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. Penitrem A is one of many secondary metabolites following the synthesis of paxilline in Penicillium crostosum. 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. It bypasses the blood-brain barrier to exert its toxicological effects on the central nervous system. In humans, penitrem A poisoning has been associated with severe tremors, hyperthermia, nausea/vomiting, diplopia, and bloody diarrhea. In animals, symptoms of penitrem A poisoning has been associated with symptoms ranging from tremors, seizures, and hyperthermia to ataxia and nystagmus. Roquefortine C has been commonly detected in documented cases of penitrem A poisoning, making it a possible biomarker for diagnoses.

Mechanism of action

Penitrem A impairs GABAergic amino acid neurotransmission and antagonizes high-conductance Ca2+-activated potassium channels in both humans and animals. 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). 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. Penitrem A also induces the production of reactive oxygen species (ROS) in the neutrophil granulocytes of humans and animals. Increased ROS production results in tissue damage in the brain and other afflicted organs as well as hemorrhages in acute poisonings.

Synthesis

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