Engineering Microbes for Plant Polyketide Biosynthesis

Abstract

Polyketides are an important group of secondary metabolites, many of which have important industrial applications in the food and pharmaceutical industries. Polyketides are synthesized from one of three classes of enzymes differentiated by their biochemical features and product structure: type I, type II or type III polyketide synthases (PKSs). Plant type III PKS enzymes, which will be the main focus of this review, are relatively small homodimeric proteins that catalyze iterative decarboxylative condensations of malonyl units with a CoA-linked starter molecule. This review will describe the plant type III polyketide synthetic pathway, including the synthesis of chalcones, stilbenes and curcuminoids, as well as recent work on the synthesis of these polyketides in heterologous organisms. The limitations and bottlenecks of heterologous expression as well as attempts at creating diversity through the synthesis of novel “unnatural” polyketides using type III PKSs will also be discussed. Although synthetic production of plant polyketides is still in its infancy, their potential as useful bioactive compounds makes them an extremely interesting area of study.

PKS-A Clade of Oil Palm Might Play Role During Defense AgainstGanoderma boninenseInfection

“…PKS in plants are specifically type III PKS, even though type III PKSs were also discovered in fungi and bacteria (Lim et al 2016). Type III PKS is a homodimeric enzyme that performed a complete series of decarboxylation, condensation, and cylization reactions by utilizing CoA thioesters as substrates to tighten polyketide's covalent attachment to the active site cysteine and does not entail the involvement of ACP domains as occurred in other type PKSs (Abe, 2008;Lussier et al 2012;Tropf et al 1995). The decarboxylation activates malonyl-CoA, iterative condensation couples the resulting acetyl anion to the growing ketide chain, and cylization forms the cyclized polyketide precursor of chalcone via an intramolecular Claisen condensation of the linear tetraketide intermediate (Austin and Noel, 2003).…”

“…The Polyketide (PK) is a class of major secondary metabolite product, beside terpenoids/steroids, alkaloids, and non-ribosomal polypeptides, produced by bacteria, fungi and plants (Lussier et al 2012;Pickens et al 2011). It is known to have diverse and important biological functions including antibiotic and antiparasitic pytoalexin (Jez et al 2000;Staunton and Weissman, 2001).…”

“…macrolides, polyethers and polyene) such as erythromycin A; type II is a monofunctional enzyme group with a single active site for each individual enzyme; and type III acts directly on acyl-CoA substrates which lack acyl carrier protein (ACP) (Pickens et al 2011). Specifically, type III PKS enzymes involve in the plant secondary metabolite biosynthesis of compounds which responsible for pigmentation, fertility, and defence against pathogens or phytoalexins (Lussier et al 2012;Schroeder, 1997a). It has been shown in sorghum that the activity level of chalcone synthase, a member of type III PKS, was significantly increased after inoculated with a common cereals pathogen, Colletotrichum graminicola (Lue et al 1989;Nicholson et al 1987).…”

Heterologous Production of Curcuminoids

“…One of the approaches to produce curcuminoids is combinatorial biosynthesis, which consists of combining enzyme-encoding genes from different species and designing a new set of gene clusters to produce bioactive compounds in a heterologous host (107,108). Heterologous production of curcuminoids in microorganisms is highly advantageous, since they can grow on inexpensive substrates and, compared to plants, are easier to manipulate and have very rapid production cycles (109), allowing curcuminoids to be produced faster and maybe in larger amounts. Large-scale microbial fermentation and downstream purification can also be more easily attained, since microbes usually do not have competing pathways to transgenic metabolism (110).…”

A genomics-guided study of the biosynthesis of microbial secondary metabolites

“…Polyketides are made naturally by bacteria, fungi and plants. Some of the pharmaceutically important polyketides include the antibiotics tetracycline and erythromycin [22], the anti-cancer drugs doxorubicin [23], the antioxidants EGCG and resveratrol [24] and the cholesterol-lowering lovastatin [25].…”