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A Multi-enzyme Cascade for the Biosynthesis of AICA Ribonucleoside Di- and Triphosphate
Lobna Eltoukhy1, Christoph Loderer1
1Chair of Molecular Biotechnology Institute for Microbiology, Technische Universität Dresden, Zellescher Weg 20b, 01217, Dresden, Germany.
Chembiochem : a European Journal of Chemical Biology
|December 3, 2021
Summary
Enzymatic cascades efficiently synthesize pharmaceutically active 5'-aminoimidazole-4-carboxamide (AICA) ribonucleotides. These methods offer a cost-effective alternative to chemical synthesis for producing AICA derivatives with specific phosphorylation levels.
Area of Science:
- Biochemistry
- Enzymology
- Medicinal Chemistry
Background:
- 5 -aminoimidazole-4-carboxamide (AICA) ribonucleotides are key active metabolites for AICA nucleoside-based drugs.
- Chemical synthesis of phosphorylated AICA ribonucleotides is complex and costly.
Purpose of the Study:
- To develop enzymatic cascades for synthesizing AICA derivatives with defined phosphorylation levels.
- To establish cost-effective production methods for pharmaceutically relevant AICA metabolites.
Main Methods:
- Utilized two enzymatic cascades combining adenine phosphoribosyltransferase (EcAPT) from E. coli with different polyphosphate kinases (AjPPK and MrPPK).
- Characterized enzyme activities and optimized reaction conditions for cascade synthesis.
- Synthesized AICA ribonucleotides from the nucleobase and phosphoribosyl pyrophosphate.
Main Results:
- The EcAPT/AjPPK cascade achieved up to 91% conversion for the diphosphorylated AICA derivative (ZDP).
- The EcAPT/MrPPK cascade produced the triphosphorylated AICA derivative (ZTP) with up to 65% conversion, yielding ZDP as a byproduct.
Conclusions:
- Enzymatic cascades provide a viable and efficient strategy for producing specifically phosphorylated AICA ribonucleotides.
- These biocatalytic methods overcome the limitations of chemical synthesis for pharmaceutical applications.
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