Fig. 1

Metabolic rewiring for high-level production of squalene in yeast. Schematic illustration of metabolic engineering strategies for squalene production from glucose, which include (i) optimizing the key rate-limiting enzyme expression by multiple integration (green box), (ii) controlling the competitive ergosterol biosynthesis pathway using the N-degron-dependent protein degradation system (gray box), and (iii) enhancing the availability of the precursor acetyl-CoA via the metabolic recycling of the surplus energy of LDs (yellow box). Specified pathways related to squalene biosynthesis are highlighted in different colored boxes (top), and corresponding metabolic engineering strategies are shown in boxes with the same color code (bottom). Solid lines or arrows indicate a single metabolic reaction, and dashed lines or arrows indicate multiple reactions. Increased and decreased proteins are shown in blue and red, respectively. G3P glycerol-3-phosphate, HMG-CoA 3-hydroxy-3-methylglutaryl-CoA, IPP isopentenyl pyrophosphate, DMAPP dimethylallyl pyrophosphate, GPP geranyl diphosphate, FPP farnesyl pyrophosphate, 2,3-OSQ 2,3-oxidosqualene, ERG ergosterol, DHAP dihydroxyacetone phosphate, DAG diacylglycerol, TAG triacylglycerol, FFA free fatty acid, tHmg1 truncated 3-hydroxy-3-methylglutaryl-CoA reductase 1, Erg1 squalene epoxidase, Tgl3/4 triacylglycerol lipase, Faa1/4 acyl-CoA synthetase, Upc2 sterol regulatory element-binding protein, SRE sterol regulatory element, UBI ubiquitin