Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications

Abstract

Fumagillin is a mycotoxin produced, above all, by the saprophytic filamentous fungus Aspergillus fumigatus. This mold is an opportunistic pathogen that can cause invasive aspergillosis, a disease that has high mortality rates linked to it. Its ability to adapt to environmental stresses through the production of secondary metabolites, including several mycotoxins (gliotoxin, fumagillin, pseurotin A, etc.) also seem to play an important role in causing these infections. Since the discovery of the A. fumigatus fumagillin in 1949, many studies have focused on this toxin and in this review we gather all the information currently available. First of all, the structural characteristics of this mycotoxin and the different methods developed for its determination are given in detail. Then, the biosynthetic gene cluster and the metabolic pathway involved in its production and regulation are explained. The activity of fumagillin on its target, the methionine aminopeptidase type 2 (MetAP2) enzyme, and the effects of blocking this enzyme in the host are also described. Finally, the applications that this toxin and its derivatives have in different fields, such as the treatment of cancer and its microsporicidal activity in the treatment of honeybee hive infections with Nosema spp., are reviewed. Therefore, this work offers a complete review of all the information currently related to the fumagillin mycotoxin secreted by A. fumigatus, important because of its role in the fungal infection process but also because it has many other applications, notably in beekeeping, the treatment of infectious diseases, and in oncology. Key Contribution:Fumagillin is a mycotoxin produced during infections caused by A. fumigatus and in the adaptation processes of this species to multiple environmental stresses. In this review; we include detailed information on the fungal mechanisms employed in the production of this mycotoxin and those present in its regulation, how it acts on its target, and how it can be detected, all of which may be useful for diagnosis or the development of new treatments. Its usefulness in different fields is also described; because of its anti-angiogenic activity it is used to attack different types of tumors; at the same time its antibiotic activity is useful against several parasites.

In vitro study on aspects of molecular mechanisms underlying invasive aspergillosis caused by gliotoxin and fumagillin, alone and in combination

“…Decrease in the RNA expression/activity of caspase 8 and increase in the expression/activity of caspase 3 authenticate that caspase-dependent mitochondria-mediated intrinsic pathway of apoptosis is induced by GT, FUM and GT + FUM in lung epithelial cells. Our results with regard to apoptosis are consistent with previous findings in respect of GT and FUM 41,42 .…”

“…On the other hand in case of FUM, total glutathione content is significantly higher in cell lines insensitive (human umbilical vein endothelial cells) to FUM than in sensitive cell lines (human colon cancer cell line) 51 . Also, FUM has been demonstrated to affect not only methionine aminopeptidases proteins (family of intracellular proteolytic enzymes) but also all the subsequent activities necessary for the effective functioning of proteins related to cell viability and growth 41 . These studies clearly show that glutathione, the hall mark of cellular redox homeostasis, is affected by both GT and FUM, and the structural advantages of theses mycotoxins could be the reason for the generation of intracellular ROS and thus affect several intracellular proteins and induce apoptosis.…”

Genome-Inspired Chemical Exploration of Marine Fungus Aspergillus fumigatus MF071

“…The gene fumR regulates the production of pseurotin A and fumagillin. It was intriguing that the presence of genes in the cluster which were similar to fumagillin targets conferred the strain resistance to fumagillin [ 60 ]. However, fumagillin was not isolated from the extract of MF071, possibly due to the low yield.…”

Phenotypic and Molecular Biological Analysis of Polymycovirus AfuPmV-1M From Aspergillus fumigatus: Reduced Fungal Virulence in a Mouse Infection Model

“…In contrast to gliotoxin, gene expression levels and production of fumagillin, which is another toxin produced by A. fumigatus, were enhanced by the virus infection. Fumagillin is used as an antimicrobial agent and can block mammal blood vessel formation by binding to the enzyme methionine aminopeptidase 2; it is also toxic to erythrocytes at high doses (Guruceaga et al, 2019). At present, the effect of fumagillin in the pathogenicity of the fungal hosts remains unknown (Guruceaga et al, 2018).…”