Comparative genomics analysis of a series of Yarrowia lipolytica WSH-Z06 mutants with varied capacity for α-ketoglutarate production

•High-throughput screening combined with random mutagenesis screened varied mutants.•Comparative genomic analysis was performed to identify gene variation.•Partial mechanisms of α-KG accumulation were demonstrated in Y. lipolytica mutants.

Yarrowia lipolytica is one of the most intensively investigated α-ketoglutaric acid (α-KG) producers, and metabolic engineering has proven effective for enhancing production. However, regulation of α-KG metabolism remains poorly understood. Genetic engineering of new strains is accompanied by potential safety concerns in some countries and regions. A series of mutants with varied capacity for α-KG production were obtained using random mutagenesis of Y. lipolytica WSH-Z06. Comparative genomics analysis was implemented to identify genes candidates associated with α-KG production. Manipulation of genes regulating mitochondrial biogenesis and energy metabolism could improve α-KG production, while genes involved in regulating transformation between keto acids and amino acids may decrease production. One gene associated with cell cycle control well represented in all mutants, whereas this gene involved in cell concentration do not appear to influence α-KG production. The results shed light on α-KG production in eukaryotic cells, and pave the way for a high-throughput screening and random mutagenesis method for enhancing α-KG production.