Recent advances in microbial production of 5-aminolevulinic acid by metabolic engineering

5-aminolevulinic acid (5-ALA) is a naturally occurring, functional, non-protein amino acid that is ubiquitously present in biological cells, including microorganisms, plants, and animals. It functions as a key precursor in the biosynthesis of tetrahydropyrrole compounds in organisms. Due to its biodegradable, non-toxic, and residue-free properties, 5-ALA has been extensively utilized in medicine, agriculture, and animal production. In recent years, rapid advances in biotechnology have intensified interest in the biological synthesis of 5-ALA. This review provides a comprehensive summary of recent developments in microbial 5-ALA production via the C4 or C5 pathway, including engineering of key enzymes, enhancing the supply of precursors and cofactors, engineering product transporters, reducing by-product generation, dynamic regulation based on biosensors, and utilization of omics technology. These technologies have enabled the production of 5-ALA using bacteria, thereby significantly promoting the industrialization of 5-ALA synthesis. In addition, this review addresses the current challenges associated with the biological synthesis of 5-ALA and proposes prospects that offer guidance for its biosynthesis and industrial production.