(34)19-12-10-13-21(24(19)33)29-15-31/h10,12-13,15-18,20,23,25,33H,6-9,11,14H2,1-5H3,(H,29,31)(H,30,34)/t17-,18+,20-,23+,25+/m1/s1 Yes check.svgY
    Key: UIFFUZWRFRDZJC-SBOOETFBSA-N Yes check.svgY
  • InChI=1/C28H40N2O9/c1-6-7-8-9-11-20-25(39-22(32)14-16(2)3)18(5)38-28(36)23(17(4)37-27(20)35)30-26(34)19-12-10-13-21(24(19)33)29-15-31/h10,12-13,15-18,20,23,25,33H,6-9,11,14H2,1-5H3,(H,29,31)(H,30,34)/t17-,18+,20-,23+,25+/m1/s1
    Key: UIFFUZWRFRDZJC-SBOOETFBBB
  • O=CNc1cccc(c1O)C(=O)N[C@@H]2C(=O)O[C@H]([C@H](OC(=O)CC(C)C)[C@H](C(=O)O[C@@H]2C)CCCCCC)C
Properties
C28H40N2O9
Molar mass 548.633 g·mol−1
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Acute toxic
GHS labelling:
GHS-pictogram-skull.svg
Danger
H301, H311, H331
P261, P264, P270, P271, P280, P301+P310, P302+P352, P304+P340, P311, P312, P321, P322, P330, P361, P363, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Antimycin A (more exactly Antimycin A1b) is a secondary metabolite produced by Streptomyces bacteria [1] and a member of a group of related compounds called antimycins. Antimycin A is classified as an extremely hazardous substance in the United States, as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities. [2]

Contents

Use

Antimycin A is the active ingredient in Fintrol, a chemical piscicide (fish poison) used in fisheries management.[ citation needed ]

Antimycin A was first discovered in 1945 and registered for use as a fish toxicant in 1960. [3] Fintrol ® is the only currently registered product containing Antimycin A and is classified as a restricted use pesticide because of its aquatic toxicity and requirement for highly specialized training in order to use it. In 1993, several toxicology studies were submitted to the United States Environmental Protection Agency yielding its toxicity. [3]

Fintrol is used primarily by federal and state governments in order to eliminate invasive species in an area where resident species are threatened. Antimycin A is added drop-wise in order to reach a concentration of 25 parts per billion. [3] These drip stations are typically used upstream in an area that is accessible to boats and traffic. In deeper bodies of water, a pump mechanism is used to disperse Antimycin A through a perforated hose stretching the length of the water column.[ citation needed ]

In aquaculture, Antimycin A is used as an agent to enhance catfish production via selective killing small and more sensitive species. When Antimycin A is added at 25 ppb it provides a complete kill. However at 10 ppb, Antimycin A is used as a selective killing agent to kill smaller or more sensitive species that may reduce the yield of commercial farming.

Products Containing Antimycin A can be registered providing they follow risk mitigation procedures. [3]

Risk of ConcernMitigation Measures
Exposure from consuming treated water
  • Flowing water must be treated with potassium permanganate
  • Drinking water within the treatment areas must be closed during treatment and until all monitoring of samples is below the limit of Antimycin A detection, 0.015 parts per billion
Exposure from consuming treated fish
  • The certified applicator or designee under his/her direct supervision must prohibit consumption of dead fish taken from treatment areas.
  • The registrant must amend labels to specify maximum treatment concentrations of 10 ppb for use as a ‘selective kill’ in aquaculture.
  • When Antimycin A is applied as a selective kill in aquaculture, the Certified Applicator must inform the owner/operator of the aquaculture site being treated that surviving fish must not be harvested for food or feed for a minimum of 12 months after treatment.
  • When Antimycin A is applied as a complete kill in aquaculture, the Certified Applicator must inform the owner/operator of the aquaculture site being treated that the water body must not be restocked for a minimum of 7 days after treatment
Exposure from recreational activities in the treated water
  • The certified applicator or his/her designee must prohibit access to treated area for 7 days following treatment.
Occupational Exposure
  • The registrant must specify maximum treatment levels of 25 ppb
  • Anitmycin A must be applied by a certified applicator who attends a certification program for piscicide applications.
  • The applicator is required to wear long sleeved shirt and long pants, chemical resistant gloves, closed toed shoes and socks, and protective eyeware. Applicators using handheld equipment like a nozzle must wear a dust/mist respirator and coveralls. The applicator should not be wearing contact lenses.
Ecological Risk Quotients for non-target species
  • Antimycin A is forbidden to be used in marine or estuarine environments
  • The certified applicator or designee must ensure treatment does not pass beyond the designated treatment area
  • The certified applicator or designee should collect and bury any dead fish

To date there has been no usage in human medicine, although its possibility as a chemotherapeutic was explored. [3]

Mechanism of action

Antimycin A is an inhibitor of cellular respiration, specifically oxidative phosphorylation. Antimycin A binds to the Qi site of cytochrome c reductase, inhibiting the reduction of ubiquinone to ubiquinol in the Qi site, thereby disrupting the Q-cycle of enzyme turn over. It also will cause the disruption of the entire electron transport chain. Due to this, there can be no production of ATP. Cytochrome c reductase is a central enzyme in the electron transport chain of oxidative phosphorylation. [4] The inhibition of this reaction disrupts the formation of the proton gradient across the inner membrane of the mitochondria. The production of ATP is subsequently inhibited, as protons are unable to flow through the ATP synthase complex in the absence of a proton gradient. This inhibition also results in the formation of the toxic free radical superoxide. [5] In presence of antimycin A the dependence of the superoxide production rate on oxygen level is hyperbolic. [6] In cultured cells at the background of mitochondrial respiration inhibition, the rate of superoxide production exceeds the cellular mechanisms to scavenge it, overwhelming the cell and leading to cell death.[ citation needed ]

It has also been found to inhibit the cyclic electron flow within photosynthetic systems along the proposed ferredoxin quinone reductase pathway. [7]

Although cyanide acts to block the electron transport chain, Antimycin A and cyanide act in different mechanisms. Cyanide binds a site in neighboring protein where iron normally binds, preventing oxygen from binding at all. This prevents cellular respiration completely leading to cell death. [8] Because Antimycin A binds to a specific protein in the electron transport chain, its toxicity can be highly species dependent because of subtle species specific differences in ubiquinol. This is why Fintrol can be used a selective killing agent in commercial farming.[ citation needed ]

Fungus-growing attine ants have been shown to use antimycins - produced by symbiotic Streptomyces bacteria - in their fungiculture, to inhibit non-cultivar (i.e. pathogenic) fungi. [9] One research group studying these symbiotic Streptomyces bacteria recently identified the biosynthetic gene cluster for antimycins, which was unknown despite the compounds themselves being identified 60 years ago. Antimycins are synthesised by a hybrid polyketide synthase (PKS)/non-ribosomal peptide synthase (NRPS). [10]

Toxicity

Lethal Doses

Lethal doses in fish and amphibian species [11]

SpeciesLC50/24 hours exposureLC50/96 hours exposure
Trout0.07 ppb0.04 ppb
Black Bullhead Catfish200 ppb45 ppb
Channel Catfish>10 ppb9 ppb
Goldfish1 ppb
Snails800 ppb
Tiger salamander>1080 ppb
Tadpoles45 ppb10 ppb
Leopard Frog45 ppb10 ppb

Lethal Doses in Mammals [12]

AnimalLD50 mg/kg ingested
Rat28
Mouse25
Lamb1-5
Dog>5
Rabbit10

Human Exposure and First Aid

Exposure to Treated Water: The effects of chronic, sub-lethal human exposure have estimated and extrapolated from murine (=pertaining to rodents) toxicology studies. Estimates in the literature have been determined using EPA risk assessment protocols. [13] Studies aimed at determining these levels found a concentration in mice where there is "No Observed Adverse Effect Level." From there, the EPA describes methods to determine a reference dose (RfD), the upper limit of the substance that can be consumed daily for the rest of one's life without any observable consequences. The RfD was determined to be 1.7 micrograms/kg/day. [14] For a grown adult, weighing around 70 kg, they can safely consume 2 liters of treated water at 60ppb.

Toxic effects may result from accidental ingestion of the material. Animal toxicology studies suggest that exposure to less than 40 grams of Antimycin A can result in serious adverse health effects to the individual. [15]

Route of ExposureEffect
Eye
  • Direct contact to the eye may result in discomfort with tearing and redness. There may be slight abrasion and the Antimycin has the potential to produce a foreign body sensation in some individuals.
Skin
  • Open cuts should not be exposed to the material.
  • It is crucial that good hygiene practices are followed to prevent abrasion from prolonged exposure
Inhaled

Treatment is focused on relieving symptoms and monitoring for respiratory distress, pulmonary edema, seizures, and shock. [15] Emesis after ingestion is not recommended for the potential of central nervous system depression. [16] Activated charcoal can be given as 240mL of water with 30g of charcoal. [16] The patient should be monitored for development of systemic symptoms and signs. After inhalation the patient should be moved to fresh air and monitored for bronchospasm, difficulty breathing, and respiratory distress. If needed, provide the patient with oxygen and secure an airway via tracheal intubation. Treat bronchospasm with inhaled beta2-adrenergic agonist and severe bronchospasm can be treated with systemic corticosteroids. [16]

Related Research Articles

<span class="mw-page-title-main">Oxidative phosphorylation</span> Metabolic pathway

Oxidative phosphorylation 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 triphosphate (ATP). In eukaryotes, this takes place inside mitochondria. Almost all aerobic organisms carry out oxidative phosphorylation. This pathway is so pervasive because it releases more energy than alternative fermentation processes such as anaerobic glycolysis.

An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H+ ions) across a membrane. Many of the enzymes in the electron transport chain are embedded within the membrane.

<span class="mw-page-title-main">Cytochrome c oxidase</span> Complex enzyme found in bacteria, archaea, and mitochondria of eukaryotes

The enzyme cytochrome c oxidase or Complex IV, is a large transmembrane protein complex found in bacteria, archaea, and the mitochondria of eukaryotes.

<span class="mw-page-title-main">Respiratory complex I</span> Protein complex involved in cellular respiration

Respiratory complex I, EC 7.1.1.2 is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes the transfer of electrons from NADH to coenzyme Q10 (CoQ10) and translocates protons across the inner mitochondrial membrane in eukaryotes or the plasma membrane of bacteria.

<span class="mw-page-title-main">Coenzyme Q – cytochrome c reductase</span> Class of enzymes

The coenzyme Q : cytochrome c – oxidoreductase, sometimes called the cytochrome bc1 complex, and at other times complex III, is the third complex in the electron transport chain, playing a critical role in biochemical generation of ATP. Complex III is a multisubunit transmembrane protein encoded by both the mitochondrial and the nuclear genomes. Complex III is present in the mitochondria of all animals and all aerobic eukaryotes and the inner membranes of most eubacteria. Mutations in Complex III cause exercise intolerance as well as multisystem disorders. The bc1 complex contains 11 subunits, 3 respiratory subunits, 2 core proteins and 6 low-molecular weight proteins.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown. In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.

<span class="mw-page-title-main">Obligate anaerobe</span> Microorganism killed by normal atmospheric levels of oxygen

Obligate anaerobes are microorganisms killed by normal atmospheric concentrations of oxygen (20.95% O2). Oxygen tolerance varies between species, with some species capable of surviving in up to 8% oxygen, while others lose viability in environments with an oxygen concentration greater than 0.5%.

<span class="mw-page-title-main">Nitric oxide synthase</span> Enzyme catalysing the formation of the gasotransmitter NO(nitric oxide)

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

<span class="mw-page-title-main">Succinate dehydrogenase</span> Enzyme

Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates in both the citric acid cycle and the electron transport chain. Histochemical analysis showing high succinate dehydrogenase in muscle demonstrates high mitochondrial content and high oxidative potential.

Cytochrome b<sub>6</sub>f complex Enzyme

The cytochrome b6f complex (plastoquinol/plastocyanin reductase or plastoquinol/plastocyanin oxidoreductase; EC 7.1.1.6) is an enzyme found in the thylakoid membrane in chloroplasts of plants, cyanobacteria, and green algae, that catalyzes the transfer of electrons from plastoquinol to plastocyanin:

Histotoxic hypoxia is the inability of cells to take up or use oxygen from the bloodstream, despite physiologically normal delivery of oxygen to such cells and tissues. Histotoxic hypoxia results from tissue poisoning, such as that caused by cyanide and certain other poisons like hydrogen sulfide.

Microbial metabolism is the means by which a microbe obtains the energy and nutrients it needs to live and reproduce. Microbes use many different types of metabolic strategies and species can often be differentiated from each other based on metabolic characteristics. The specific metabolic properties of a microbe are the major factors in determining that microbe's ecological niche, and often allow for that microbe to be useful in industrial processes or responsible for biogeochemical cycles.

<span class="mw-page-title-main">Nitrate reductase</span> Class of enzymes

Nitrate reductases are molybdoenzymes that reduce nitrate to nitrite. This reaction is critical for the production of protein in most crop plants, as nitrate is the predominant source of nitrogen in fertilized soils.

<span class="mw-page-title-main">Oligomycin</span> Group of chemical compounds

Oligomycins are macrolides created by Streptomyces that are strong antibacterial agents but are often poisonous to other organisms, including humans.

Myxothiazol is a chemical compound produced by the myxobacterium Myxococcus fulvus. It is an inhibitor of the mitochondrial cytochrome bc1 complex.

<span class="mw-page-title-main">Alternative oxidase</span>

The alternative oxidase (AOX) is an enzyme that forms part of the electron transport chain in mitochondria of different organisms. Proteins homologous to the mitochondrial oxidase and the related plastid terminal oxidase have also been identified in bacterial genomes.

<span class="mw-page-title-main">Ubiquinol</span> Chemical compound

A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans.

Dioxygen plays an important role in the energy metabolism of living organisms. Free oxygen is produced in the biosphere through photolysis of water during photosynthesis in cyanobacteria, green algae, and plants. During oxidative phosphorylation in cellular respiration, oxygen is reduced to water, thus closing the biological water-oxygen redox cycle.

<span class="mw-page-title-main">Light-dependent reactions</span> Photosynthetic reactions

Light-dependent reactions refers to certain photochemical reactions that are involved in photosynthesis, the main process by which plants acquire energy. There are two light dependent reactions, the first occurs at photosystem II (PSII) and the second occurs at photosystem I (PSI).

<span class="mw-page-title-main">Cytochrome d</span>

Cytochrome d, previously known as cytochrome a2, is a name for all cytochromes that contain heme D as a cofactor. Two unrelated classes of cytochrome d are known: Cytochrome bd, an enzyme that generates a charge across the membrane so that protons will move, and cytochrome cd1, a nitrite reductase.

References

  1. ↑ Neft N, Farley TM (March 1972). "Conditions influencing antimycin production by a Streptomyces species grown in chemically defined medium". Antimicrob. Agents Chemother. 1 (3): 274–6. doi:10.1128/aac.1.3.274. PMC   444205 . PMID   4558141.
  2. ↑ "40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantities" (PDF) (July 1, 2008 ed.). Government Printing Office. Archived from the original (PDF) on February 25, 2012. Retrieved October 29, 2011.{{cite journal}}: Cite journal requires |journal= (help)
  3. 1 2 3 4 5 Caulkins, Peter. "Reregistration Eligibility Decision for Antimycin A" (PDF). United States EPA. Retrieved April 17, 2017.
  4. ↑ Kim, Hoeon; Esser, Lothar; Hossain, M. Bilayet; Xia, Di; Yu, Chang-An; Rizo, Josep; van der Helm, Dick; Deisenhofer, Johann (1999). "Structure of Antimycin A1, a Specific Electron Transfer Inhibitor of Ubiquinol−CytochromecOxidoreductase". Journal of the American Chemical Society. 121 (20): 4902–4903. doi:10.1021/ja990190h. ISSN   0002-7863.
  5. ↑ Dairaku N, Kato K, Honda K, et al. (March 2004). "Oligomycin and antimycin A prevent nitric oxide–induced apoptosis by blocking cytochrome C leakage". J. Lab. Clin. Med. 143 (3): 143–51. doi:10.1016/j.lab.2003.11.003. PMID   15007303.
  6. ↑ Stepanova, Anna; Konrad, Csaba; Manfredi, Giovanni; Springett, Roger; Ten, Vadim; Galkin, Alexander (2019). "The dependence of brain mitochondria reactive oxygen species production on oxygen level is linear, except when inhibited by antimycin A". Journal of Neurochemistry. 148 (6): 731–745. doi:10.1111/jnc.14654. ISSN   1471-4159. PMC   7086484 . PMID   30582748.
  7. ↑ Taira, Yoshichika (1 January 2013). "Antimycin A-like molecules inhibit cyclic electron transport around photosystem I in ruptured chloroplasts". FEBS Open Bio. 3 (1): 406–410. doi:10.1016/j.fob.2013.09.007. PMC   3821020 . PMID   24251103.
  8. ↑ Ott, Kevin. "Antimycin. A Brief Review of It's Chemistry, Environmental Fate, and Toxicology" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2017-04-25.
  9. ↑ Schoenian, I.; et al. (2011). "Chemical basis of the synergism and antagonism in microbial communities in the nests of leaf-cutting ants". Proc Natl Acad Sci USA. 108 (5): 1955–1960. Bibcode:2011PNAS..108.1955S. doi: 10.1073/pnas.1008441108 . PMC   3033269 . PMID   21245311.
  10. ↑ Yu, Jae-Hyuk; Seipke, Ryan F.; Barke, Jörg; Brearley, Charles; Hill, Lionel; Yu, Douglas W.; Goss, Rebecca J. M.; Hutchings, Matthew I. (2011). "A Single Streptomyces Symbiont Makes Multiple Antifungals to Support the Fungus Farming Ant Acromyrmex octospinosus". PLOS ONE. 6 (8): e22028. Bibcode:2011PLoSO...622028S. doi: 10.1371/journal.pone.0022028 . ISSN   1932-6203. PMC   3153929 . PMID   21857911.
  11. ↑ Ott, Kevin. "Antimycin. A Brief Review of It's Chemistry, Environmental Fate, and Toxicology" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2017-04-25.
  12. ↑ Ott, Kevin. "Antimycin. A Brief Review of It's Chemistry, Environmental Fate, and Toxicology" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2017-04-25.
  13. ↑ Draft EIS, Flathead Westslope Cutthroat Trout Project. June 2004. p. Chapter 3.
  14. ↑ J. O. Kuhn, “Final Report. Acute Oral Toxicity Study in Rats”, Stillmeadow, Inc., Submitted to Aquabiotics Corp. (March 2001)
  15. 1 2 "Material Safety Data Sheet - Antimycin A" (PDF). Santa Cruz Biotechnology.
  16. 1 2 3 "Antimycin A". TOXNET. National Institutes of Health.
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