Distribution, biosynthesis, and synthetic biology of phenylethanoid glycosides in the order Lamiales

Abstract

Phenylethanoid glycosides (PhGs), with a C₆-C₂ glucoside unit as the basic skeleton, are specialized (secondary) metabolites found in several medicinal plants. As PhGs exhibit various pharmacological activities, they are expected to be used as lead compounds in drug discovery. However, mass-production systems have not yet been established even for acteoside, a typical PhG that is widely distributed in nature (more than 150 species). This review focuses on recent studies on the accumulation and distribution of PhGs in plants, biosynthetic pathways of PhGs, and the bioproduction of PhGs.

Keywords: Lamiales-order; acteoside; biosynthesis; mass production; phenylethanoid glycoside.

Figure 1. Basic structure of phenylethanoid glycoside and frequently occurring substituents.

Figure 2. Typical structures of phenylethanoid glycosides.

Figure 3. Structure of family-specific phenylethanoid glycosides in the order Lamiales. (A) Chemical structures of the Plantaginaceae family; (B) Chemical structures of the Oleaceae family; (C) Chemical structures of the Orobanchaceae family; (D) Chemical structures of the Gesneriaceae family.

Figure 4. Proposed acteoside biosynthetic pathway. The solid arrow represents the known steps, and the dashed arrows denote the putative steps. Black arrows indicate the proposed pathways from transcriptome analysis of several plant species, yellow arrows indicate the proposed pathway based on the in vitro enzymatic assay and in vivo in Rehmannia glutinosa by Yang et al. (2022) and Li et al. (2022), red arrows indicate the proposed pathway based on the in vitro enzymatic assay in Sesamum indicum by Fuji et al. (2023), blue arrows indicate the proposed pathway based on the in vitro enzymatic assay in Ligustrum robustum by Yang et al.(2023), and green arrows indicate the proposed pathway based on the in vitro enzymatic assay in Osmanthus fragrans by Liu et al. (2024). Enzyme abbreviation: PAL, phenylalanine ammonia-lyase; C4H, cinnamate-4-hydroxylase; C3H, coumarate-3-hydroxylase; 4CL, 4-coumoyl-CoA ligase; HCT, 4-hydroxycinnamoyl CoA:shikimate/quinate hydroxycinnamoyltransferase; TyDC, tyrosine decarboxylase; CuAO, copper-containing amine oxidase; ALDH, alcohol dehydrogenase; PPO, polyphenol oxidase; CYP, cytochrome P450; URT, UDP-rhamnose glycosyltransferase; AT, acyltransferase; SHCT, hydroxycinnamoyl-CoA:salidroside hydroxycinnamoyltransferase; OBH, osmanthuside B hydroxylase.