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Protometabolic pathways: exploring the chemical roots of systems biology

Periodic Reporting for period 1 - ProtoMet (Protometabolic pathways: exploring the chemical roots of systems biology)

Reporting period: 2018-11-01 to 2020-10-31

Nonenzymatic chemical paths similar to extant metabolism likely existed on the prebiotic Earth, which many believe were catalysed by minerals. However, it remains unclear how such chemistry could have led to life-as-we-know-it. Commonly invoked theories do not address how mineral catalysts could have been superseded by RNA or protein enzymes nor how such reactions could have been harnessed in the absence of a cell-like container. We seek to overcome these challenges by probing the role of (metallo)peptide catalysts on previously identified protometabolic reaction paths and by integrating these pathways with prebiotically plausible, cell-like compartments. Together, we hope to determine how the resulting systems chemistry can lead to the persistence of cell-like structures, thereby helping to reveal scenarios where purely abiotic chemistry could have proceeded towards biological chemistry.

The objectives of the project focus on uncovering prebiotic peptide catalysts for protometablic reactions, determining the impact of comparts on reaction networks, articulating a more cohesive, integrated view of the emergence of the Earth's first cells, and to exploit what we have learned to develop new technologies. More specifically, (metallo)peptides that accelerate the triose glycolysis and the citric acid pathways and catalyse the homochiral synthesis of amino acids via the reductive amination of ketoacids will be identified. The ability of coacervates and soft organic interfaces formed by lipids to shape metabolic-like reaction networks will be elucidated. To rapidly screen protometabolic reaction conditions outside of a compartment, microfluidic devices that allow for precise, multi-parametric control of reaction parameters, including pH, will be designed and built. Finally, science philosophy will be used to tie all the pieces together into a theory that broadly accounts for the different chemistries needed to support a nascent, life-like system.
Thus far, we have made good progress towards the objectives, despite the challenges faced by the global pandemic. New prebiotic routes towards the synthesis of peptides from α-aminonitriles were uncovered, which is important for generating peptide catalysts. The rules governing the catalytic activity of these peptides have also begun to be deciphered. Assays were setup to quantify enantiomeric ratios so that the homochiral synthesis of peptides can be evaluated. A new peptide was synthesized that could catalyse a step of the citric acid cycle. Novel types of coacervates made from metabolites and peptides were made and phase diagrams generated. Heme groups embedded within membranes showed catalytic activity. Microfluidic droplet generators and devices that host protometabolic reactions were assembled as first step towards more complex designs. The first manuscript on minimal metabolism is being written and will be submitted shortly
This work will likely facilitate future efforts in synthetic biology that seek to exploit living systems as a technology. This is because the current attempts at engineering bacteria essentially try to append genetically encoded devices to an existing platform that has no interest in the appendage. That is, billions of years of evolution have led to organisms with their own agency. Attaching devices to an organism without understanding the underlying chemistry of life will continue to provide short-term successes that will likely fail to maintain integrity over prolonged periods of time. If, however, new technologies were built by considering the fundamental chemistry of the organism, then greater engineered stability and thus success may be achieved since the new activity could be designed to spring from the metabolic foundation of the cell rather than acting as additional baggage placed on top of an existing cell. The microfluidic devices that are being built for this project may aid efforts in synthesis and organ on a chip technologies. Finally, removing the mysteries surrounding the origins of life will significantly impact society in ways that are difficult to predict. A deeper understanding of where we come will hopefully more forcefully connect us to our environment in our psyches and thus make us more cognizant of the impact of our lifestyles.
Proposed protometabolic pathway