Penitrem A (tremortin) is an indole-diterpenoid

mycotoxin A mycotoxin (from the Greek μύκης , "fungus" and τοξίνη , "toxin") is a toxic secondary metabolite produced by organisms of kingdom Fungi and is capable of causing disease and death in both humans and other animals. The term 'mycotoxin' ...

produced by certain species of ''

Aspergillus ' () is a genus consisting of several hundred mold species found in various climates worldwide. ''Aspergillus'' was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli. Viewing the fungi under a microscope, Miche ...

'', ''Claviceps'', and ''

Penicillium ''Penicillium'' () is a genus of ascomycetous fungi that is part of the mycobiome of many species and is of major importance in the natural environment, in food spoilage, and in food and drug production. Some members of the genus produce pe ...

'', which can be found growing on various plant species such as

ryegrass ''Lolium'' is a genus of tufted grasses in the bluegrass subfamily (Pooideae). It is often called ryegrass, but this term is sometimes used to refer to grasses in other genera. They are characterized by bunch-like growth habits. ''Lolium'' is ...

. Penitrem A is one of many

secondary metabolite Secondary metabolites, also called specialised metabolites, toxins, secondary products, or natural products, are organic compounds produced by any lifeform, e.g. bacteria, fungi, animals, or plants, which are not directly involved in the norm ...

s following the synthesis of

paxilline Paxilline is a toxic, tremorgenic diterpene indole polycyclic alkaloid molecule produced by ''Penicillium paxilli ''which was first characterized in 1975. Paxilline is one of a class of tremorigenic mycotoxins, is a potassium channel blocker, ...

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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

. In humans, penitrem A poisoning has been associated with severe tremors,

hyperthermia Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...

diplopia Diplopia is the simultaneous perception of two images of a single object that may be displaced horizontally or vertically in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often v ...

, and

bloody diarrhea Dysentery (UK pronunciation: , US: ), historically known as the bloody flux, is a type of gastroenteritis that results in bloody diarrhea. Other symptoms may include fever, abdominal pain, and a feeling of incomplete defecation. Complications ...

. In animals, symptoms of penitrem A poisoning has been associated with symptoms ranging from tremors, seizures, and hyperthermia to

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

and

nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...

Roquefortine C Roquefortine C is a mycotoxin that belongs to a class of naturally occurring 2,5-diketopiperazines produced by various fungi, particularly species from the genus ''Penicillium''. It was first isolated from a strain of ''Penicillium roqueforti'', a ...

has been commonly detected in documented cases of penitrem A poisoning, making it a possible

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

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 Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

and

aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

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 In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

(ROS) in the

neutrophil granulocytes Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

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

s follows the synthesis of

. Synthesis of penitrem A involves six oxidative-transformation enzymes (four

cytochrome P450 monooxygenase Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...

s and two

flavin adenine dinucleotide Flavin may refer to: Placename * Flavin, Aveyron, a commune in southern France Surname * Adrian Flavin (born 1979), a professional rugby player * Christopher Flavin, president of the Worldwatch Institute * Dan Flavin (1933–1996), a minimalis ...

(FAD)-dependent

monooxygenase Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation o ...

s), two

acetyltransferase Acetyltransferase (or transacetylase) is a type of transferase enzyme that transfers an acetyl group. Examples include: * Histone acetyltransferases including CBP histone acetyltransferase * Choline acetyltransferase * Chloramphenicol acetyltransf ...

s, one

oxidoreductase In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...

, and one

prenyltransferase Prenyltransferases (PTs) are a class of enzymes that transfer allylic prenyl groups to acceptor molecules. Prenyl transferases commonly refer to isoprenyl diphosphate syntheses (IPPSs). Prenyltransferases are a functional category and include seve ...

. These enzymes are encoded by a cluster of genes used in paxilline synthesis and penitrem A-F synthesis. The pathway is described below: # Oxidoreductase catalyzes the reduction of paxilline's ketone and also adds a dimethylallyl group to its aromatic ring. # 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. # 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. # Prenyltransferase catalyzes the formation of a dimethyl-cyclopentane and a

cyclobutane Cyclobutane is a cycloalkane and organic compound with the formula (CH2)4. Cyclobutane is a colourless gas and commercially available as a liquefied gas. Derivatives of cyclobutane are called cyclobutanes. Cyclobutane itself is of no commercial ...

using the intermediate's aromatic ring-alcohol group. # Oxidative-transformation enzyme catalyzes the formation of a

methylenecyclohexane Methylenecyclohexane (IUPAC name: methylidenecyclohexane) is an organic compound with the molecular formula C7H12. Synthesis It can be produced by a Wittig reaction or a reaction with a Tebbe's reagent from cyclohexanone. It can also be synth ...

using the intermediate's dimethyl-cyclopentane, forming secopenitrem D. # Oxidative-transformation enzyme catalyzes the formation of a

cyclooctane Cyclooctane is a cycloalkane with the molecular formula (CH2)8. It is a simple colourless hydrocarbon, but it is often a reference compound for saturated eight-membered ring compounds in general. Cyclooctane has a camphoraceous odor. Conformat ...

using cyclobutane's

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

group and the carbon joining secopenitrem D's

cyclohexane Cyclohexane is a cycloalkane with the molecular formula . Cyclohexane is non-polar. Cyclohexane is a colorless, flammable liquid with a distinctive detergent-like odor, reminiscent of cleaning products (in which it is sometimes used). Cyclohexan ...

and

cyclopentane Cyclopentane (also called C pentane) is a highly flammable alicyclic hydrocarbon with chemical formula C5H10 and CAS number 287-92-3, consisting of a ring of five carbon atoms each bonded with two hydrogen atoms above and below the plane. It occur ...

, forming penitrem D. # Oxidative-transformation enzyme catalyzes the addition a chlorine atom at penitrem D's aromatic ring, forming penitrem C. # Oxidative-transformation enzyme catalyzes the formation of an

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...

ring at penitrem C's

oxane Tetrahydropyran (THP) is the organic compound consisting of a saturated six-membered ring containing five carbon atoms and one oxygen atom. It is named by reference to pyran, which contains two double bonds, and may be produced from it by addin ...

-double bond, forming penitrem F. # Oxidative-transformation enzyme catalyzes the addition of a hydroxyl group at the carbon joining penitrem F's methylenecyclohexane and cyclobutane, forming penitrem A.

References

{{Neurotoxins Indole alkaloids Neurotoxins Penicillium Cell communication Chloroarenes Alcohols Halogen-containing natural products Cyclobutanes Mycotoxins

Mechanism of action

Synthesis

See also

References