Tenuazonic acid

Last updated
Tenuazonic acid
Tenuazonic Acid Final.svg
Names
Preferred IUPAC name
(5S)-3-Acetyl-5-[(2S)-butan-2-yl]-4-hydroxy-1,5-dihydro-2H-pyrrol-2-one
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.164.201 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C10H15NO3/c1-4-5(2)8-9(13)7(6(3)12)10(14)11-8/h5,8,13H,4H2,1-3H3,(H,11,14)/t5-,8-/m0/s1 X mark.svgN
    Key: CEIZFXOZIQNICU-XNCJUZBTSA-N X mark.svgN
  • O=C1C(C(C)=O)=C(O)[C@@]([C@H](CC)C)([H])N1
Properties
C10H15NO3
Molar mass 197.234 g·mol−1
AppearanceWhite crystalline powder
Acidity (pKa)3.5
Hazards
Lethal dose or concentration (LD, LC):
* 182 mg kg−1 (Mice, ♂, oral) [1]
  • 225 mg kg−1 (Mice, ♂, oral) [2]
  • 81 mg kg−1 (Mice, ♀, oral) [1]
Pharmacology
Ingested or Inhaled
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Tenuazonic acid is a mycotoxin produced by Alternaria species. [3] It is a powerful eukaryotic protein synthesis inhibitor. [4] It is a tetrameric acid that is ubiquitous in biological environments and prevents the release of newly synthesized protein from the ribosome. Its toxicity is the highest among all Alternaria mycotoxins and has both phytotoxic and cytotoxic properties. [5] In 1991 Tenuazonic acid was reported to inhibit skin tumor promotion in mice. [6]

Inhibitory properties

Tenuazonic acid (TeA) is a potent phytotoxin and an effective bio-herbicide due to its ability to block the photosynthetic pathway. It specifically plays an inhibitory role in photosystem II (PSII) by blocking the flow of electrons from QA to QB. [7] Studies aimed to determine the exact binding site of TeA in photosystem II found that it binds to the QB site, preventing QA from transferring its electrons to QB. [7] [8] Chlorophyll fluorescence study of the croftonweed plant treated by TeA in vivo show a time dependent increase of reduced QA as electron transfer is halted. This resulted in decreased photosynthesis in vivo. Tenuazonic acid also resulted in inactivation of PSII QA and QB reaction centers. [8] Understanding this inhibitory mechanism of tenuazonic acid in photosynthesis allows for creation of new herbicides which are more targeted and less lethal to the environment.

Tenuazonic acid has been a compound of interest in drug development research for Alzheimer's disease (AD). Several factors contribute to the onset of AD, including low levels of the neurotransmitter acetylcholine (Ach), heightened production of free radicals, and reactive oxygen species (ROS) that cause increased oxidative stress. [9] A drug for AD must target multiple factors of the disease to have a successful therapeutic effect. One study examining six natural compounds determined tenuazonic acid to be a viable compound to treat this multi-factorial disease due to its anti-oxidative and acetylcholinesterase inhibiting properties. [10] Acetylcholinesterase inhibitors (AChEIs) inhibit the breakdown of acetylcholine — allowing for prolonged action of acetylcholine in the nervous system. Tenuazonic acid was also observed to have the ability to chelate heavy metals that directly contribute to increasing oxidative stress. [9] [10] ) Five derivatives of tenuazonic acid synthesized and tested for effectiveness in AD treatment showed multi-target activity. Hybrids created using TeA and a known AD drug exhibit even better acetylcholinesterase inhibiting activity. [10]

Related Research Articles

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

<span class="mw-page-title-main">Cholinergic</span> Agent which mimics choline

Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin. Choline also prevents fat deposits in the liver and facilitates the movement of fats into cells.

<span class="mw-page-title-main">Cholinesterase</span> Esterase that lyses choline-based esters

The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters:

Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifically, a neurotoxin or neurotoxicant– alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue. This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from organ transplants, radiation treatment, certain drug therapies, recreational drug use, exposure to heavy metals, bites from certain species of venomous snakes, pesticides, certain industrial cleaning solvents, fuels and certain naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction. Chronic mold exposure in homes can lead to neurotoxicity which may not appear for months to years of exposure. All symptoms listed above are consistent with mold mycotoxin accumulation.

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

Physostigmine is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and the fruit of the Manchineel tree.

<span class="mw-page-title-main">Plastoquinone</span> Molecule which moves electron in photosynthesis

Plastoquinone (PQ) is a terpenoid-quinone (meroterpenoid) molecule involved in the electron transport chain in the light-dependent reactions of photosynthesis. The most common form of plastoquinone, known as PQ-A or PQ-9, is a 2,3-dimethyl-1,4-benzoquinone molecule with a side chain of nine isoprenyl units. There are other forms of plastoquinone, such as ones with shorter side chains like PQ-3 as well as analogs such as PQ-B, PQ-C, and PQ-D, which differ in their side chains. The benzoquinone and isoprenyl units are both nonpolar, anchoring the molecule within the inner section of a lipid bilayer, where the hydrophobic tails are usually found.

<span class="mw-page-title-main">Galantamine</span> Neurological medication

Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of Galanthus nivalis, Galanthus caucasicus, Galanthus woronowii, and other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata. It can also be produced synthetically.

In biochemistry, dephosphorylation is the removal of a phosphate group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deactivate enzymes by detaching or attaching phosphoric esters and anhydrides. A notable occurrence of dephosphorylation is the conversion of ATP to ADP and inorganic phosphate.

Phytotoxins are substances that are poisonous or toxic to the growth of plants. Phytotoxic substances may result from human activity, as with herbicides, or they may be produced by plants, by microorganisms, or by naturally occurring chemical reactions.

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

Photoinhibition is light-induced reduction in the photosynthetic capacity of a plant, alga, or cyanobacterium. Photosystem II (PSII) is more sensitive to light than the rest of the photosynthetic machinery, and most researchers define the term as light-induced damage to PSII. In living organisms, photoinhibited PSII centres are continuously repaired via degradation and synthesis of the D1 protein of the photosynthetic reaction center of PSII. Photoinhibition is also used in a wider sense, as dynamic photoinhibition, to describe all reactions that decrease the efficiency of photosynthesis when plants are exposed to light.

<span class="mw-page-title-main">Acetylcholinesterase</span> Primary cholinesterase in the body

Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme that catalyzes the breakdown of acetylcholine and some other choline esters that function as neurotransmitters:

<span class="mw-page-title-main">Photosynthetic reaction centre protein family</span>

Photosynthetic reaction centre proteins are main protein components of photosynthetic reaction centres (RCs) of bacteria and plants. They are transmembrane proteins embedded in the chloroplast thylakoid or bacterial cell membrane.

<span class="mw-page-title-main">Cytochrome b559</span> Family of protein complexes

Cytochrome b559 is an important component of Photosystem II (PSII) is a multisubunit protein-pigment complex containing polypeptides both intrinsic and extrinsic to the photosynthetic membrane. Within the core of the complex, the chlorophyll and beta-carotene pigments are mainly bound to the antenna proteins CP43 (PsbC) and CP47 (PsbB), which pass the excitation energy on to chlorophylls in the reaction centre proteins D1 and D2 that bind all the redox-active cofactors involved in the energy conversion process. The PSII oxygen-evolving complex (OEC) provides electrons to re-reduce the PSII reaction center, and oxidizes 2 water molecules to recover its reduced initial state. It consists of OEE1 (PsbO), OEE2 (PsbP) and OEE3 (PsbQ). The remaining subunits in PSII are of low molecular weight, and are involved in PSII assembly, stabilisation, dimerization, and photoprotection.

<span class="mw-page-title-main">Acetylcholinesterase inhibitor</span> Drugs that inhibit acetylcholinesterase

Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and duration of action of acetylcholine in the central nervous system, autonomic ganglia and neuromuscular junctions, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of cholinesterase inhibitors; the other being butyryl-cholinesterase inhibitors. Acetylcholinesterase is the primary member of the cholinesterase enzyme family.

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

Rivastigmine, sold under the brand name Exelon among others, is an acetylcholinesterase inhibitor used for the treatment of dementia associated with Alzheimer's disease and with Parkinson's disease. Rivastigmine can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, which typically include nausea and vomiting.

<span class="mw-page-title-main">Ycf9 protein domain</span> Plastid protein involved in photosynthesis

In molecular biology, the PsbZ (Ycf9) is a protein domain, which is low in molecular weight. It is a transmembrane protein and therefore is located in the thylakoid membrane of chloroplasts in cyanobacteria and plants. More specifically, it is located in Photosystem II (PSII) and in the light-harvesting complex II (LHCII). Ycf9 acts as a structural linker, that stabilises the PSII-LHCII supercomplexes. Moreover, the supercomplex fails to form in PsbZ-deficient mutants, providing further evidence to suggest Ycf9's role as a structural linker. This may be caused by a marked decrease in two LHCII antenna proteins, CP26 and CP29, found in PsbZ-deficient mutants, which result in structural changes, as well as functional modifications in PSII.

Methanesulfonyl fluoride (MSF) has long been known to be a potent inhibitor of acetylcholinesterase (AChE), the enzyme that regulates acetylcholine, an important neurotransmitter in both the central and peripheral nervous systems.

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

Phenserine is a synthetic drug which has been investigated as a medication to treat Alzheimer's disease (AD), as the drug exhibits neuroprotective and neurotrophic effects.

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

Huprine X is a synthetic cholinergic compound developed as a hybrid between the natural product Huperzine A and the synthetic drug tacrine. It is one of the most potent reversible inhibitors of acetylcholinesterase known, with a binding affinity of 0.026nM, as well as showing direct agonist activity at both nicotinic and muscarinic acetylcholine receptors. In animal studies it has nootropic and neuroprotective effects, and is used in research into Alzheimer's disease, and although huprine X itself has not been researched for medical use in humans, a large family of related derivatives have been developed.

References

  1. 1 2 Miller, F. A. et al.; Nature, 200 (1963), S. 1338–1339
  2. Smith, E. R. et al.; Cancer Chemother. Rep. 52 (1968), S. 579–585.
  3. Alisa D. Hocking (Editor), John I. Pitt (Editor) and Robert A. Samson (Editor): Advances in Food Mycology. Springer 2006; ISBN   978-0-387-28385-2; p. 23
  4. Dilip K. Arora and Arora K. Arora: Fungal Biotechnology in Agricultural, Food, and Environmental Applications. Marcel Dekker Inc; illustrated edition 2003; ISBN   978-0-8247-4770-1; p. 336
  5. Mikula, Hannes; Horkel, Ernst; Hans, Philipp; Hametner, Christian; Fröhlich, Johannes (2013-04-15). "Structure and tautomerism of tenuazonic acid--a synergetic computational and spectroscopic approach". Journal of Hazardous Materials. 250–251: 308–317. Bibcode:2013JHzM..250..308M. doi:10.1016/j.jhazmat.2013.02.006. ISSN   1873-3336. PMID   23474405.
  6. Tenuazonic acid page from Fermentek
  7. 1 2 Chen, Shiguo; Xu, Xiaoming; Dai, Xinbin; Yang, Chunlong; Qiang, Sheng (2007-04-01). "Identification of tenuazonic acid as a novel type of natural photosystem II inhibitor binding in QB-site of Chlamydomonas reinhardtii". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1767 (4): 306–318. doi:10.1016/j.bbabio.2007.02.007. ISSN   0005-2728. PMID   17379181.
  8. 1 2 Chen, Shiguo; Strasser, Reto Jörg; Qiang, Sheng (2014-11-01). "In vivo assessment of effect of phytotoxin tenuazonic acid on PSII reaction centers". Plant Physiology and Biochemistry. 84: 10–21. Bibcode:2014PlPB...84...10C. doi:10.1016/j.plaphy.2014.09.004. ISSN   0981-9428. PMID   25240106.
  9. 1 2 Poliseno, Viviana; Chaves, Sílvia; Brunetti, Leonardo; Loiodice, Fulvio; Carrieri, Antonio; Laghezza, Antonio; Tortorella, Paolo; Magalhães, João D.; Cardoso, Sandra M.; Santos, M. Amélia; Piemontese, Luca (2021-01-15). "Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer's Disease Agents". Biomolecules. 11 (1): 111. doi: 10.3390/biom11010111 . ISSN   2218-273X. PMC   7830597 . PMID   33467709.
  10. 1 2 3 Piemontese, Luca; Vitucci, Gabriele; Catto, Marco; Laghezza, Antonio; Perna, Filippo Maria; Rullo, Mariagrazia; Loiodice, Fulvio; Capriati, Vito; Solfrizzo, Michele (2018-08-29). "Natural Scaffolds with Multi-Target Activity for the Potential Treatment of Alzheimer's Disease". Molecules (Basel, Switzerland). 23 (9): 2182. doi: 10.3390/molecules23092182 . ISSN   1420-3049. PMC   6225478 . PMID   30158491.