Bioengineered yeast for preventing age-related diseases.

The aging process entails a multifaceted decline in the capacity to restore homeostasis in response to stress. A prevalent characteristic of many age-related diseases is the presence of low-grade chronic inflammation, a risk factor contributing significantly to morbidity and mortality in the elderly population. Specific lifestyle interventions, such as regular physical activity, targeted diet, and supplementation, can delay the accumulation of chronic age-associated conditions by mitigating inflammation processes.

Synthetic biology advances towards a bio-based society in the era of artificial intelligence.

Synthetic biology is a rapidly emerging field with broad underlying applications in health, industry, agriculture, or environment, enabling sustainable solutions for unmet needs of modern society. With the very recent addition of artificial intelligence (AI) approaches, this field is now growing at a rate that can help reach the envisioned goals of bio-based society within the next few decades. Integrating AI with plant-based technologies, such as protein engineering, phytochemicals production, plant system engineering, or microbiome engineering, potentially disruptive applications have already been reported.

Enhanced production of withaferin A from the hairy root culture of Withania somnifera via synergistic effect of Methyl jasmonate and β-cyclodextrin.

Due to low amounts of withanolides produced in some plants and high demand for various applications, their biotechnological production is widely researched. The effects of two explant types (i.e.

Widespread biosynthesis of 16-carbon terpenoids in bacteria.

Terpenoids are the most diverse group of specialized metabolites with numerous applications. Their biosynthesis is based on the five-carbon isoprene building block and, as a result, almost all terpenoids isolated to date are based on backbones that contain multiples of five carbon atoms. Intrigued by the discovery of an unusual bacterial terpenoid with a 16-carbon skeleton, here we investigate whether the biosynthesis of 16-carbon terpenoids is more widespread than this single example.

Engineering yeast for the production of plant terpenoids using synthetic biology approaches.

Covering: 2011-2022The low amounts of terpenoids produced in plants and the difficulty in synthesizing these complex structures have stimulated the production of terpenoid compounds in microbial hosts by metabolic engineering and synthetic biology approaches. Advances in engineering yeast for terpenoid production will be covered in this review focusing on four directions: (1) manipulation of host metabolism, (2) rewiring and reconstructing metabolic pathways, (3) engineering the catalytic activity, substrate selectivity and product specificity of biosynthetic enzymes, and (4) localizing terpenoid production enzymatic fusions and scaffolds, or subcellular compartmentalization.

Engineering membrane architecture for biotechnological applications.

Cellular membranes, predominantly described as a dynamic bilayer, are composed of different lipids, transmembrane proteins, and carbohydrates. Most research on biological membranes focuses on the identification, characterization, and mechanistic aspects of their different components. These studies provide a fundamental understanding of membrane structure, function, and dynamics, establishing a basis for the development of membrane engineering strategies.

Expanding the terpene biosynthetic code with non-canonical 16 carbon atom building blocks.

Humankind relies on specialized metabolites for medicines, flavors, fragrances, and numerous other valuable biomaterials. However, the chemical space occupied by specialized metabolites, and, thus, their application potential, is limited because their biosynthesis is based on only a handful of building blocks. Engineering organisms to synthesize alternative building blocks will bypass this limitation and enable the sustainable production of molecules with non-canonical chemical structures, expanding the possible applications.

Transforming yeast peroxisomes into microfactories for the efficient production of high-value isoprenoids.

Current approaches for the production of high-value compounds in microorganisms mostly use the cytosol as a general reaction vessel. However, competing pathways and metabolic cross-talk frequently prevent efficient synthesis of target compounds in the cytosol. Eukaryotic cells control the complexity of their metabolism by harnessing organelles to insulate biochemical pathways.

Orthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate.

Synthetic biology efforts for the production of valuable chemicals are frequently hindered by the structure and regulation of the native metabolic pathways of the chassis. This is particularly evident in the case of monoterpenoid production in Saccharomyces cerevisiae, where the canonical terpene precursor geranyl diphosphate is tightly coupled to the biosynthesis of isoprenoid compounds essential for yeast viability. Here, we establish a synthetic orthogonal monoterpenoid pathway based on an alternative precursor, neryl diphosphate.

Synthesis of 11-carbon terpenoids in yeast using protein and metabolic engineering.

One application of synthetic biology is the redesign of existing biological systems to acquire new functions. In this context, expanding the chemical code underlying key biosynthetic pathways will lead to the synthesis of compounds with new structures and potentially new biological activities. Terpenoids are a large group of specialized metabolites with numerous applications.

Isoprenoid biosynthesis in the diatom Haslea ostrearia.

Diatoms are eukaryotic, unicellular algae that are responsible for c. 20% of the Earth's primary production. Their dominance and success in contemporary oceans have prompted investigations on their distinctive metabolism and physiology.

Overcoming the plasticity of plant specialized metabolism for selective diterpene production in yeast.

Plants synthesize numerous specialized metabolites (also termed natural products) to mediate dynamic interactions with their surroundings. The complexity of plant specialized metabolism is the result of an inherent biosynthetic plasticity rooted in the substrate and product promiscuity of the enzymes involved. The pathway of carnosic acid-related diterpenes in rosemary and sage involves promiscuous cytochrome P450s whose combined activity results in a multitude of structurally related compounds.

Carnosic acid biosynthesis elucidated by a synthetic biology platform.

Synthetic biology approaches achieving the reconstruction of specific plant natural product biosynthetic pathways in dedicated microbial "chassis" have provided access to important industrial compounds (e.g., artemisinin, resveratrol, vanillin).

Production of the forskolin precursor 11β-hydroxy-manoyl oxide in yeast using surrogate enzymatic activities.

Background: Several plant diterpenes have important biological properties. Among them, forskolin is a complex labdane-type diterpene whose biological activity stems from its ability to activate adenylyl cyclase and to elevate intracellular cAMP levels. As such, it is used in the control of blood pressure, in the protection from congestive heart failure, and in weight-loss supplements.

Use of the de novo transcriptome analysis of silver-leaf nightshade (Solanum elaeagnifolium) to identify gene expression changes associated with wounding and terpene biosynthesis.

Background: Solanum elaeagnifolium, an invasive weed of the Solanaceae family, is poorly studied although it poses a significant threat to crops. Here the analysis of the transcriptome of S. elaeagnifolium is presented, as a means to explore the biology of this species and to identify genes related to its adaptation to environmental stress.

Iterative carotenogenic screens identify combinations of yeast gene deletions that enhance sclareol production.

Background: Terpenoids (isoprenoids) have numerous applications in flavors, fragrances, drugs and biofuels. The number of microbially produced terpenoids is increasing as new biosynthetic pathways are being elucidated. However, efforts to improve terpenoid production in yeast have mostly taken advantage of existing knowledge of the sterol biosynthetic pathway, while many additional factors may affect the output of the engineered system.

Efficient diterpene production in yeast by engineering Erg20p into a geranylgeranyl diphosphate synthase.

Terpenes have numerous applications, ranging from pharmaceuticals to fragrances and biofuels. With increasing interest in producing terpenes sustainably and economically, there has been significant progress in recent years in developing methods for their production in microorganisms. In Saccharomyces cerevisiae, production of the 20-carbon diterpenes has so far proven to be significantly less efficient than production of their 15-carbon sesquiterpene counterparts.

Engineering monoterpene production in yeast using a synthetic dominant negative geranyl diphosphate synthase.

Monoterpenes have an established use in the food and cosmetic industries and have recently also found application as advanced biofuels. Although metabolic engineering efforts have so far achieved significant yields of larger terpenes, monoterpene productivity is lagging behind. Here, we set out to establish a monoterpene-specific production platform in Saccharomyces cerevisiae and identified the sequential reaction mechanism of the yeast farnesyl diphosphate synthase Erg20p to be an important factor limiting monoterpene yield.

The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection.

Earlier studies had suggested that epigenetic mechanisms play an important role in the control of human cytomegalovirus (HCMV) infection. Here we show that productive HCMV infection is indeed under the control of histone H3K27 trimethylation. The histone H3K27 methyltransferase EZH2, and its regulators JARID2 and NDY1/KDM2B repress GFI1, a transcriptional repressor of the major immediate-early promoter (MIEP) of HCMV.

Positive genetic interactors of HMG2 identify a new set of genetic perturbations for improving sesquiterpene production in Saccharomyces cerevisiae.

Background: Terpenoids and isoprenoids are an important class of natural products, which includes currently used drugs, high value bioactive and industrial compounds, and fuel candidates. Due to their industrial application, there is increasing interest in the development of S. cerevisiae strains capable of producing high levels of terpenoids.