A new diketopiperazine alkaloid from Aspergillus oryzae

Abstract

Investigation of bioactive secondary metabolites from terrestrial Aspergillus oryzae sp. MMAO1 using M2 medium afforded a new diketopiperazine alkaloid, 7,9-dihydroxy-3-(1H-indol-3-ylmethyl)-8-methoxy-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione (1a), containing the unusual amino acid L-6,8-dihydroxy-7-methoxyphenylalanine. This was co-isolated with ditryptophenaline (2), cyclo-(Tryp,Tyr) (4), cyclo-(Pro,Val), α-cyclopiazonic acid (3), kojic acid and uridine. Re-cultivation of the fungal strain on Dox medium led to the production of bisdethio(bismethylthio)gliotoxin (5), pseurotin A (6) along with linoleic acid, α-cyclopiazonic acid (3) and kojic acid. The chemical structure of the new diketopiperazine alkaloid including the relative configuration was determined by 1D and 2D NMR spectroscopy and HR-ESI-MS spectrometry, and by comparison with the related literature. The new alkaloid (1a) showed no antimicrobial activity or cytotoxicity against brine shrimps.

Safety of the fungal workhorses of industrial biotechnology: update on the mycotoxin and secondary metabolite potential of Aspergillus niger, Aspergillus oryzae, and Trichoderma reesei

“…It was originally isolated from a fungus identified as Penicillium cyclopium , but the strains of Penicillium -producing cyclopiazonic acid were Penicillium griseofulvum and Penicillium commune (Frisvad 1989 ; Frisvad et al 2004 ). CPA has also been isolated repeatedly from Aspergillus oryzae (Orth 1977 ; Ohmomo et al 1973 , erroneously reported as A. versicolor ; see Domsch et al 2007 ; Frisvad 1989 ; Tokuoda et al 2008 ; Shaaban et al 2014 ). It is possible to remove the CPA gene cluster and thus avoid CPA production in biotechnological processes (Kato et al 2011 ).…”

“…The related mycotoxin gliotoxin was reported from 4 and 13% of clinical Aspergillus flavus strains (Lewis et al 2005 ; Kupfahl et al 2008 ), but there is some doubt whether these data are correct (Patron et al 2007 ; Manzanares-Miralles et al 2016 ; Vidal-Garcia et al 2018 ). On the other hand, Shaaban et al ( 2014 ) isolated the reduced form of gliotoxin from A . “ oryzae ” MMAO1, and this latter isolate could be Aspergillus flavus sensu stricto.…”

“…Pseurotins are hybrid NRP/PKS compounds that have been found in A. leporis and A. nomius from Aspergillus section Flavi (Varga et al 2011b ) and were also reported from A . “ oryzae ” MMAO1 (Shaaban et al 2014 ) and A. flavus (Rodríguez et al 2015 ). The pseurotins are not regarded as mycotoxins, but these compounds should be examined in more detail, as they have neuritogenic (Komagata et al 1996 ), antibiotic (Mehedi et al 2010 ; Pinheiro et al 2013 ), anti-inflammatory (Shi et al 2015 ), chitin-synthase inhibitor (Wenke et al 1993 ), and antileishmanial and anticancer (Martinez-Luis et al 2012 ) characteristics.…”

“…A fungus identified as A. oryzae (MMAO1) was isolated from rice hulls, and this fungus produced a dimeric diketopiperazine compound, ditryptophenaline, 7,9-dihydroxy-3-(1H-indol-3-ylmethyl)-8-methoxy-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione, cyclo-(Trp-Tyr), cyclo-(Pro-Val), α-cyclopiazonic acid, (bismethylthio)gliotoxin, pseurotin A, kojic acid, linoleic acid, and uridine (Shaaban et al 2014 ). Since the isolate was from rice hulls in a domesticated field, it was probably an A. flavus , but it could also be an A. nomius since pseurotin A has only been found once in A. flavus (see Varga et al 2011b ; Rodríguez et al 2015 ).…”

Oryzines A & B, Maleidride Congeners from Aspergillus oryzae and Their Putative Biosynthesis

“…Thus, A. oryzae produces kojic acid, the diterpene indoles aflavinines, the aflatrem precursor 13-desoxypaxilline, the sesquiterpenes parasiticolides and various alkaloids, e.g., ditryptoleucine and oryzamides [ 9 ]. Other compounds produced by A. oryzae have been reported recently [ 10 , 11 , 12 ]. However, identifications of the respective producing strains were solely based on morphological characteristics and ribosomal genes, which are insufficient to clearly differentiate them from A. flavus [ 13 ].…”