Development of a process for the production of the anticancer lead compound pleurotin by fermentation of Hohenbuehelia atrocaerulea

Abstract

Pleurotin is a naphthoquinone antibiotic originally isolated from Pleurotus griseus. Two pleurotin producing strains of Hohenbuehelia atrocaerulea have been identified, which, on solid substrate fermentation for 2 months yield 1-2 mg/l of the antibiotic. Described here is the lengthy developmental process which resulted in a production protocol being developed which reliably yields pleurotin from liquid fermentation at >300 mg/l. Critical to obtaining this increase in titer was inclusion in the media of an aqueous extract of alder wood.

A novel ribonuclease with antiproliferative activity toward leukemia and lymphoma cells and HIV-1 reverse transcriptase inhibitory activity from the mushroom, Hohenbuehelia serotina

“…The adsorbed proteins were eluted sequentially with 0.2 M NaCl and 1 M NaCl in Tris-HCl buffer and collected as fractions B2 and B3, respectively. Fraction B2 was dialyzed against 10 mM NH 4 OAc buffer (pH 5) subjected to ion exchange chromatography on a 2.5x20 cm CM-cellulose (Sigma) column in 10 mM NH 4 OAc buffer (pH 5). Following the removal of the unadsorbed proteins (fraction CM1), the adsorbed proteins were eluted with 10 mM NH 4 OAc buffer (pH 5) containing a linear gradient of 0-1 M NaCl, and collected as fractions CM2 and CM3.…”

Antiviral 4-Hydroxypleurogrisein and Antimicrobial Pleurotin Derivatives from Cultures of the Nematophagous Basidiomycete Hohenbuehelia grisea

“…Pleurotin ( 1 ; Figure 1 ) and its derivatives leucopleurotin ( 2 ) and dihydropleurotinic acid ( 3 ) were shown to have activity against Gram-positive bacteria [ 4 , 5 ] and pathogenic fungi [ 6 ], as well as to exhibit anticancerogenic effects [ 5 , 7 ]. Moreover, the total synthesis of (±)-pleurotin ( 1 ) [ 8 ] and its production in multi-gram scale by fermentation [ 9 ] have already been accomplished. In recent years, pleurotin has become the center of attention as a potential new anti-cancer lead drug for its highly effective inhibition of the thioredoxin (Trx)–thioredoxin reductase (TrxR) system [ 10 ], a favorable target in the treatment of cancer as well as mercury intoxication [ 11 ].…”

Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition

“…9 Though pleurotin has been synthesized, 10 a multi-gram fermentation process using Hohenbuehelia atrocaerulea for supply of pleurotin to the NCI has been reported. 11 Pleurotin possesses antibacterial, 9 antifungal, 12 and anti-cancer activity, including inhibiting the hypoxia-induced factor (HIF-1α), a transcription factor associated with many aspects of tumor growth. 13 The underlying pathway to much of this biological activity is pleurotin's ability to act as a potent inhibitor (IC 50 0.17 μM) of the thioredoxin (Trx)-thioredoxin reductase (TrxR) system.…”