Metabolic engineering of microbial pathways for 5-aminolevulinic acid biosynthesis: Recent advances and...

5-Aminolevulinic acid (5-ALA) is a basic precursor in the bioproduction of tetrapyrrole compounds, such as heme, chlorophyll, and vitamin B₁₂. Its extensive applications in agriculture, medicine, cosmetics and animal feed industry have garnered substantial attention. In agriculture, 5-ALA works as an effective plant growth regulator, improving crop yield, stress tolerance, and product quality. Nonetheless, old chemical production of 5-ALA faces challenges because of complex reaction pathways, low productivity, and environmental concerns. This has directed towards a rising interest in sustainable microbial production approaches. Latest developments in metabolic engineering and synthetic biology have assisted the development of effective bacterial cell factories for 5-ALA bioproduction. Key approaches comprise optimizing precursor supply and cofactor regeneration, reworking inborn C4 and C5 biosynthetic pathways, classifying and alleviating rate-limiting enzymes, engineering transport systems for 5-ALA secretion, decreasing competing pathways, and reducing by-product formation. Furthermore, the addition of biosensor-based vigorous regulation and systems-level metabolic control has considerably boosted production robustness and yield. These technical novelties have accelerated the evolution of microbial 5-ALA production from the laboratory to industrial uses. This review offers a comprehensive overview of recent advancements in bacterial 5-ALA bioproduction, focusing on host selection, pathway engineering strategies, regulatory mechanisms, and evolving biotechnological applications. Lastly, it discusses present challenges and future perspectives to guide the development of next-generation microbial platforms for competent and sustainable 5-ALA synthesis.