Penitrem A: Difference between revisions

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| verifiedrevid = 366609839

| ImageFile=Penitrem A.svg

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| OtherNames=Tremortin

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| CASNo_Ref = {{cascite|correct|??}}

| CASNo=12627-35-9

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 244AU85PR7

| PubChem=337313

| SMILES=CC(=C)C1C(C2C3(O2)C(O1)CCC4(C3(CCC5C4(C6=C7C5OC(C8CC9C8(C1=C7C(=CC(=C1CC9=C)Cl)N6)O)(C)C)C)O)C)O

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| ChemSpiderID=298950

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| StdInChI = 1S/C37H44ClNO6/c1-15(2)28-27(40)31-37(45-31)23(43-28)9-10-33(6)34(7)18(8-11-35(33,37)41)29-25-24-21(39-30(25)34)14-20(38)17-12-16(3)19-13-22(32(4,5)44-29)36(19,42)26(17)24/h14,18-19,22-23,27-29,31,39-42H,1,3,8-13H2,2,4-7H3/t18-,19+,22+,23-,27-,28+,29-,31-,33+,34+,35-,36?,37+/m0/s1

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| StdInChIKey = JDUWHZOLEDOQSR-JHMXYHNCSA-N

|Section2={{Chembox Properties

| Formula=C₃₇H₄₄ClNO₆

| MolarMass=633.20136

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'''Penitrem A''' ('''tremortin''') is an indole-diterpenoid [[mycotoxin]] produced by certain species of ''[[Aspergillus]]'', [[Ergot|''Claviceps'']], and ''[[Penicillium]]'', which can be found growing on various plant species such as [[Lolium|ryegrass]].<ref>{{Cite journal|last=Walter|first=Sean L.|date=2002|title=Acute penitrem A and roquefortine poisoning in a dog|journal=The Canadian Veterinary Journal|volume=43|issue=5|pages=372–374|issn=0008-5286|pmid=12001505|pmc=339273}}</ref> Penitrem A is one of many [[secondary metabolite]]s following the synthesis of [[paxilline]] in ''[[Penicillium crustosum|Penicillium crostosum]]''.<ref name=":0">{{Cite journal|date=2017-12-01|title=The fungal neurotoxin penitrem A induces the production of reactive oxygen species in human neutrophils at submicromolar concentrations|journal=Toxicology|language=en|volume=392|pages=64–70|doi=10.1016/j.tox.2017.10.008|pmid=29037868|issn=0300-483X|last1=Berntsen|first1=H.F|last2=Bogen|first2=I.L|last3=Wigestrand|first3=M.B|last4=Fonnum|first4=F|last5=Walaas|first5=S.I|last6=Moldes-Anaya|first6=A}}</ref> Penitrem A poisoning in humans and animals usually occurs through the consumption of contaminated foods by mycotoxin-producing species, which is then distributed through the body by the bloodstream.<ref name=":0" /> It bypasses the [[Blood–brain barrier|blood-brain barrier]] to exert its toxicological effects on the [[central nervous system]].<ref name=":0" /> In humans, penitrem A poisoning has been associated with severe tremors, [[hyperthermia]], [[nausea]]/[[vomiting]], [[diplopia]], and [[Dysentery|bloody diarrhea]].<ref name=":0" /> In animals, symptoms of penitrem A poisoning has been associated with symptoms ranging from tremors, seizures, and hyperthermia to [[ataxia]] and [[nystagmus]].<ref name=":0" />

[[Roquefortine C]] has been commonly detected in documented cases of penitrem A poisoning, making it a possible [[biomarker]] for diagnoses.<ref>{{Cite journal|last=Tiwary|first=AK|date=March 2009|title=Using roquefortine C as a biomarker for penitrem A intoxication|journal=Journal of Veterinary Diagnostic Investigation|volume=21|issue=2|pages=237–239|pmid=19286504|doi=10.1177/104063870902100210|doi-access=free}}</ref>

==Mechanism of action==

Penitrem A impairs GABAergic amino acid neurotransmission and antagonizes high-conductance [[Voltage-gated potassium channel|Ca²⁺-activated potassium channels]] in both humans and animals.<ref name=":1">{{Cite journal|date=2011-12-01|title=In vitro neuropharmacological evaluation of penitrem-induced tremorgenic syndromes: Importance of the GABAergic system|journal=Neurochemistry International|language=en|volume=59|issue=7|pages=1074–1081|doi=10.1016/j.neuint.2011.08.014|pmid=21924313|issn=0197-0186|last1=Moldes-Anaya|first1=Angel S|last2=Fonnum|first2=Frode|last3=Eriksen|first3=Gunnar S|last4=Rundberget|first4=Thomas|last5=Walaas|first5=S. Ivar|last6=Wigestrand|first6=Mattis B|s2cid=36629380}}</ref> Impairment of the GABAergic amino acid neurotransmission comes with the spontaneous release of the excitatory amino acids [[Glutamic acid|glutamate]] and [[Aspartic acid|aspartate]] as well as the inhibitory neurotransmitter [[Gamma-Aminobutyric acid|γ-aminobutyric acid]] (GABA).<ref name=":1" /> The sudden release of these neurotransmitters results in imbalanced GABAergic signalling, which gives rise to neurological disorders such as the tremors associated with penitrem A poisoning.<ref name=":1" />

Penitrem A also induces the production of [[reactive oxygen species]] (ROS) in the [[Neutrophil|neutrophil granulocytes]] of humans and animals.<ref name=":0" /> Increased ROS production results in tissue damage in the brain and other afflicted organs as well as hemorrhages in acute poisonings.<ref name=":0" />

== Synthesis ==

In ''[[Penicillium crustosum]]'', synthesis of penitrem A and other [[secondary metabolite]]s follows the synthesis of [[paxilline]].<ref name=":2">{{Cite journal|last1=Liu|first1=Chengwei|last2=Tagami|first2=Koichi|last3=Minami|first3=Atsushi|last4=Matsumoto|first4=Tomoyuki|last5=Frisvad|first5=Jens Christian|last6=Suzuki|first6=Hideyuki|last7=Ishikawa|first7=Jun|last8=Gomi|first8=Katsuya|last9=Oikawa|first9=Hideaki|date=2015-04-01|title=Reconstitution of Biosynthetic Machinery for the Synthesis of the Highly Elaborated Indole Diterpene Penitrem|journal=Angewandte Chemie International Edition|language=en|volume=54|issue=19|pages=5748–5752|doi=10.1002/anie.201501072|pmid=25831977|s2cid=205386781|issn=1433-7851}}</ref> Synthesis of penitrem A involves six oxidative-transformation enzymes (four [[cytochrome P450 monooxygenase]]s and two [[flavin adenine dinucleotide]] (FAD)-dependent [[monooxygenase]]s), two [[acetyltransferase]]s, one [[oxidoreductase]], and one [[prenyltransferase]].<ref name=":2" /> These enzymes are encoded by a cluster of genes used in paxilline synthesis and penitrem A-F synthesis.<ref name=":2" /> The pathway is described below:

# Oxidoreductase catalyzes the reduction of paxilline's ketone and also adds a dimethylallyl group to its aromatic ring.<ref name=":2" />

# Acetyltransferases catalyze the removal of the intermediate's lower right-hand hydroxyl group and reduce of one of the nearby methyl groups to a [[Methylene (compound)|methylene]] group.<ref name=":2" />

# Oxidative-transformation enzyme catalyzes the addition of a hydroxyl group to the intermediate's dimethylallyl group. The dimethylallyl's double bond migrates down one carbon.<ref name=":2" />

# Prenyltransferase catalyzes the formation of a dimethyl-cyclopentane and a [[cyclobutane]] using the intermediate's aromatic ring-alcohol group.<ref name=":2" />

# Oxidative-transformation enzyme catalyzes the formation of a [[methylenecyclohexane]] using the intermediate's dimethyl-cyclopentane, forming secopenitrem D.<ref name=":2" />

# Oxidative-transformation enzyme catalyzes the formation of a [[cyclooctane]] using cyclobutane's [[Alcohol (chemistry)|alcohol]] group and the carbon joining secopenitrem D's [[cyclohexane]] and [[cyclopentane]], forming penitrem D.<ref name=":2" />

# Oxidative-transformation enzyme catalyzes the addition a chlorine atom at penitrem D's aromatic ring, forming penitrem C.<ref name=":2" />

# Oxidative-transformation enzyme catalyzes the formation of an [[epoxide]] ring at penitrem C's [[oxane]]-double bond, forming penitrem F.<ref name=":2" />

# Oxidative-transformation enzyme catalyzes the addition of a hydroxyl group at the carbon joining penitrem F's methylenecyclohexane and cyclobutane, forming penitrem A.<ref name=":2" />

* [[Paxilline]]

* [[Roquefortine C]]

{{reflist}}

[[Category:Indole alkaloids]]

[[Category:Penicillium]]

[[Category:Chloroarenes]]

[[Category:Halogen-containing natural products]]

[[Category:Cyclobutanes]]

[[Category:Mycotoxins]]