Mushroom-Derived Indole Alkaloids

This review (2017) discusses the isolation of mushroom-derived indole alkaloids.

Abstract

“Mushrooms are known to produce over 140 natural products bearing an indole heterocycle. In this review, the isolation of these mushroom-derived indole alkaloids is discussed, along with their associated biological activities.”

Authors: Joshua A. Homer & Jonathan Sperry

Summary

■ INTRODUCTION

Mushrooms are an important source of bioactive compounds, including lectins, lanostanoids, sterols, phenolic compounds, and alkaloids. Many of these compounds have been used in the development of new agrochemicals and pharmaceuticals, including strobilurins AH(18), which are fungicidal compounds that interrupt electron transfer within mitochondria, thus causing fungal death. Pleuromutilin, a diterpene natural product, was isolated from mushrooms Pleurotus mutilus and Clitopilus passeckerianus in 1951, and its structure was fully elucidated in 1962. It has since been used to treat a variety of cancers, but has yet to be approved for clinical use.

A variety of bioactive compounds have been isolated from mushrooms, including indole alkaloids, indoleamines/tryptophols, bisindoles, -carbolines, pyrroloquinolines, and peptides/peptaibols. These compounds have a rich history of use as pharmaceuticals and have a broad range of biological properties.

Simple Indoles are a class of hormones that play an important role in gravitropism. They have been identified in mushroom extracts. Certain mushroom species are notorious for their potent, disagreeable odors. Indoles, skatoles, and 3-chloroindoles have been identified in numerous members of the genus Tricholoma, and methyllindole-3-carboxylate has been isolated from Antrodiella albocinnamomea, a mushroom found throughout the subtropical regions of China.

The pigment indigo (32) is found in mutant variants of the North American “meadow mushroom” Agaricus campestris and is used to treat chronic myeloid leukemia. It inhibits a variety of cyclin-dependent kinases and thus induces cell cycle arrest in cancerous cells.

A collection of N-glycosylated indoles was isolated from the fruiting bodies of Cortinarius brunneus and found to have no significant auxin-like activity.

Indoleamines and tryptophols are found in a diverse range of mushrooms, and the trimethylated derivative of L-tryptophan, hypaphorine, is found in Astraeus odoratus mushrooms. Hypaphorine acts as an auxin antagonist, limiting root growth and elongation, but shows no significant antimycobacterial activity against Mycobacterium tuberculosis.

Certain mushroom species have been used for thousands of years to induce psychoactive effects, such as changes in perception, alteration to mood, and colorful hallucinations. Psilocin, a 4-hydroxyindole alkaloid, is found in the genus Psilocybe and is believed to act through nonselective agonism of various serotonin receptors.

Termitomyces titanicus, Leucocoprinus birnbaumii, and Hericium coralloides are edible mushrooms from West Africa that are noted for their symbiotic relationship with termites. Several of these mushrooms have been found to contain indole alkaloids that have been found to stimulate neurotrophin expression in human 1321N1 astrocytes.

The edible Craterellus cornucopioides couples externally supplied tryptophol with endogenous fatty acids to generate esters. These esters are produced by a variety of bacteria and plant species.

The genus Tricholoma of mushrooms produces a number of indole alkaloids containing a methyl group at the C2-position. These alkaloids are believed to be formed via an enzymatic hydrolysis and radical-mediated oxidative coupling of an unidentified, pungent indole precursor.

-Carbolines are a class of compounds found in a variety of mushrooms, including Hygrophorus eburneus, Cortinarius infractus, Boletus curtisii, and Cortinarius brunneus. They have been shown to have a variety of biological activities, including inhibition of acetylcholinesterase and butyrylcholinesterase.

The fruiting bodies of Cortinarius infractus and Boletus curtisii contain a variety of sulfur-containing -carboline derivatives, including infractopicrin (85) and 10-hydroxyinfractopicrin (86). Flazin (94) from Suillus granulatus and Boletus umbriniporus exhibits anti-HIV activity.

The inedible mushroom Mycena metata produces 16-carboline natural products, which have been identified using HR-MALDI-MS. Some of these compounds have shown limited antiproliferative activity against glioma cell lines.

Numerous pyrroloquinoline natural products have been isolated as pigment molecules from the genus Mycena, including the red alkaloids mycenarubin A (111) and mycenarubin B (112), as well as the blue pyrroloquinolines sanguinones A (113) and B (114), and the red alkaloid sanguinolentaquinone (116).

The black-edged bonnet mushroom produces two novel pyrroloquinolines, which have been found to have no antibacterial or herbicidal activity. Lentinus strigellus produces a peptide-based diketopiperazine that has modest activity against Mycobacterium tuberculosis H37Ra and is cytotoxic to HeLa cells at 100 gmL.

The death cap mushroom, Amanita phalloides, contains a cocktail of toxic peptides that inhibit RNA polymerase II, a vital enzyme in the synthesis of mRNA. This reduces DNA translocation from several thousand to a handful of nucleotides per minute, thus causing widespread damage in the human body.

Phalloidin (137) is a group of seven bicyclic heptapeptides isolated from the genus Amanita. They damage hepatocytes, interact with cellular actin, and disrupt microfilament depolymerization.

Cortinarius speciosissimus is another mushroom notorious for its acute toxicity. Several research groups have been unable to replicate the studies that isolated cortinarins AC(150152), and it has been strongly suggested that the dimeric pyridine N-oxide orellanine (153) is the potent compound responsible for the toxicity of these mushrooms.

Omphalotins AI are a family of dodecapeptides isolated from the jack-o’-lantern mushroom Omphalotus olearius, which have been found to have strong, selective nematicidal activity against the economically important plant pathogen Meloidogyne incognita.

Peptaibols are a class of fungal peptides that contain a C-terminal amino alcohol in conjunction with an N-alkylated terminus and a high content of ,-dialkylated amino acids. They have pronounced antibiotic activity and act through the formation of transmembrane, voltage-gated ion channels that disrupt cell wall permeability and ultimately cause bacterial cell death.

The authors collected all known indole alkaloids derived from mushrooms and reviewed their biological activities. They hope that this review will stimulate further research into this class of natural products.