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词条 Penitrem A
释义

  1. Mechanism of action

  2. Synthesis

  3. See also

  4. References

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| verifiedrevid = 366609839
| ImageFile=Penitrem A.svg
| ImageSize=200px
| IUPACName=
| OtherNames=Tremortin
|Section1={{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|??}}
| CASNo=12627-35-9
| 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=C37H44ClNO6
| MolarMass=634.20136
| 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.[1] Penitrem A is one of many secondary metabolites following the synthesis of paxilline in Penicillium crostosum.[2] 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.[2] It bypasses the blood-brain barrier to exert its toxicological effects on the central nervous system.[2] In humans, penitrem A poisoning has been associated with severe tremors, hyperthermia, nausea/vomiting, diplopia, and bloody diarrhea.[2] In animals, symptoms of penitrem A poisoning has been associated with symptoms ranging from tremors, seizures, and hyperthermia to ataxia and nystagmus.[2]Roquefortine C has been commonly detected in documented cases of penitrem A poisoning, making it a possible biomarker for diagnoses.[3]

Mechanism of action

Penitrem A impairs GABAergic amino acid neurotransmission and antagonizes high-conductance Ca2+-activated potassium channels in both humans and animals.[4] 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).[4] 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.[4]

Penitrem A also induces the production of reactive oxygen species (ROS) in the neutrophil granulocytes of humans and animals.[2] Increased ROS production results in tissue damage in the brain and other afflicted organs as well as hemorrhages in acute poisonings.[2]

Synthesis

In Penicillium crustosum, synthesis of penitrem A and other secondary metabolites follows the synthesis of paxilline.[5] 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.[5] These enzymes are encoded by a cluster of genes used in paxilline synthesis and penitrem A-F synthesis.[5] The pathway is described below:

  1. Oxidoreductase catalyzes the reduction of paxilline's ketone and also adds a dimethylallyl group to its aromatic ring.&91;5&93;
  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.&91;5&93;
  3. 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.&91;5&93;
  4. Prenyltransferase catalyzes the formation of a dimethyl-cyclopentane and a cyclobutane using the intermediate's aromatic ring-alcohol group.&91;5&93;
  5. Oxidative-transformation enzyme catalyzes the formation of a methylenecyclohexane using the intermediate's dimethyl-cyclopentane, forming secopenitrem D.&91;5&93;
  6. 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.&91;5&93;
  7. Oxidative-transformation enzyme catalyzes the addition a chlorine atom at penitrem D's aromatic ring, forming penitrem C.&91;5&93;
  8. Oxidative-transformation enzyme catalyzes the formation of an epoxide ring at penitrem C's oxane-double bond, forming penitrem F.&91;5&93;
  9. Oxidative-transformation enzyme catalyzes the addition of a hydroxyl group at the carbon joining penitrem F's methylenecyclohexane and cyclobutane, forming penitrem A.&91;5&93;

See also

  • Paxilline
  • Roquefortine C

References

1. ^{{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}}
2. ^1 2 3 4 5 6 {{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|url=https://www.sciencedirect.com/science/article/pii/S0300483X17303141|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}}
3. ^{{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|via=Sage Journal|pmid=19286504|doi=10.1177/104063870902100210}}
4. ^1 2 {{Cite journal|date=2011-12-01|title=In vitro neuropharmacological evaluation of penitrem-induced tremorgenic syndromes: Importance of the GABAergic system|url=https://www.sciencedirect.com/science/article/pii/S0197018611003093|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}}
5. ^1 2 3 4 5 6 7 8 9 10 11 {{Cite journal|last=Liu|first=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|issn=1433-7851|url=http://orbit.dtu.dk/en/publications/reconstitution-of-biosynthetic-machinery-for-the-synthesis-of-the-highly-elaborated-indole-diterpene-penitrem(3941efe6-6cf1-4efa-b550-a5a92e08a27a).html}}
{{Neurotoxins}}

9 : Indole alkaloids|Neurotoxins|Penicillium|Cell communication|Chloroarenes|Alcohols|Halogen-containing natural products|Cyclobutanes|Mycotoxins
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