Benzylisoquinoline Alkaloids Biosynthesis in Sacred Lotus

Abstract

Sacred lotus (Nelumbo nucifera Gaertn.) is an ancient aquatic plant used throughout Asia for its nutritional and medicinal properties. Benzylisoquinoline alkaloids (BIAs), mostly within the aporphine and bisbenzylisoquinoline structural categories, are among the main bioactive constituents in the plant. The alkaloids of sacred lotus exhibit promising anti-cancer, anti-arrhythmic, anti-HIV, and anti-malarial properties. Despite their pharmacological significance, BIA metabolism in this non-model plant has not been extensively investigated. In this review, we examine the diversity of BIAs in sacred lotus, with an emphasis on the distinctive stereochemistry of alkaloids found in this species. Additionally, we discuss our current understanding of the biosynthetic genes and enzymes involved in the formation of 1-benzylisoquinoline, aporphine, and bisbenzylisoquinoline alkaloids in the plant. We conclude that a comprehensive functional characterization of alkaloid biosynthetic enzymes using both in vitro and in vivo methods is required to advance our limited knowledge of BIA metabolism in the sacred lotus.

Keywords: Nelumbo nucifera; benzylisoquinoline alkaloids; cytochrome P450 monooxygenase; medicinal properties; methyltransferase; norcoclaurine synthase; sacred lotus; stereochemistry.

Figure 1

Major 1-benzylisoquinoline alkaloids reported in sacred lotus. Asterisk indicates a chiral center.

Figure 2

Major aporphine alkaloids reported in sacred lotus.

Figure 3

Major bisbenzylisoquinoline alkaloids reported in sacred lotus.

Figure 4

The tribenzylisoquinoline alkaloid, neoliensinine, reported in sacred lotus.

Figure 5

Suggested BIA biosynthetic pathway in sacred lotus. The scheme shows norcoclaurine as the common precursor and N-methylcoclaurine as the branch point intermediate in the formation of aporphine and bisbenzylisoquinoline alkaloids. Tailoring reactions, such as O- and N-methylations, hydroxylation, oxidation, C-C and C-O coupling (and a possible dehydration represented by the dashed arrow) yield the diverse BIAs reported in Nelumbo nucifera. Note that other 1-benzylisoquinolines derived from norcoclaurine could be used in the formation of aporphine and bisbenzylisoquinoline alkaloids, as this representation is merely one of many possible routes (e.g., major BIAs in sacred lotus such as nuciferine and neferine are not represented). Stereochemistry has been omitted for simplicity. Abbreviations: 6OMT, norcoclaurine 6-O-methyltransferase; CNMT, coclaurine N-methyltransferase; CYP719A, cytochrome P450 monooxygenase 719A, CYP80A, cytochrome P450 monooxygenase 80A; CYP80G: cytochrome P450 monooxygenase 80G; NCS, norcoclaurine synthase.