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Penitrem A
Names
	Other names Tremortin
Identifiers
CAS Number	12627-35-9 ;
3D model (JSmol)	Interactive image;
ChemSpider	298950 ;
ECHA InfoCard	100.162.141
PubChem CID	337313;
UNII	244AU85PR7 ;
CompTox Dashboard (EPA)	DTXSID00320093 ;
	InChI InChI=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 Key: JDUWHZOLEDOQSR-JHMXYHNCSA-N ;
	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;
Properties
Chemical formula	C37H44ClNO6
Molar mass	633.20136
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

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:

Oxidoreductase catalyzes the reduction of paxilline's ketone and also adds a dimethylallyl group to its aromatic ring.^[5]
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]
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]
Prenyltransferase catalyzes the formation of a dimethyl-cyclopentane and a cyclobutane using the intermediate's aromatic ring-alcohol group.^[5]
Oxidative-transformation enzyme catalyzes the formation of a methylenecyclohexane using the intermediate's dimethyl-cyclopentane, forming secopenitrem D.^[5]
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]
Oxidative-transformation enzyme catalyzes the addition a chlorine atom at penitrem D's aromatic ring, forming penitrem C.^[5]
Oxidative-transformation enzyme catalyzes the formation of an epoxide ring at penitrem C's oxane-double bond, forming penitrem F.^[5]
Oxidative-transformation enzyme catalyzes the addition of a hydroxyl group at the carbon joining penitrem F's methylenecyclohexane and cyclobutane, forming penitrem A.^[5]

References

^ 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.
^ ^a ^b ^c ^d ^e ^f ^g 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. Bibcode:2017Toxgy.392...64B. doi:10.1016/j.tox.2017.10.008. hdl:11250/3149223. ISSN 0300-483X. PMID 29037868.
^ 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.
^ ^a ^b ^c 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. S2CID 36629380.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l 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. S2CID 205386781.