YouTube video by KennyChesneyVEVO

YouTube video by Lee Miller

Modular polyketide synthases (PKSs) are multidomain, assembly line enzymes that biosynthesize complex antibiotics such as erythromycin and rapamycin. The modular characteristic of PKSs makes them an ideal platform for the custom production of designer polyketides by combinatorial biosynthesis. However, engineered hybrid PKS pathways often exhibit severe loss of enzyme activity, and a general principle for PKS reprogramming has not been established. Here we present a widely applicable strategy for designing hybrid PKSs. We reveal that two conserved motifs are robust cut sites to connect modules from different PKS pathways and demonstrate the custom production of polyketides with different starter units, extender units and variable reducing states. Furthermore, we expand the applicability of these cut sites to construct hybrid pathways involving cis-AT PKS, trans-AT PKS and even nonribosomal peptide synthetase. Collectively, our findings enable plug-and-play reprogramming of modular PKSs

Polyunsaturated fatty acid (PUFA) synthase-like enzymes are best known for their role in membrane lipid biosynthesis in marine bacteria, but have also been repurposed for the assembly of specialized l...

Modular megasynthases, such as polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs), are molecular assembly lines that biosynthesize many pharmaceutically and ecologically import....

In this special episode of the Latino Newsletter podcast, host Michelle Zacarias is joined by founder Julio Ricardo Varela on the sexual abuse allegations against César Chávez. Michelle and Julio…

Multifunctional polyketide synthases (PKSs) can be an attractive platform for biomanufacturing. Here, the authors report an automated retrobiosynthesis tool, BioPKS pipeline, that integrates the desig...

Acyl carrier proteins (ACPs) are key domains in fatty acid and polyketide synthases (PKSs), shuttling intermediates to catalytic partners. Here, we pr…

Type II polyketide synthases (PKSs) normally synthesize polycyclic aromatic compounds, but the potential for the synthesis of further diverse skeletons remains under investigated. Here, the authors re...

Covering: up to 2025Polyketide synthases (PKSs) are essential enzymatic systems that produce a wide range of natural products. Their biosynthetic features offer significant opportunities to create a…

The value of microbial natural product pathways extends beyond the chemicals they produce, as the enzymes they encode can be harnessed as biocatalysts. Microbial type II polyketide synthases (PKSs) ar...

Abstract. Microbial natural products (NPs) represent one of the most important sources of bioactive compounds in medicine, agriculture, and biotechnology. Non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are large multidomain complexes that enable the efficient generation of highly diverse and complex NPs. Advances in genome sequencing and bioinformatics have revealed an enormous and largely untapped biosynthetic potential encoded in microbial genomes. However, the majority of NPs remain inaccessible due to a lack of genetic tools, silent biosynthetic gene clusters (BGCs) or the inability to culture the vast majority of microbes. Heterologous expression has therefore emerged as a key strategy to access and engineer NPs. Among available expression platforms, Escherichia coli is a pivotal host due to its rapid growth, genetic tractability, and unparalleled molecular toolbox. This review focuses on heterologous expression of NRPS/PKS pathways in E. coli, with particular emphasis on experimental optimisation strategies. Drawing on selected case studies, we highlight how systematic approaches—such as promoter refactoring, expression-rate tuning, chaperone or helper protein co-expression, metabolic engineering, precursor feeding, and cultivation optimisation—can transform initially unsuccessful systems into productive expression platforms. Collectively, these examples illustrate that apparent limitations in E. coli are engineering challenges rather than intrinsic barriers.

Decarboxylative condensation drives chain elongation and translocation of polyketides and fatty acids. However, the mechanism by which nonelongating modules in trans-acyltransferase polyketide synthases (trans-AT PKSs) enable intramodular polyketide chain translocation without decarboxylation remains poorly understood. Here we elucidate a condensation-independent intramodular translocation mechanism in which KS0 within the nonelongating module operates as a transacylase, directly translocating the polyketide chain to its downstream cognate acyl carrier protein (ACP). Notably, the inherent demalonylation activity of trans-ATHtmA7 facilitates efficient ACP recycling ensuring intramodular translocation. Structural modeling and site-directed mutagenesis studies uncover a conserved KS0–ACP binding mode that underpins intramodular translocation across diverse nonelongating modules. Additionally, the strict discrimination of polyketide intermediate by the nonelongating module highlights its c

Covering: up to 2025 Modular polyketide synthases (PKSs) are often described as molecular-scale assembly lines – a moniker that implies a high-degree of coordinated and regulated activity. Belying…

Engineering polyketide synthases can be challenging due to the absence of efficient high-throughput methods. Here, the authors used a solubility biosensor to identify stable variants from libraries of...