Cyclopiazonic acid: Difference between revisions

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| PIN=(6a''R'',11a''S'',11b''R'')-10-Acetyl-11-hydroxy-7,7-dimethyl-2,6,6a,7,11a,11b-hexahydro-9''H''-pyrrolo[1′,2′:2,3]isoindolo[4,5,6-''cd'']indol-9-one

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| CASNo=18172-33-3

| IUPHAR_ligand = 5350

| Beilstein = 707309

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| EINECS = 634-041-6

| KEGG = C03032

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| UNII = X9TLY4580Z

| PubChem=65261

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| ChEBI = 22450

| SMILES = CC(=O)C1=C(O)[C@H]5N(C1=O)[C@@](C)(C)[C@@H]4Cc2cccc3[nH]cc(c23)[C@@H]45

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'''Cyclopiazonic acid''' (α-CPA), a [[mycotoxin]] and a fungal [[neurotoxin]], is made by the molds ''[[Aspergillus]]'' and ''[[Penicillium]]''.<ref name = "Holzapfel_1968">{{cite journal | vauthors = Holzapfel CW | title = The isolation and structure of cyclopiazonic acid, a toxic metabolite of Penicillium cyclopium Westling | journal = Tetrahedron | volume = 24 | issue = 5 | pages = 2101–19 | date = March 1968 | pmid = 5636916 | doi = 10.1016/0040-4020(68)88113-X }}</ref><ref name="Chang_2009">{{cite journal | vauthors = Chang PK, Ehrlich KC, Fujii I | title = Cyclopiazonic acid biosynthesis of Aspergillus flavus and Aspergillus oryzae | journal = Toxins | volume = 1 | issue = 2 | pages = 74–99 | date = December 2009 | pmid = 22069533 | doi = 10.3390/toxins1020074 | pmc = 3202784 | doi-access = free }}</ref><ref name="Liu_2009" /> It is an indole-tetramic acid that serves as a toxin due to its ability to inhibit calcium-dependent ATPases found in the endoplasmic and sarcoplasmic reticulum.<ref name = "Seidler_1989">{{cite journal | vauthors = Seidler NW, Jona I, Vegh M, Martonosi A | title = Cyclopiazonic acid is a specific inhibitor of the Ca2+-ATPase of sarcoplasmic reticulum | journal = The Journal of Biological Chemistry | volume = 264 | issue = 30 | pages = 17816–23 | date = October 1989 | doi = 10.1016/S0021-9258(19)84646-X | pmid = 2530215 | doi-access = free }}</ref> This inhibition disrupts the muscle contraction-relaxation cycle and the calcium gradient that is maintained for proper cellular activity in cells.<ref name="Chang_2009" />

Cyclopiazonic acid is known to contaminate multiple foods because the molds that produce them are able to grow on different agricultural products, including but not limited to grains, corn, peanuts, and cheese.<ref name="Chang_2009" /><ref name="Nishie_1985">{{cite journal | vauthors = Nishie K, Cole RJ, Dorner JW | title = Toxicity and neuropharmacology of cyclopiazonic acid | journal = Food and Chemical Toxicology | volume = 23 | issue = 9 | pages = 831–9 | date = September 1985 | pmid = 4043883 | doi = 10.1016/0278-6915(85)90284-4 }}</ref> Due to this contamination, α-CPA can be harmful to both humans and farm animals that were exposed to contaminated animal feeds. However, α-CPA needs to be introduced in very high concentrations to produce mycotoxicosis in animals. Due to this, α-CPA is not a potent acute toxin.<ref name="Chang_2009" />

Chemically, CPA is related to [[ergoline]] [[alkaloids]]. CPA was originally isolated from ''[[Penicillium cyclopium]]'' and subsequently from other fungi including ''[[Penicillium griseofulvum]]'', ''[[Penicillium camemberti]]'', ''[[Penicillium commune]]'', ''[[Aspergillus flavus]]'', and ''[[Aspergillus versicolor]]''. CPA only appears to be toxic in high concentrations. Ingestion of CPA causes anorexia, dehydration, weight loss, immobility, and signs of spasm when near death. CPA can be found in molds, corns, peanuts, and other fermented products, such as cheese and sausages.<ref name=":0">{{cite book |doi=10.1016/B0-12-227055-X/00821-X |chapter=MYCOTOXINS &#124; Classifications |title=Encyclopedia of Food Sciences and Nutrition |pages=4080–4089 |year=2003 | vauthors = Bullerman LB |isbn=978-0-12-227055-0 }}</ref> Biologically, CPA is a specific inhibitor of [[SERCA|SERCA ATPase]] in intracellular Ca²⁺ storage sites.<ref name = "Sosa_2002">{{cite journal | vauthors = Sosa MJ, Córdoba JJ, Díaz C, Rodríguez M, Bermúdez E, Asensio MA, Núñez F | title = Production of cyclopiazonic acid by Penicillium commune isolated from dry-cured ham on a meat extract-based substrate | journal = Journal of Food Protection | volume = 65 | issue = 6 | pages = 988–92 | date = June 2002 | pmid = 12092733 | doi = 10.4315/0362-028X-65.6.988 | doi-access = free }}</ref> CPA inhibits SERCA ATPase by keeping it in one specific conformation, thus, preventing it from forming another.<ref name = "Soler_1998">{{cite journal | vauthors = Soler F, Plenge-Tellechea F, Fortea I, Fernandez-Belda F | title = Cyclopiazonic acid effect on Ca2+-dependent conformational states of the sarcoplasmic reticulum ATPase. Implication for the enzyme turnover | journal = Biochemistry | volume = 37 | issue = 12 | pages = 4266–74 | date = March 1998 | pmid = 9521749 | doi = 10.1021/bi971455c }}</ref> CPA also binds to SERCA ATPase at the same site as another inhibitor, [[Thapsigargin|thapsigargin (TG)]]. In this way, CPA lowers the ability of SERCA ATPase to bind an ATP molecule.<ref name = "Ma_1999">{{cite journal | vauthors = Ma H, Zhong L, Inesi G, Fortea I, Soler F, Fernandez-Belda F | title = Overlapping effects of S3 stalk segment mutations on the affinity of Ca2+-ATPase (SERCA) for thapsigargin and cyclopiazonic acid | journal = Biochemistry | volume = 38 | issue = 47 | pages = 15522–7 | date = November 1999 | pmid = 10569935 | doi = 10.1021/bi991523q }}</ref>

== Toxicity ==

Cases of α-CPA mycotoxicosis in humans are rare. However, the occurrence of α-CPA in foods consumed by humans suggests that the toxin is indeed ingested by humans, though at concentrations low enough to be of no serious health concern.<ref name = "Voss_1990">{{cite book | vauthors = Voss KA | chapter = In Vivo and In Vitro Toxicity of Cyclopiazonic Acid (CPA)|date= May 1990 | title = Biodeterioration Research: Mycotoxins, Biotoxins, Wood Decay, Air Quality, Cultural Properties, General Biodeterioration, and Degradation|pages=67–84 | veditors = Llewellyn GC, O'Rear CE |place=Boston, MA|publisher=Springer US|language=en|doi=10.1007/978-1-4757-9453-3_5|isbn=978-1-4757-9453-3 }}</ref> Even if its toxicity in humans is rare, large doses of α-CPA have been seen to adversely affect animals such as mice, rats, chickens, pigs, dogs, and rabbits.<ref name="Nishie_1985" /> Cyclopiazonic acid's toxicity mirrors that of antipsychotic drugs when taken up these animals.<ref name="Nishie_1985" /> This mycotoxin has been extensively studied in mice to discern its toxic properties. The severity of toxicity is dose-dependent, and exposure to α-CPA has led to [[hypokinesia]], [[hypothermia]], [[catalepsy]], tremors, irregular respiration, [[Ptosis (eyelid)|ptosis]], weight loss, and eventual death in mice.<ref name="Nishie_1985" /> The adverse health effects of α-CPA studied in mice are similar to those found in other animals.

== Biosynthesis ==

Three enzymes are utilized in the biosynthesis of α-CPA: the polypeptide CpaS, dimethylallyltransferase (CpaD), and flavoprotein oxidocyclase (CpaO).<ref name="Liu_2009">{{cite journal | vauthors = Liu X, Walsh CT | title = Cyclopiazonic acid biosynthesis in Aspergillus sp.: characterization of a reductase-like R* domain in cyclopiazonate synthetase that forms and releases cyclo-acetoacetyl-L-tryptophan | journal = Biochemistry | volume = 48 | issue = 36 | pages = 8746–57 | date = September 2009 | pmid = 19663400 | pmc = 2752376 | doi = 10.1021/bi901123r }}</ref> CpaS is the first enzyme in the biosynthetic pathway and is a hybrid polyketide synthase- nonribosomal peptide synthetase (PKS-NRPS). It uses the precursors acetyl-CoA, malonyl-CoA, and tryptophan to produce ''cyclo''-acetoaceytl-L-tryptophan (''c''AATrp).<ref name="Liu_2009" /> The intermediate ''c''AATrp is then prenylated with [[dimethylallyl pyrophosphate]] (DMAPP) by the enzyme CpaD to form the intermediate β-CPA. CpaD has high substrate specificity and will not catalyze prenylation in the presence of DMAPP's isomer isopentyl pyrophosphate (IPP) or the derivatives of ''c''AATrp.<ref name="Chang_2009" /> The third enzyme, CpaO, then acts on β-CPA through a redox mechanism that allows for intramolecular cyclization to form α-CPA.<ref name="Liu_2009" />

[[File:Biosynthesis_of_alpha-CPA.png|center|thumb|821x821px|The biosynthesis of alpha-CPA involves three main enzymes.]]

=== Mechanism of Action of CpaS ===

CpaS is made of several domains that belong either to the PKS portion or the NRPS portion of the 431 kDa protein.<ref name="Chang_2009" /><ref name="Liu_2009" /> The PKS portion is made up of three catalytically important domains and three additional tailoring domains that are common to polyketide synthases but not used in the biosynthesis of α-CPA. The catalytically important acyl carrier protein domain (ACP), acyl transferase domain (AT), and ketosynthase domain (KS) work together to form acetoacetyl-CoA from the precursors acetyl-CoA and malonyl-CoA.<ref name="Chang_2009" /> The acetoacetyl-CoA is then acted on by the NRPS portion of CpaS. The NRPS portion, like the PKS portion, contains many catalytically active domains. The adenylation domain (A) acts first to activate the amino acid tryptophan and subsequently transfer it to the peptidyl carrier protein (PCP) domain (T).<ref name="Chang_2009" /> Following this, the condensation domain (C) catalyzes an amide bond formation between the acetoacetyl moiety attached to the ACP and tryptophan attached to the PCP.<ref name="Chang_2009" /> The releasing domain (R) catalyzes a [[Dieckmann condensation]] to both cyclize and release the ''c''AATrp product.<ref name="Chang_2009" /><ref name="Liu_2009" />

=== Formation of β-CPA ===

The second enzyme, CpaD, converts the ''c''AATrp produced by CpaS to β-CPA. CpaD, also known as cycloacetoacetyltyptophanyl dimethylallyl transferase, places DMAPP at the tryptophan indole ring, specifically at position C-4.<ref name="Chang_2009" /> CpaD then catalyzes selective prenylation at position C-4 through a [[Friedel–Crafts reaction|Friedel-Craft alkylation]], producing β-CPA.<ref name="Chang_2009" /> It is important to note here that the biosynthesis of α-CPA is dependent on other pathways, specifically the [[mevalonate pathway]], which serves to form DMAPP.<ref name="Chang_2009" />

=== Formation of α-CPA ===

The final enzyme in the biosynthetic pathway, CpaO, converts β-CPA to α-CPA. CpaO is a FAD-dependent [[oxidoreductase]]. [[Flavin adenine dinucleotide|FAD]] oxidizes β-CPA in a two-electron process, subsequently allowing for ring closure and formation of α-CPA.<ref name="Chang_2009" /> To regenerate the oxidized FAD cofactor used by CpaO, the reduced FAD reacts with molecular oxygen to produce hydrogen peroxide.

[[File:Possible cyclization mechanism.png|thumb|Possible cyclization mechanism to form cyclopiazonic acid.|center|821x821px]]

== References ==

{{Reflist|30em}}

[[Category:Tryptamine alkaloids]]

[[Category:Nitrogen heterocycles]]

[[Category:Enols]]

[[Category:Heterocyclic compounds with 5 rings]]