Pictet–Spengler reaction-based biosynthetic machinery in fungi

Abstract

The Pictet-Spengler (PS) reaction constructs plant alkaloids such as morphine and camptothecin, but it has not yet been noticed in the fungal kingdom. Here, a silent fungal Pictet-Spenglerase (FPS) gene of Chaetomium globosum 1C51 residing in Epinephelus drummondhayi guts is described and ascertained to be activable by 1-methyl-Ltryptophan (1-MT). The activated FPS expression enables the PS reaction between 1-MT and flavipin (fungal aldehyde) to form "unnatural" natural products with unprecedented skeletons, of which chaetoglines B and F are potently antibacterial with the latter inhibiting acetylcholinesterase. A gene-implied enzyme inhibition (GIEI) strategy has been introduced to address the key steps for PS product diversifications. In aggregation, the work designs and validates an innovative approach that can activate the PS reaction-based fungal biosynthetic machinery to produce unpredictable compounds of unusual and novel structure valuable for new biology and biomedicine.Pictet-Spengler reaction | FPS | Chaetomium globosum 1C51 | GIEI

Diversity and taxonomy ofChaetomiumand chaetomium-like fungi from indoor environments

“…2008). It has been known that, in order to adapt to diverse environments, the species of Chaetomium sensu lato are capable of producing various secondary metabolites, which display a wide range of biological activities (Udagawa et al., 1979, Sekita et al., 1981, Ding et al., 2006, Ge et al., 2008, Momesso et al., 2008, Phonkerd et al., 2008, Kharwar et al., 2011, Yamada et al., 2012, Zhang et al., 2012, Lu et al., 2013, Awad et al., 2014, Yan et al., 2014). Some of them are mycotoxins and can cause health hazards (Polizzi et al., 2009, Mason et al., 2010, Andersen et al., 2011, Miller and McMullin, 2014, Wang et al., 2015).…”

Structural Basis for β-Carboline Alkaloid Production by the Microbial Homodimeric Enzyme McbB

“…The catalytic diversity of the McbB homologs is very intriguing. However, there is currently no direct evidence as to whether these microbial proteins, including McbB, actually catalyze the PS reactions in vitro, and thus the biosynthesis of bC alkaloids in microorganisms is still poorly understood (Aroonsri et al, 2012;Chen et al, 2013;Yan et al, 2014). Therefore, biochemical characterizations and crystallographic studies are required to understand the structures and functions of these presumed PS reaction catalyzing enzymes, to provide a solid knowledge base for bC biosynthesis in microorganisms.…”

The Pictet-Spengler Reaction Updates Its Habits

“…(2014) A comparative genomic analysis has clarified that C. globosum does have a fungal Pictet-Spengler (FPS) gene, which remains silent or poorly activated in laboratory cultivations. Therefore, a C. globosum IC5I strain was adopted to test for the activation of its "unworking" P-S reaction-based biosynthetic machinery, and 1-methyl-L-tryptophan (1-MT) was demonstrated to be able to up-regulate the FPS expression and condense with the fungal aldehyde flavipin (3,4,5-trihydroxy-6-methylphthalaldehyde) to unexpectedly form a family of skeletally unprecedented alkaloids (Scheme 86), trivially named chaetoglines A-H. Chaetogline B and F have been found to have antibacterial activity comparable to that of tinidazole (a coassayed drug prescribed in clinic for bacterial infections) against pathogenic anaerobes Veillonella parvula, Bacteroides vulgatus, Streptococcus sp., and Peptostreptococcus sp., whereas chaetogline F was also shown to be a potent inhibitor of acetyl-cholinesterase (AChE) [299]. Kasanah and coworkers studied the in vitro activity of the β-carboline-containing manzamine alkaloids against Fusarium solani, Fusarium oxysporum, and Fusarium proliferatum [300].…”