Medicinally important secondary metabolites in recombinant microorganisms or plants: Progress in alkaloid biosynthesis

Abstract

Plants produce a high diversity of natural products or secondary metabolites which are important for the communication of plants with other organisms. A prominent function is the protection against herbivores and/or microbial pathogens. Some natural products are also involved in defence against abiotic stress, e.g. UV-B exposure. Many of the secondary metabolites have interesting biological properties and quite a number are of medicinal importance. Because the production of the valuable natural products, such as the anticancer drugs paclitaxel, vinblastine or camptothecin in plants is a costly process, biotechnological alternatives to produce these alkaloids more economically become increasingly important. This review provides an overview of the state of art to produce alkaloids in recombinant microorganisms, such as bacteria or yeast. Some progress has been made in metabolic engineering usually employing a single recombinant alkaloid gene. More importantly, for benzylisoquinoline, monoterpene indole and diterpene alkaloids (taxanes) as well as some terpenoids and phenolics the proof of concept for production of complex alkaloids in recombinant Escherichia coli and yeast has already been achieved. In a long-term perspective, it will probably be possible to generate gene cassettes for complete pathways, which could then be used for production of valuable natural products in bioreactors or for metabolic engineering of crop plants. This will improve their resistance against herbivores and/or microbial pathogens.

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

“…[246] More than 20 000 chemicals including a significant number of essential medicines listed by the World Health Organization (WHO) belong to this group. The core scaffolds of alkaloids are synthesized from a common reaction, Pictet-Spengler condensation of amines and aldehydes.…”

“…Other alkaloids, which have been hard to be produced in microbes, include purine alkaloids, tropane alkaloids, and quinolizidine alkaloids. [246] Since alkaloids include numerous medicinally important drugs, there have been a lot of efforts to increase the production of these important chemicals by engineering their natural producers, which are mostly plants, to meet the worldwide demand. However, as described in earlier sections, slow growth of plants and limited comprehension of the plant systems has hindered the progress in this field.…”

“…[248] In this section, successful studies and milestones of transforming the alkaloid pathways in microbial platforms, especially for MIAs and BIAs production, will be described. Readers are encouraged to read other excellent reviews on alkaloids [246,249] or heterologous alkaloid production. [249b,250] …”

Bench-top fermentative production of plant benzylisoquinoline alkaloids using a bacterial platform

“…[1][2][3][4][5] We previously constructed an (S)-reticuline-producing strain of Escherichia coli, which can produce (S)-reticuline from glucose or glycerol. The platform strain has three pathways: (1) an L-tyrosine over-producing pathway; (2) a dopamineproducing pathway from L-tyrosine; and (3) an (S)-reticuline-producing pathway from dopamine 6 (Fig.…”

Editorial: Breaking down the walls to achieve interdisciplinary science and engineering

“…These methods can be used to produce plants with a higher nutritional value, for instance unsaturated fatty acids [1], and the same technology can be used to produce drugs such as taxol for cancer and artemisin for malaria therapy [1], or to engineer tissues [2]. The production of artemisin [3][4][5] and taxans [6][7][8] has been very popular topics in our Journal because conventional chemical synthesis methods have failed to meet the demands and new technology is needed to produce these highly bioactive compounds. Similar principles are applied for the production of substrates for ethanol fermentation and organic compounds in industrial biotechnology [9].…”