Biotechnological Approaches to Optimize the Production of Amaryllidaceae Alkaloids

Abstract

Amaryllidaceae alkaloids (AAs) are plant specialized metabolites with therapeutic properties exclusively produced by the Amaryllidaceae plant family. The two most studied representatives of the family are galanthamine, an acetylcholinesterase inhibitor used as a treatment of Alzheimer's disease, and lycorine, displaying potent in vitro and in vivo cytotoxic and antiviral properties. Unfortunately, the variable level of AAs' production in planta restricts most of the pharmaceutical applications. Several biotechnological alternatives, such as in vitro culture or synthetic biology, are being developed to enhance the production and fulfil the increasing demand for these AAs plant-derived drugs. In this review, current biotechnological approaches to produce different types of bioactive AAs are discussed.

Keywords: amaryllidaceae alkaloids; bioactive molecules; biosynthesis; biotechnological approach; in vitro cultures; synthetic biology.

Figure 1

Current and future biotechnological approaches to produce Amaryllidaceae alkaloids.

Figure 2

Biosynthetic routes to main types (boxed) of Amaryllidaceae alkaloid (AA). Arrows without labeling reflect chemical reactions where no enzyme was characterized. Enzymes that have been identified are labeled in blue. A solid arrow shows one enzymatic step, whereas a broken arrow symbolizes multiple enzymatic reactions. Following 4′O-methylnorbelladine, the regioselective phenol-phenol’ coupling reaction is indicated in the broken arrow, leading to various AA-types. Enzyme abbreviations: 3,4-DHBA, 3,4-dihydroxybenzaldehyde; PAL, phenylalanine ammonia-lyase; C4H, cinnamate 4-hydroxylase; C3H, coumarate 3-hydroxylase; TYDC, tyrosine decarboxylase; NBS, norbelladine synthase; NR, noroxomaritidine/norcraugsodine reductase; N4OMT, norbelladine 4′-O-methyltransferase; CYP96T1, cytochrome P450 monooxygenase 96T1.