Cytochrome P450 Enzymes as Key Drivers of Alkaloid Chemical Diversification in Plants

Abstract

Plants produce more than 20,000 nitrogen-containing heterocyclic metabolites called alkaloids. These chemicals serve numerous eco-physiological functions in the plants as well as medicines and psychedelic drugs for human for thousands of years, with the anti-cancer agent vinblastine and the painkiller morphine as the best-known examples. Cytochrome P450 monooxygenases (P450s) play a key role in generating the structural variety that underlies this functional diversity of alkaloids. Most alkaloid molecules are heavily oxygenated thanks to P450 enzymes’ activities. Moreover, the formation and re-arrangement of alkaloid scaffolds such as ring formation, expansion, and breakage that contribute to their structural diversity and bioactivity are mainly catalyzed by P450s. The fast-expanding genomics and transcriptomics databases of plants have accelerated the investigation of alkaloid metabolism and many players behind the complexity and uniqueness of alkaloid biosynthetic pathways. Here we discuss recent discoveries of P450s involved in the chemical diversification of alkaloids and how these inform our approaches in understanding plant evolution and producing plant-derived drugs.

Synthesis of (±)‐Setigerumine I: Biosynthetic Origins of the Elusive Racemic Papaveraceae Isoxazolidine Alkaloids**

“…In contrast, rather surprisingly, the reaction of nitrone 10' to form Isosetigerumine I (11) is better described as an ambiphilic dipolar cycloaddition, where both the Nualkene-Enitrone and Nunitrone-Ealkene energy gaps are very similar. For nitrone 10' forming Isosetigerumine I (11), the HOMOenol-LUMO+1nitrone = +2.99 eV interaction energy is very close to the alternative orbital energy gap HOMO-2nitrone-LUMOenol = +3.03 eV (See ESI). Although, intuitively, a dominant Nu contribution of the electron-rich enol-lactone could be expected for both systems 10 and 10', this highlights that the electronic nature of even seemingly similar 1,3-dipolar cycloadditions can be vastly different.…”

“…This Cope elimination reaction could proceed through the formation of Noscapine-Noxide, which is known to form via P450 oxidation of Noscapine (4). [8][9][10][11] If the axial chirality, transferred to 6 from enantiopure parent phtalideisoquinoline alkaloid, is scrambled due to interconversion of rotamers, all materials downstream from this precursor 6 would be racemic. Further C-H oxidation of 6 could generate a nitrone dipole 7, which could take part in an intramolecular 1,3-dipolar cycloaddition with the previously generated enol-lactone dipolarophile.…”

“…We expected the major product to be the desired aliphatic C-2 oxidized nitrone precursor 10 leading to Setigerumine I (1), as similar regiochemical oxidation preferences have previously been reported for Nmethyl-N-alkyl hydroxylamines with several different oxidants. [20][21][22][23] Scheme 2: Synthesis of Setigerumine I (1) and Isosetigerumine I (11). Reagents and conditions: 1. m-CPBA (2.0 equiv.…”

“…[27][28][29] In addition to Setigerumine I (1), we also isolated the regioisomeric cycloaddition product 11 in 14% isolated yield. We named this regioisomeric product Isosetigerumine I (11). This isomer of Setigerumine I (1) results from a similar spontaneous 1,3-dipolar cycloaddition domino reaction of the N-methyl oxidized nitrone regioisomer 10'.…”

Functional Studies of Plant Latex as a Rich Source of Bioactive Compounds: Focus on Proteins and Alkaloids

“…Another group of secondary metabolites sequestered in laticifers are alkaloids. Those amino acid derivatives, which are highly bioactive and often toxic, serve eco-physiological functions in plants, providing better fitness to specific environmental niches [33]. Alkaloids for thousands of years have been used and abused by humans, even leading to military conflicts (like opium wars in the 19th century or ongoing drug wars in many countries).…”