Terpenoids: Opportunities for Biosynthesis of Natural Product Drugs Using Engineered Microorganisms

Abstract

Terpenoids represent a diverse class of molecules that provide a wealth of opportunities to address many human health and societal issues. The expansive array of structures and functionalities that have been evolved in nature provide an excellent pool of molecules for use in human therapeutics. While this class of molecules has members with therapeutic properties including anticancer, antiparasitic, antimicrobial, antiallergenic, antispasmodic, antihyperglycemic, anti-inflammatory, and immunomodulatory properties, supply limitations prevent the large scale use of some molecules. Many of these molecules are only found in ppm levels in nature thus requiring massive harvesting to obtain sufficient amounts of the drug. Synthetic biology and metabolic engineering provide innovative approaches to increase the production of the desired molecule in the native organism, and most importantly, transfer the biosynthetic pathways to other hosts. Microbial systems are well studied, and genetic manipulations allow the optimization of microbial metabolisms for the production of common terpenoid precursors. Using a host of tools, unprecedented advancements in the large scale production of terpenoids have been achieved in recent years. Identification of limiting steps and pathway regulation, coupled with design strategies to minimize terpenoid byproducts wih a high flux to the desired biosynthetic pathways, have yielded greater than 100-fold improvements in the production of a range of terpenoids. This review focuses on the biodiversity of terpenoids, the biosynthetic pathways involved, and engineering efforts to maximize the production through these pathways.

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

“…According to the number of isoprene units in their backbone, the terpenoids are classified into hemiterpinoids (one isoprene unit, 5C), monoterpinoids (two isoprene units, 10C), sesquiterpinoids (three isoprene units, 15C), diterpinoids (four isoprene units, 20C), sesterterpinoid (five isoprene unit, 25C) and so on [36]. Many terpenoids show therapeutic potential as antibacterial [37], anti-viral [38], anti-malarial [39], anti-parasitic [40], anti-hyperglycemic [41], anti-inflammatory [42] and anti-cancer agents [36]. One such terpenoid compound that holds tremendous potential for the prevention/treatment of cancer is zerumbone (2,6,9,9-tetramethyl-[2E,6E,10E]-cycloundeca-2,6,10-trien-1-one), a cyclic eleven-membered sesquiterpene, isolated from the rhizomes of the tropical plant Zingiber zerumbet Smith.…”

Orthologs of the archaeal isopentenyl phosphate kinase regulate terpenoid production in plants

“…Some compounds, like quinones, chlorophylls, and certain proteins, which require targeting to membranes for their functions, are anchored by terpenoid structures. In addition to their vital biological roles, terpenoids are also widely used by humans as nutritional supplements, flavors, fragrances, biofuels, and pharmaceuticals (4)(5)(6). Multiple metabolic pathways operate in parallel, often intersect, and routinely exchange intermediates, leading to one of the most chemically complex groups of natural products in the biosphere.…”

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

“…[19] Despite their versatile uses, large scale supplies of many useful terpenoids have been limited, since they are usually found only in small amounts from natural resources. [20] Furthermore, their complex structures made them difficult to be chemically synthe sized as well. [21] For instance, although the clinical demands for taxol-an anticancer drug extracted from the bark of Taxus brevifolia [22] -were growing rapidly, the limited natural resources led to its supply crisis.…”