{{chembox | Verifiedfields = changed | verifiedrevid = 366609839 | ImageFile=Penitrem A.svg | ImageSize=200px | IUPACName= | OtherNames=Tremortin |Section1={{Chembox Identifiers | 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 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID=298950 | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | 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 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = JDUWHZOLEDOQSR-JHMXYHNCSA-N }} |Section2={{Chembox Properties | Formula=C<sub>37</sub>H<sub>44</sub>ClNO<sub>6</sub> | MolarMass=633.20136 | Appearance= | Density= | MeltingPt= | BoilingPt= | Solubility= }} |Section3={{Chembox Hazards | MainHazards= | FlashPt= | AutoignitionPt = }} }}
'''Penitrem A''' ('''tremortin''') is an indole-diterpenoid mycotoxin produced by certain species of ''Aspergillus'', ''Claviceps'', and ''Penicillium'', which can be found growing on various plant species such as 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 metabolites following the synthesis of paxilline in ''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|bibcode=2017Toxgy.392...64B |hdl=11250/3149223|hdl-access=free}}</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 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 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 Ca<sup>2+</sup>-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 glutamate and aspartate as well as the inhibitory neurotransmitter 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 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 metabolites 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|bibcode=2015ACIE...54.5748L |s2cid=205386781|issn=1433-7851}}</ref> Synthesis of penitrem A involves six oxidative-transformation enzymes (four cytochrome P450 monooxygenases and two flavin adenine dinucleotide (FAD)-dependent monooxygenases), two acetyltransferases, 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 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 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" />
==See also== * Paxilline * Roquefortine C
==References== {{reflist}}
{{Neurotoxins}}
Category:Indole alkaloids Category:Neurotoxins Category:Penicillium Category:Cell communication Category:Chloroarenes Category:Triols Category:Chlorine-containing natural products Category:Cyclobutanes Category:Mycotoxins Category:Heterocyclic compounds with 7 or more rings