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.

Keywords: Aspergillus fumigatus; MetAP2 enzyme; cancer treatment; chemical detection; fumagillin; honeybee hive infections.; metabolic pathway and regulation; microsporicidal activity.

Figure 1

Chemical structure of fumagillin.

Figure 2

Absorption spectrum of fumagillin solution at pH 2.

Figure 3

Arrangement of genes in the fumagillin cluster of A. fumigatus Af293 strain (Afu8g00370-Afu8g00520; ORF names, Source NCBI Database [65]. Green: genes implicated in biosynthetic pathway; blue: regulatory gene; gray and black: other genes related with fumagillin; white: non-related fumagillin genes.

Figure 4

Fumagillin biosynthetic pathway.

Figure 5

Human MetAP2 3D image. (A) Frontal view of enzyme with the active site and (B) a view of the MetAP2 chain coupled to TNP-470, a fumagillin derivative in active site. Rainbow colors: blue (N-terminus) to red (C-terminus). TNP-470 view as ball and stick. (PDB ID: 1B6A, NGL Viewer [108] RCSB PDB [109,110]).

Figure 6

Schematic diagram depicting MetAP2 implication in different pathways. The scheme represents the normal functioning of cascades (black arrows) and the effect of MetAP2 inhibited by fumagillin (red discontinuous arrows). Fumagillin (F) binds covalently to MetAP2 and provokes the inhibition of G protein, SRC, and the ARF signaling pathway at different levels, and the protection of Rb and IF2 against phosphorylation (P).