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5-Aminolevulinic acid (5-ALA) has recently received much attention for its wide applications in medicine and agriculture. In this study, we investigated the effect of NCgl0580 in Corynebacterium glutamicum on 5-ALA biosynthesis as well as its possible mechanism. It was found that the overexpression of NCgl0580 increased 5-ALA production by approximately 53.3%. Interestingly, the knockout of this gene led to an even more significant 2.49-fold increase in 5-ALA production. According to transcriptome analysis and functional validation of phenotype-related targets, the deletion of NCgl0580 brought about considerable changes in the transcript levels of genes involved in central carbon metabolism, leading to fluxes redistribution toward the 5-ALA precursor succinyl-CoA as well as ATP-binding cassette (ABC) transporters affecting 5-ALA biosynthesis. In particular, the positive effects of enhanced sugar transport (by overexpressing NCgl1445 and iolT1), glycolysis (by overexpressing pyk2), iron uptake (by overexpressing afuABC), and phosphate uptake (by overexpressing pstSCAB and ugpQ) on 5-ALA biosynthesis were demonstrated for the first time. Thus, the transcriptional mechanism underlying the effect of NCgl0580 deletion on 5-ALA biosynthesis was elucidated, providing new strategies to regulate the metabolic network of C. glutamicum to achieve a further increase in 5-ALA production. [ABSTRACT FROM AUTHOR]