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To mark the inaugural issue of Nature Chemical Engineering, we asked a collection of scientists working in different branches of chemical engineering to share their perspectives on the challenges and opportunities that lie ahead for their respective fields.

Triacetic acid lactone (TAL) is a platform chemical with a wide range of applications. Here, the authors report the discovery of a polyketoacyl-CoA thiolase from Burkholderia sp. RF2-non_BP3, termed as BktBbr, which has unusually high in vivo and in vitro activity for production of TAL.

The increasing cost of energy and concerns about the environment have emphasized the need to find new sources of fuel, with the microbial production of high-energy fuels a promising approach. Here, Escherichia coli is engineered to produce more complex biofuels — fatty esters (biodiesel), fatty alcohols and waxes — directly from simple sugars. Some cells are further engineered to express hemicellulases, a step towards producing these compounds directly from hemicellulose.

Synthetic chemistry has long been used to prepare useful compounds — especially those that are hard to obtain from natural sources. But synthetic biology is coming of age as an alternative strategy. A biologist and two chemists debate the merits of their fields' synthetic prowess.

Cells can adapt rapidly to survive and efficiently exploit constantly changing environments by varying their mutation rate. Here the authors construct an in silicosystem to modulate mutation rate, and demonstrate that this method can be used in the laboratory to create specific phenotypes.

The process of cellular engineering is rapidly accelerating owing to advances in technologies to manipulate DNA and other biomolecules, giving rise to the field of synthetic biology. A meeting was held in August 2005 to present progress in the field and to discuss topics in ethics, safety and security.

Malonyl-CoA (M-CoA) is essential for polyketide biosynthesis, but its limited availability constrains production. Here the authors engineer and evolve an orthogonal M-CoA pathway in Escherichia coli to improve M-CoA metabolism, increasing M-CoA levels and polyketide yields.

Low formate dehydrogenase (FDH) activity limits formate assimilation via the synthetic reductive glycine pathway. In this study, the authors introduce a faster FDH in synthetic formatotrophic E. coli, which boosts growth rates and bioproduction titers from formate as sole carbon source.

Medium- and branched-chain diols and amino alcohols are important industrial feedstocks, but they are biosynthetically challenging to produce. Here the authors introduce a modular polyketide synthase platform for the efficient production of these compounds.

Engineered polyketide synthases (PKSs) have great potential as biocatalysts for the synthesis of chemically challenging molecules. Here the authors show a retrobiosynthesis approach to design and construct PKSs to produce a series of valerolactams for biopolymer production.

The authors develop a metabolic engineering strategy for improving polyketide production of industrial interest and discovering new natural products in bacteria.

A multi-omics analysis of oncom, an Indonesian fermented food made from soymilk waste, shows how associated fungi break down food waste to yield nutritious and positively received foods.

QS-21—an FDA-approved vaccine adjuvant—and several structural analogues of QS-21 can be synthesized in engineered yeast strains, and this process is much less laborious compared with the conventional mode of extraction from the Chilean soapbark tree.

Engineered metabolic pathways are usually devoid of the regulatory mechanisms characteristic of natural metabolism. Using pathways not normally found in E. coli, Dueber et al. show that synthetic scaffolds built using protein-protein interaction domains can boost yields of mevalonate and glucaric acid.

Entry of the antimalarial drug precursor semi-synthetic artemisinin into industrial production is the first major milestone for the application of synthetic biology. In this Review, Paddon and Keasling discuss the metabolic engineering and synthetic biology approaches that were used to engineerEscherichia coli and Saccharomyces cerevisiaeto synthesize a precursor of artemisinin, which should aid the development of other pharmaceutical products.

This study presents CSNN, a tool leveraging network homophily and training-free graph neural networks with labels as features to predict drug-target-interactions (DTIs). The model is then experimentally validated on a new dataset of 3773 DTIs from a yeast-based screen on 7 human GPCRs.

Low-carbon chemicals generated from CO₂ provide a possible path to improve the sustainability of microbial bioproduction of food and chemicals. Now, using a metabolic engineering approach, yeast is engineered to produce glucose, myo-inositol, glucosamine, sucrose and starch from C_1–3 molecules.

The chemical synthesis of jasmonates is typically low yielding and can be laborious, whereas their extraction can be costly or environmentally hazardous. Now a de novo biosynthesis of jasmonic acid and its derivatives, methyl jasmonate and jasmonoyl isoleucine, is reported, using an engineered baker’s yeast.

The ability to produce 'higher-chain' alcohols in Escherichia coli could pave the way for advanced biofuels.

The α-diazoester azaserine can be produced by Streptomyces albus engineered with a biosynthetic gene cluster and act as the carbene precursor for coupling with intracellularly produced styrene to generate unnatural amino acids containing a cyclopropyl group.

De novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast and in vitro chemical coupling to vinblastine is carried out, positioning yeast as a scalable platform to produce many monoterpene indole alkaloids.

Natural products are produced by living organisms practising nature’s chemical transformations. Now, an unnatural product has been generated by creating hybrid biosynthetic microorganisms. These microorganisms combine an unnatural chemical transformation—catalysis by an artificial metalloenzyme containing an iridium-based, unnatural cofactor—with a natural biosynthetic pathway within the same cell.

Multifunctional polyketide synthases (PKSs) can be an attractive platform for biomanufacturing. Here, the authors report an automated retrobiosynthesis tool, BioPKS pipeline, that integrates the design of PKSs with enzymatic chemistry to propose biosynthetic routes.

Fungi have the potential to produce sustainable foods for a growing population, but current products are based on a small number of strains with inherent limitations. Here, the authors develop genetic tools for an edible fungus and engineer its nutritional value and sensory appeal for alternative meat applications.

Saccharomyces cerevisiae can be engineered to slowly use methanol; however, a co-carbon source is usually required to support its growth. Now, a Saccharomyces cerevisiae strain that can use methanol as the sole carbon source for growth, and produce value-added bioproducts, is developed.

Vaccine immunoadjuvants are central to vaccine efficiency. Now, the complete characterization of the biosynthetic pathway of QS-21, a potent immunoadjuvant produced by the Chilean soapbark tree, has been reported. These findings open the door to heterologous production of QS-21 and new-to-nature adjuvants.

Agrobacterium-mediated transformation of plants and fungi is enhanced by plasmid copy number variants.

Through the bio-engineering of Saccharomyces cerevisiae high titres of artemisinic acid were produced using a novel cytochrome P450 monooxygenase. Optimization of this process on an industrial scale may significantly reduce the cost of artemisinin, which could then be used to combat malaria in resource-poor settings.

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 modified polyketide synthases.

A circular economy for plastics offers a promising solution to the pollution crisis. Here the authors take advantage of the unique chemistry of polydiketoenamine resins, showing how plastics can be biorenewable and recyclable by incorporating biosourced triacetic acid lactone.

Methyl jasmonate triggers saponin production in Saponaria vaccaria. Using transcriptome data and heterologous expression, the authors identify P450s and glycosyltransferases that modify triterpenoids. They also discover the pathway for UDP-D-fucose biosynthesis.

A yeast platform for de novo biosynthesis of medicinal plant compounds has now been reported. The platform was used to explore the biocatalytic potential of refactored plant pathways and resulted in the production of 19 halogenated derivatives with therapeutic potential.

The problem of toxic intermediates in engineered metabolic pathways is mitigated by dynamic gene-expression regulation using stress-responsive promoters.

Hydroxyglutarate synthase (HglS) converts 2-oxoadipate to D-2- hydroxyglutarate during lysine catabolism in bacteria. Here the authors use structural and biochemical approaches to show that HglS acts via successive decarboxylation and intramolecular hydroxylation and that homologous enzymes catalyze the final step of lysine catabolism in plants.

Propionate addition is a common strategy for production of valuable polyketides by supplying the substrate methylmalonyl-CoA in the industrial microbe Corynebacterium glutamicum; however, propionate inhibits C. glutamicum growth, thus hampering polyketide production. In this study, Zhan et al. identify the reasons for propionate-elicited growth inhibition and metabolically engineer C. glutamicum to circumvent this roadblock and increase polyketide production.

Prediction of enzyme kinetic parameters is essential for designing and optimising enzymes for various biotechnological and industrial applications. Here, authors presented a prediction framework (UniKP), which improves the accuracy of predictions for three enzyme kinetic parameters.

Biotechnology offers a sustainable route to manufacturing, but closing the loop towards safeguarding biodiversity remains challenging. Here, we explore how partnerships with Indigenous Peoples and Local Communities (IP&LC) can promote an ethical and circular bioeconomy.

Mutating natural enzymes is effective in broadening the substrate or product range, but generally leads to reduced titers. Here the authors engineer hybrid polyketide synthases for efficient production of short-chain ketones from plant biomass hydrolysates in Streptomyces, which can increase the octane of gasoline.

Biofuels produced by conversion of biomass by engineered microorganisms have the potential to replace fossil fuels and reduce carbon emissions. In this Review, Keasling and colleagues discuss engineering of metabolic pathways to produce advanced biofuels and approaches to reduce metabolite toxicity and cost and increase titre, rate and yield.

The trade-off between growth and production affects the application of engineered microbes. Here, the authors take the minimal cut set approach to predict metabolic reactions for elimination to couple metabolite production strongly with growth and achieve high production of indigoidine in Pseudomonas putida.

Structurally complex polyamines and polyamine analogues show potential as therapeutics and agrochemicals, but their production remains hampered. Here a polyamine yeast cell factory is developed that enables the gram-per-litre-scale titres of spermidine and the complete biosynthesis of a broad set of these compounds.

In metabolic engineering, mechanistic models require prior metabolism knowledge of the chassis strain, whereas machine learning models need ample training data. Here, the authors combine the mechanistic and machine learning models to improve prediction performance of tryptophan metabolism in baker’s yeast.