Microbial production of isoquinoline alkaloids as plant secondary metabolites based on metabolic engineering research

Abstract

Plants produce a variety of secondary metabolites that possess strong physiological activities. Unfortunately, however, their production can suffer from a variety of serious problems, including low levels of productivity and heterogeneous quality, as well as difficulty in raw material supply. In contrast, microorganisms can be used to produce their primary and some of their secondary metabolites in a controlled environment, thus assuring high levels of efficiency and uniform quality. In an attempt to overcome the problems associated with secondary metabolite production in plants, we developed a microbial platform for the production of plant isoquinoline alkaloids involving the unification of the microbial and plant metabolic pathways into a single system. The potential applications of this system have also been discussed.

Microbial production of plant specialized metabolites

“…Many medicinal plants containing alkaloids were traditionally used as folk medicines, and some alkaloids are clinically used today. The benzylisoquinoline alkaloids are one of the largest groups, with 2,500 different structures known to date (Sato and Kumagai 2013). They include clinically important compounds, such as morphine, codeine, berberine, papaverine, and tubocurarine (Liscombe and Facchini 2008).…”

“…The resulting (S)-norcoclaurine is then successively modified by norcoclaurine 6-O-methyltransferase (6OMT), coclaurine Nmethyltransferase (CNMT), (S)-N-methylcoclaurine 3-hydroxylase (NMCH; CYP80B1), and 3′-hydroxy-N-methylcoclaurine 4′-O-methyltransferase (4′OMT) to yield the central intermediate (S)-reticuline. (S)-Reticuline undergoes diverse intramolecular coupling reactions resulting in the formation of various backbone structures such as protoberberine, benzophenanthridine, morphinan, and aporphine alkaloids (Liscombe and Facchini 2008;Sato and Kumagai 2013) (Figure 4).…”

“…To date, various benzylisoquinoline alkaloids have been produced in E. coli and S. cerevisiae systems (Matsumura et al 2013;Sato and Kumagai 2013). For example, five enzymes required for the conversion of dopamine to (S)-reticuline [i.e., monoamine oxidase (MAO), NCS, 6OMT, CNMT, and 4′OMT] were expressed in E. coli cells (Minami et al 2008).…”

“…In this context, this review focuses on the progress of microbial production of major plant specialized metabolites, including phenylpropanoids, flavonoids, stilbenoids, diarylheptanoids, phenylbutanoids, terpenoids, and alkaloids (Limem et al 2008;Matsumura et al 2013;Putignani et al 2013;Sato and Kumagai 2013;Wang et al 2011). Additionally, future challenges in this field are discussed.…”

Phenolic Contents, Antioxidant Capacity and Antibacterial Activity of Extracts from Bacillus spp. Associated with The Leaves of Some Medicinal Plants

“…Although phenolic compounds produced by the plants are physiologically active, they suffer from many problems in their production as the quality level and insufficient quantities (Singh et al, 2017). In contrast, the production of bioactive secondary metabolites from microorganisms perform under controlled conditions which achieve high quality and maximum amounts (Sato and Kumagai, 2013). Therefore, in this study, the antioxidant and antibacterial evaluations of the phenolic compounds produced by various Bacillus spp.…”