Aflatrem

Fungal Genet Biol. 2017 Jul;104:29-37.

Aspergillus flavus aswA, a gene homolog of Aspergillus nidulans oefC, regulates sclerotial development and biosynthesis of sclerotium-associated secondary metabolites.[Pubmed: 28442441]

METHODS AND RESULTS:
Aspergillus flavus aswA (AFLA_085170) is a gene encoding a Zn(II)2Cys6 DNA-binding domain and a transcriptional activation domain, DUF3468. Disruption of aswA yielded strains that made a truncated gene transcript and generated a fungus that produced a greatly increased number of sclerotia. These sclerotia were odd-shaped and non-pigmented (white) and different from oval and pigmented (dark brown to black) mature sclerotia. Transcriptomic analysis of the ΔaswA strain grown on potato dextrose agar plates and Wickerham agar plates showed that expression of clustering genes involved in the biosynthesis of three sclerotium-associated secondary metabolites was down-regulated. These included gene clusters of asparasone, Aflatrem, and aflavarin. In contrast, those of aflatoxin, cyclopiazonic acid and kojic acid were not affected.
CONCLUSIONS:
Metabolite analyses confirmed that the non-pigmented sclerotia contained aflatoxin and cyclopiazonic acid but not other aforementioned metabolites, three asparasone analogs and dihydroxyaflavinine commonly present in mature sclerotia. Impairment in aswA gene function stalls normal sclerotial development, which in turn prevents biosynthesis and accumulation of sclerotium-specific metabolites.

Mol Pharmacol. 1989 Mar;35(3):319-23.

The tremorigen aflatrem is a positive allosteric modulator of the gamma-aminobutyric acidA receptor channel expressed in Xenopus oocytes.[Pubmed: 2538710]

Aflatrem, a mycotoxin from Aspergillus flavus, potentiates the gamma-aminobutyric acid (GABA)-induced chloride current.
METHODS AND RESULTS:
This positive allosteric regulatory action of Aflatrem was quantitatively studied on the GABAA receptor channel expressed in Xenopus oocytes after injection with chick brain mRNA under voltage-clamp conditions. In this model system, Aflatrem potentiates the current induced by 5 microM GABA in a concentration-dependent manner. Half-maximal potentiation was obtained with 2.4 microM Aflatrem and maximal stimulation of the GABA (5 microM) response was more than 10-fold. The potentiation was not associated with a change of the reversal potential of the GABA-induced current. In the presence of 2 microM Aflatrem, the GABA dose-response curve shifted to lower concentrations, with the Ka decreasing from 28 to 7 microM and the Hill coefficient, n, from 1.5 to 0.8, as measured at a membrane potential of -100 mV. At saturating concentration of GABA (250 microM), Aflatrem (10 microM) was still able to enhance the current by about 21%. Further experiments suggest that the site of action of Aflatrem on the GABAA receptor channel complex is different from that of benzodiazepines, pentobarbital, and picrotoxin. Aflatrem (10 microM) had no significant effect on the coexpressed voltage-dependent sodium and calcium channels and on the kainate channel.
CONCLUSIONS:
The potentiating action of Aflatrem on the GABAA receptor channel may explain the initial symptoms of intoxication caused by Aflatrem in vivo, i.e., diminished activity or immobility of the affected animal.

Environ Health Perspect. 1985 Oct;62:459-63.

Aflatrem: a tremorgenic mycotoxin with acute neurotoxic effects.[Pubmed: 2867895 ]

Tremorgenic mycotoxins induce neurologic symptoms ranging from mental confusion to tremors, seizures and death, and are apparently the only class of mycotoxins with significant central nervous system activity. Tremorgens have been implicated in a number of neurologic diseases of cattle collectively known as staggers syndromes, and pose significant agricultural and health problems for both cattle and humans. Although the effects of tremorgens are thought to result from transient perturbations of amino acid neurotransmitter release mechanisms, there is reason to believe that acute exposures to toxins with such synaptic effects may result in degeneration of neuronal fiber processes.
METHODS AND RESULTS:
To test this hypothesis, rats were given a single tremorgenic (3 mg/kg, IP) dose of Aflatrem, and kinetics of amino acid neurotransmitter uptake was assessed in isolated hippocampal nerve terminals at 1 day, 1 week, and 2 weeks after injection. Results indicate a decrease in the capacity of the GABA and glutamate uptake systems, which was interpreted as a loss of nerve terminals.
CONCLUSIONS:
The affinity constants suggest a decrease in release of these transmitters as well. In addition to its transient influence on transmitter release, a single low dose of Aflatrem is able to induce degeneration of neuronal processes in hippocampal neurotransmitter systems and therefore represents a long-term health threat.