Periodic Reporting for period 3 - ABIONYS (Artificial Enzyme Modules as Tools in a Tailor-made Biosynthesis)
Periodo di rendicontazione: 2023-08-01 al 2025-01-31
Chemical production is historically tightly linked to fossil resources and a very significant fraction of chemicals around us have been derived from crude oil and natural gas. Today, we are painfully aware of all the consequences that come along with these production strategies. The exploitation of fossil fuels represents one main factor in anthropogenic global warming and oil-based production contributes significantly to key risks for health and the environment. Humanity as a whole has the responsibility to take actions to minimize the destructive impact of our value chains and to transform to sustainable alternatives that are built on renewable and recyclable chemicals and materials.
ABIONYS is aiming to develop solutions that employ biological tools for the production of chemicals. All living creatures continuously conduct chemical transformations inside their cells, and for a long time, we have been able to harvest this chemistry when we made use of biobased materials such as wood, or of microorganism to ferment food or beverages or more recently produce biogas. Yet, the chemistry of nature is limited and does in many regards not overlap too well with the demands to produce the products of our current chemical value chains.
ABIONYS creates new methods and techniques in which natural catalysts, so-called enzymes, are utilized to perform unnatural but chemically relevant reactions. The enzymes can be produced naturally through expression in bacteria or yeasts and thus, offer a more sustainable alternative to traditional chemical catalysts. In nature, many of these enzymes are connect to a complex metabolic network based on which all bioproducts are synthesized. ABIONYS tries to mimic these networks and to use the initially discovered modules for the assembly of metabolism-like cascades. This approach streamlines the synthesis of valuable molecules and often eliminates tedious isolation/purification steps that pose a significant burden in classical synthesis. Moreover, ABIONYS brings this new enzyme-driven chemistry back into a natural environment where it makes use of tailor-made microbes as promising new production facilities. Through genetic manipulation of bacteria or yeasts, we are able to introduce novel chemistries and teach the natural producers to utilize the transformations that we deem necessary, useful, and valuable. The ABIONYS cellular factories are sustainable, self-replicating microreactors, programmed to conduct the chemistry we want. Thus, bioproduction can take the necessary leap from a more specialized technique to a more generic tool to produce value-added products from renewable feedstocks.
ABIONYS is aiming to develop solutions that employ biological tools for the production of chemicals. All living creatures continuously conduct chemical transformations inside their cells, and for a long time, we have been able to harvest this chemistry when we made use of biobased materials such as wood, or of microorganism to ferment food or beverages or more recently produce biogas. Yet, the chemistry of nature is limited and does in many regards not overlap too well with the demands to produce the products of our current chemical value chains.
ABIONYS creates new methods and techniques in which natural catalysts, so-called enzymes, are utilized to perform unnatural but chemically relevant reactions. The enzymes can be produced naturally through expression in bacteria or yeasts and thus, offer a more sustainable alternative to traditional chemical catalysts. In nature, many of these enzymes are connect to a complex metabolic network based on which all bioproducts are synthesized. ABIONYS tries to mimic these networks and to use the initially discovered modules for the assembly of metabolism-like cascades. This approach streamlines the synthesis of valuable molecules and often eliminates tedious isolation/purification steps that pose a significant burden in classical synthesis. Moreover, ABIONYS brings this new enzyme-driven chemistry back into a natural environment where it makes use of tailor-made microbes as promising new production facilities. Through genetic manipulation of bacteria or yeasts, we are able to introduce novel chemistries and teach the natural producers to utilize the transformations that we deem necessary, useful, and valuable. The ABIONYS cellular factories are sustainable, self-replicating microreactors, programmed to conduct the chemistry we want. Thus, bioproduction can take the necessary leap from a more specialized technique to a more generic tool to produce value-added products from renewable feedstocks.
ABIONYS addresses the key challenges through three individual yet interconnected work packages. The Tools Work Package develops a range of new-to-nature biocatalytic modules that help the scientific community to broaden the enzymatic reaction portfolio and make enzymes a more attractive, renewable and sustainable catalysts. The long-term goal of these efforts is to support the industrial transition of chemical production, where enzyme-based strategies are slowly being considered more and more often in process designs.
Since the start of ABIONYS in November 2020, the Tools Work Package has delivered a series of new methodologies, all of which are based on non-natural transformations with high relevance in modern organic synthesis. We have successfully developed new enzymatic modules to carry out ene reactions & cycloadditions for the formation of heterocycles (Angew. Chem. Int. Ed. 2023, e202213671 & Green Chem. 2023, 3166-3174). Furthermore, we have completed in-depth studies on rearrangements and ring contractions (to be published within the coming months). In addition, ABIONYS has commenced investigations on (cyclo)isomerizations that have so far led to general proof-of-concept results, and that are further refined in the second half of this ERC Consolidator campaign.
Even though the Tools Work Package is designed to fuel the other efforts downstream, we are not fully reliant on the progress but can take advantage of a number of enzyme modules that were previously developed in the Deska Lab. As such, the Applications Work Package has been utilizing an in-house furan valorization strategy to develop highly complex reaction cascades. Furans represent a valuable resource as they can be derived as side stream of wood biorefinery. In the first half of ABIONYS, we succeeded to construct an elegant and effective reaction sequence to synthesize lactones from a simple furan feed. Here, the enzymes' intrinsic property to tolerate other enzymes allows us to run multiple chemical transformations in just one reaction vessel, which means that typical isolation and purification steps of reaction intermediates become obsolete. In the bigger picture, such an approach helps to save time resources and particularly limits the amounts of problematic waste. As one of ABIONYS' trademark achievements, we recently published the implementation of this strategy into the total synthesis of Angiopterlactone B, a highly complex tricyclic plant metabolite (Angew. Chem. Int. Ed. 2023, e202301178).
One of the main goals of ABIONYS targets the introduction of our new-to-nature chemistry back into living systems. Microbes have a number of great benefits over chemical catalysts as they are self-replicating, can grow on abundant feeds and are easily manipulated by modern genetic tools. The introduction of non-natural reactions into these tailor-made cellular factories could fundamentally change the way we think about bioproduction, and allow us to massively expand the scope of microbial producers beyond its current applications. Despite its role as long-term goal within ABIONYS, we have already been able to develop individual molecular biology tools that enabled us to create bacteria with abiotic chemical capabilities. Here, we recently published our first breakthrough within the ABIONYS idea, when we transferred parts of the before mentioned furan valorization into a genetically modified bacterium (ChemSusChem 2023, e202201790).
Since the start of ABIONYS in November 2020, the Tools Work Package has delivered a series of new methodologies, all of which are based on non-natural transformations with high relevance in modern organic synthesis. We have successfully developed new enzymatic modules to carry out ene reactions & cycloadditions for the formation of heterocycles (Angew. Chem. Int. Ed. 2023, e202213671 & Green Chem. 2023, 3166-3174). Furthermore, we have completed in-depth studies on rearrangements and ring contractions (to be published within the coming months). In addition, ABIONYS has commenced investigations on (cyclo)isomerizations that have so far led to general proof-of-concept results, and that are further refined in the second half of this ERC Consolidator campaign.
Even though the Tools Work Package is designed to fuel the other efforts downstream, we are not fully reliant on the progress but can take advantage of a number of enzyme modules that were previously developed in the Deska Lab. As such, the Applications Work Package has been utilizing an in-house furan valorization strategy to develop highly complex reaction cascades. Furans represent a valuable resource as they can be derived as side stream of wood biorefinery. In the first half of ABIONYS, we succeeded to construct an elegant and effective reaction sequence to synthesize lactones from a simple furan feed. Here, the enzymes' intrinsic property to tolerate other enzymes allows us to run multiple chemical transformations in just one reaction vessel, which means that typical isolation and purification steps of reaction intermediates become obsolete. In the bigger picture, such an approach helps to save time resources and particularly limits the amounts of problematic waste. As one of ABIONYS' trademark achievements, we recently published the implementation of this strategy into the total synthesis of Angiopterlactone B, a highly complex tricyclic plant metabolite (Angew. Chem. Int. Ed. 2023, e202301178).
One of the main goals of ABIONYS targets the introduction of our new-to-nature chemistry back into living systems. Microbes have a number of great benefits over chemical catalysts as they are self-replicating, can grow on abundant feeds and are easily manipulated by modern genetic tools. The introduction of non-natural reactions into these tailor-made cellular factories could fundamentally change the way we think about bioproduction, and allow us to massively expand the scope of microbial producers beyond its current applications. Despite its role as long-term goal within ABIONYS, we have already been able to develop individual molecular biology tools that enabled us to create bacteria with abiotic chemical capabilities. Here, we recently published our first breakthrough within the ABIONYS idea, when we transferred parts of the before mentioned furan valorization into a genetically modified bacterium (ChemSusChem 2023, e202201790).
As ABIONYS consists of three interconnected scientific targets, and in the first half of its campaign, we have reached novel designs and applications that go beyond the state of the art of biocatalysis. Our aspiration, however, will be the streamlining of our different modules, from the discovery of new reactivities in the test tube to the creation of tailor-made microbial factories that will grow as sustainable catalysts for the production of chemicals. In the two and a half years of the campaign, we have gathered excessive knowledge that paved the way to reach the final goals of ABIONYS. Even more so, we have also built a whole new infrastructure within my research group, taking a more traditional synthetic-organic laboratory to in integrated work environment where we can operate everything from sensitive chemical transformations all the way to the genetic modification of our microbial host organisms. The breath-taking developments in artificial intelligence, that were still hard to imagine at the time of the draft of ABIONYS, now offer us even more tools to support and accelerate the experimental science through machine learning and simulation. We therefore anticipate a more thorough integration of AI also into the ABIONYS workflow and we expect to be able to also scientifically contribute to the general development in this field.