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.

1H and 13C NMR data, occurrence, biosynthesis, and biological activity of Piper amides

“…Its condensation with l ‐dopamine catalyzed by norcoclaurine synthase results in ( S )‐norcoclaurine, whose 6‐ O ‐methylation and ( S )‐ N ‐methylation yield ( S )‐ N ‐methylcoclaurine. 3′‐Hydoxylation and 4′‐ O ‐methylation of this last intermediate, catalyzed by ( S )‐ N ‐methylcoclaurine‐3′‐hydroxylase and 3′‐hydroxy‐ N ‐methylcoclaurine‐4′‐ O ‐methyltransferase, respectively, yields ( S )‐reticuline, the common intermediate for aristololactam (compounds 201 – 216 ), 5‐dioxo‐aporphine (compounds 217 – 222 ), and N ‐formylaporphine (compounds 223 – 226 ) alkamides, via phenolic coupling and oxidation, decarboxylation, and cyclization as secondary modifications …”

Over 100 Million Years of Enzyme Evolution Underpinning the Production of Morphine in the Papaveraceae Family of Flowering Plants

“…Opium poppy has also been reported to accumulate sanguinarine in cell cultures ( Desgagné-Penix et al., 2010 ), whereas noscapine and morphinans such as morphine and codeine are the most dominant BIAs found in aerial tissues such as stem and capsules ( Winzer et al., 2012 , Winzer et al., 2015 ). However, none of the above BIAs have been detected in sacred lotus, even though other BIAs belonging to aporphine, bisbenzylisoquinoline, and 1-benzylisoquinoline subclasses have been reported ( Menéndez-Perdomo and Facchini, 2018 ). This suggests that alternative BIA biosynthetic pathways may be present in N .…”

“…In sacred lotus, many 1-benzylisoquinoline alkaloids have both ( R ) and ( S ) stereochemical configurations ( Menéndez-Perdomo and Facchini, 2018 ). In contrast, in Ranunculales only ( S ) enantiomers have been detected in the 1-benzylisoquinoline intermediates in early biosynthetic steps up to ( S )-reticuline.…”

The scaffold-forming steps of plant alkaloid biosynthesis

“…184 Phylogenetic analysis of NCSs across published genomes place these lotus sequences away from the NCS clade indicating an independent origin of BIAs in lotus. 185 Sacred lotus produces BIAs with both (S)-and (R)-stereoisomers, 186 suggesting that: (i) both (S)and (R)-selective NCSs are present, (ii) there is an epimerisation step in the pathway or (iii) the Pictet-Spengler reaction is not enzyme catalysed.…”