Catalysts from synthetic genetic polymers.

Area of Science:

• Origin of Life Studies
• Synthetic Biology
• Biochemistry

Background:

• Catalysis in early genetic polymers like RNA was crucial for life's origin, preceding protein enzymes.
• DNA can fold into catalytic structures, but the potential of natural biopolymers as privileged scaffolds is unknown.
• Synthetic genetic polymers (XNAs) with novel backbones can fold and bind ligands, suggesting catalytic potential.

Purpose of the Study:

• To investigate if synthetic genetic polymers (XNAs) can form functional catalysts (XNAzymes).
• To discover XNAzymes with endonuclease and ligase activities across diverse XNA chemistries.
• To establish catalysis within an entirely synthetic XNA system.

Main Methods:

• Selection of XNAzymes from random pools in four different chemistries: arabino nucleic acids (ANA), 2'-fluoroarabino nucleic acids (FANA), hexitol nucleic acids (HNA), and cyclohexene nucleic acids (CeNA).
• Demonstration of in trans RNA endonuclease and ligase activities of discovered XNAzymes.
• Engineering of a FANA-based XNA-XNA ligase metalloenzyme for a fully synthetic catalytic system.

Main Results:

• Discovery of XNAzymes exhibiting RNA endonuclease and ligase activities in four distinct XNA chemistries.
• Creation of a FANA-based metalloenzyme that ligates FANA oligomers and synthesizes an active RNA endonuclease FANAzyme.
• Demonstration of catalysis independent of natural biopolymers.

Conclusions:

• Catalysis can emerge in synthetic genetic polymers beyond natural biopolymers like RNA and DNA.
• XNAzymes represent a new class of catalysts with potential applications in synthetic biology.
• This work broadens the chemical possibilities for the origin of life on Earth and potentially elsewhere.