Microbial Production of Purine Nucleotides, Nucleosides, and Nucleobases: Advances and Perspectives.

Nucleotides are indispensable biomolecules, playing vital roles in genetic information transfer, energy metabolism, cofactor biosynthesis, and cellular communication. These compounds (including purine nucleotides, nucleosides, and nucleobases) have become increasingly valuable as foodstuff additives and pharmaceutical intermediates. Although microbial production offers an eco-friendly alternative, its efficiency remains constrained by complex metabolic networks and growth-production tradeoffs. Systems metabolic engineering has emerged as a powerful approach to optimize purine biosynthesis in microorganisms. This review provides a systematic synthesis of recent advances in microbial purine biosynthesis. First, a comprehensive analysis of purine biosynthetic pathways and their regulatory networks in industrial microorganisms are presented, along with a comparative evaluation of current metabolic engineering approaches. Second, systems metabolic engineering strategies for production enhancement are examined, focusing on multi-omics integration, metabolic flux analysis, genome-scale metabolic models, dynamic regulation, and high-throughput screening platforms. Finally, the major challenges confronting efficient microbial production of purine compounds are identified, with proposed strategies to overcome these limitations.