Penitrem A

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]

Penitrem A
Names
Other names
Tremortin
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.162.141
UNII
Properties
C37H44ClNO6
Molar mass 634.20136
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

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.[5]
  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.[5]
  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.[5]
  4. Prenyltransferase catalyzes the formation of a dimethyl-cyclopentane and a cyclobutane using the intermediate's aromatic ring-alcohol group.[5]
  5. Oxidative-transformation enzyme catalyzes the formation of a methylenecyclohexane using the intermediate's dimethyl-cyclopentane, forming secopenitrem D.[5]
  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.[5]
  7. Oxidative-transformation enzyme catalyzes the addition a chlorine atom at penitrem D's aromatic ring, forming penitrem C.[5]
  8. Oxidative-transformation enzyme catalyzes the formation of an epoxide ring at penitrem C's oxane-double bond, forming penitrem F.[5]
  9. Oxidative-transformation enzyme catalyzes the addition of a hydroxyl group at the carbon joining penitrem F's methylenecyclohexane and cyclobutane, forming penitrem A.[5]

See also

References
  1. Walter, Sean L. (2002). "Acute penitrem A and roquefortine poisoning in a dog". The Canadian Veterinary Journal. 43 (5): 372–374. ISSN 0008-5286. PMC 339273. PMID 12001505.
  2. Berntsen, H.F; Bogen, I.L; Wigestrand, M.B; Fonnum, F; Walaas, S.I; Moldes-Anaya, A (2017-12-01). "The fungal neurotoxin penitrem A induces the production of reactive oxygen species in human neutrophils at submicromolar concentrations". Toxicology. 392: 64–70. doi:10.1016/j.tox.2017.10.008. ISSN 0300-483X. PMID 29037868.
  3. Tiwary, AK (March 2009). "Using roquefortine C as a biomarker for penitrem A intoxication". Journal of Veterinary Diagnostic Investigation. 21 (2): 237–239. doi:10.1177/104063870902100210. PMID 19286504.
  4. Moldes-Anaya, Angel S; Fonnum, Frode; Eriksen, Gunnar S; Rundberget, Thomas; Walaas, S. Ivar; Wigestrand, Mattis B (2011-12-01). "In vitro neuropharmacological evaluation of penitrem-induced tremorgenic syndromes: Importance of the GABAergic system". Neurochemistry International. 59 (7): 1074–1081. doi:10.1016/j.neuint.2011.08.014. ISSN 0197-0186. PMID 21924313.
  5. Liu, Chengwei; Tagami, Koichi; Minami, Atsushi; Matsumoto, Tomoyuki; Frisvad, Jens Christian; Suzuki, Hideyuki; Ishikawa, Jun; Gomi, Katsuya; Oikawa, Hideaki (2015-04-01). "Reconstitution of Biosynthetic Machinery for the Synthesis of the Highly Elaborated Indole Diterpene Penitrem". Angewandte Chemie International Edition. 54 (19): 5748–5752. doi:10.1002/anie.201501072. ISSN 1433-7851. PMID 25831977.
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