Benzylisoquinoline Alkaloid Metabolism: A Century of Discovery and a Brave New World

Abstract

Benzylisoquinoline alkaloids (BIAs) are a structurally diverse group of plant specialized metabolites with a long history of investigation. Although the ecophysiological functions of most BIAs are unknown, the medicinal properties of many compounds have been exploited for centuries. These include the narcotic analgesics codeine and morphine, the antimicrobial agents sanguinarine and berberine, and the antitussive and anticancer drug noscapine. BIA biosynthesis involves a restricted number of enzyme types that catalyze landmark coupling reactions and subsequent functional group modifications. A pathogenesis-related (PR)10/Bet v1 'Pictet-Spenglerase', several O-methyl-, N-methyl- and O-acetyltransferases, cytochromes P450, FAD-dependent oxidases, non-heme dioxygenases and NADPH-dependent reductases have been implicated in the multistep pathways leading to structurally diverse alkaloids. A small number of plant species, including opium poppy (Papaver somniferum) and other members of the Ranunculales, have emerged as model systems to study BIA metabolism. The expansion of resources to include a wider range of plant species is creating an opportunity to investigate previously uncharacterized BIA pathways. Contemporary knowledge of BIA metabolism reflects over a century of research coupled with the development of key innovations such as radioactive tracing, enzyme isolation and molecular cloning, and functional genomics approaches such as virus-induced gene silencing. Recently, the emergence of transcriptomics, proteomics and metabolomics has expedited the discovery of new BIA biosynthetic genes. The growing repository of BIA biosynthetic genes is providing the parts required to apply emerging synthetic biology platforms to the development of production systems in microbes as an alternative to plants as a commecial source of valuable BIAs.

Structure and Biocatalytic Scope of Coclaurine N‐Methyltransferase

“…(Figures 1 & S1) 1. Whilst some medically important BIAs can be isolated in high yields from plants, there are some BIAs of interest that are in limited supply 1, 2.…”

“…(Figures 1 & S1) 1. Whilst some medically important BIAs can be isolated in high yields from plants, there are some BIAs of interest that are in limited supply 1, 2. In an effort to generate more robust platforms for BIA production, recent attention has focused on reconstituting BIA biosynthetic pathways in microbial host strains, such as E. coli and yeast, which are more genetically tractable and easily cultivated 2, 3.…”

Structural and Functional Studies of Pavine N-Methyltransferase from Thalictrum flavum Reveal Novel Insights into Substrate Recognition and Catalytic Mechanism

“…Benzylisoquinoline alkaloids (BIAs) 3 are a structurally diverse class of plant specialized metabolites that display an impressive range of pharmacological properties, including the widely used analgesics morphine and codeine (1). Although a large body of knowledge has been acquired on numerous enzymes involved in the biosynthesis of BIAs, many basic biochemical questions remain unanswered.…”

Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in Saccharomyces cerevisiae

“…Consequentially, plant extraction is the only commercial source of BIAs, which limits the diversity of BIA structures available for drug discovery due to their low abundance 16 . The pharmaceutical value of BIAs and advances made in the elucidation of their biosynthesis in plants have made these compounds high-value candidates for production using microbial hosts 17 .…”