Tremorgenic and neurotoxic paspaline-derived indole-diterpenes: biosynthetic diversity, threats and applications

Abstract

Indole-diterpenes (IDTs) such as the aflatrems, janthitrems, lolitrems, paspalitrems, penitrems, shearinines, sulpinines, and terpendoles are biogenetically related but structurally varied tremorgenic and neurotoxic mycotoxins produced by fungi. All these metabolites derive from the biosynthetic intermediate paspaline, a frequently occurring IDT on its own right. In this comprehensive review, we highlight the similarities and differences of the IDT biosynthetic pathways that lead to the generation of the main paspaline-derived IDT subgroups. We survey the taxonomic distribution and the regulation of IDT production in various fungi and compare the organization of the known IDT biosynthetic gene clusters. A detailed assessment of the highly diverse biological activities of these mycotoxins leads us to emphasize the significant losses that paspaline-derived IDTs cause in agriculture, and compels us to warn about the various hazards they represent towards human and livestock health. Conversely, we also describe the potential utility of these versatile molecules as lead compounds for pharmaceutical drug discovery, and examine the prospects for their industrial scale manufacture in genetically manipulated IDT producers or domesticated host microorganisms in synthetic biological production systems.

Functional characterization of the idtF and idtP genes in the Claviceps paspali indole diterpene biosynthetic gene cluster

“…In this study, we demonstrated that targeted disruption of the idtP and idtF genes in C. paspali modulates the IDT product spectrum towards paspaline-type IDTs such as paspaline (1) and paspalinine (3). These results highlight the metabolic engineering potential of the A. tumefaciens-mediated C. paspali transformation system (Kozák et al 2018) in creating efficient platforms for the production of the IDT nucleus for combinatorial biosynthesis and the large-scale production of complex IDTs for various biomedical applications in the future (Kozák et al 2019).…”

“…Paspalitrems are derived from paspaline (1, Fig. 1), the simplest cyclic IDT that contains a tetracyclic diterpene moiety fused with an indole group (Kozák et al 2019). The cyclic diterpene of paspaline is derived from geranylgeranyl diphosphate, while the indole originates from tryptophan via indole-3-glycerol phosphate (Liu et al 2015).…”

“…The cyclic diterpene of paspaline is derived from geranylgeranyl diphosphate, while the indole originates from tryptophan via indole-3-glycerol phosphate (Liu et al 2015). Tailoring of the common paspaline core by various enzymes (e.g., P450 monooxygenases, prenyltransferases, and FAD-dependent monooxygenases) yields the considerable chemical diversity within the IDT group of fungal secondary metabolites (Kozák et al 2019).…”

Chemical repertoire and biosynthetic machinery of the Aspergillus flavus secondary metabolome: A review

“…Aspergillus flavus IDTs belong to the group of tremorgenic mycotoxins that cause a special type of neurotoxicosis characterized by mental confusion, tremors, ataxia, seizures, hyperesthesia, nystagmus, diarrhea, and vomiting. This group of metabolites has been implicated as etiological agents of a neurologic disorder of livestock recognized as “staggers syndrome,” which involves muscle tremors and general excitability, posing a serious health threat for both cattle and humans (reviewed in Kozák, Szilágyi, Tóth, Pócsi, & Molnár, 2019; Reddy et al., 2019). IDT exposure in animal models has been associated with a significant loss of hippocampal nerve terminals that is manifested with synaptic perturbation of the amino acid neurotransmitters, GABA and glutamate.…”

Tremorgenic Mycotoxins: Structure Diversity and Biological Activity

“…Neurological signs associated with ryegrass staggers disease has been reported in animals, particularly sheep, grazing on perennial ryegrass in Australia, New Zealand, as well as Pacific northwest of USA and Europe [13,14]. This imposes a negative impact on industry, particularly dairy, meat, and wool production involving grazing animals [15]. Thus, forage improvement programs have been involved in selecting novel endophytes that do not produce the known toxins; however, complex mixtures of the intermediate compounds are still present in marketed forage grasses.…”