Rational design and modification
of autotrophic bacteria to efficiently
produce high-value chemicals and biofuels are crucial for establishing
a sustainable and economically viable process for one-carbon (C1)
source utilization, which, however, remains a challenge in metabolic
engineering. In this study, autotrophic Clostridium
ljungdahlii was metabolically engineered to efficiently
co-produce three important bulk chemicals, isopropanol, 3-hydroxybutyrate
(3-HB), and ethanol (together, IHE), using syngas (CO2/CO).
An artificial isopropanol-producing pathway was first constructed
and optimized in C. ljungdahlii to
achieve an efficient production of isopropanol and an unexpected product,
3-HB. Based on this finding, an endogenous active dehydrogenase capable
of converting acetoacetate to 3-HB was identified in C. ljungdahlii, thereby revealing an efficient 3-HB-producing
pathway. The engineered strain was further optimized to reassimilate
acetic acid and synthesize 3-HB by introducing heterologous functional
genes. Finally, the best-performing strain was able to produce 13.4,
3.0, and 28.4 g/L of isopropanol, 3-HB, and ethanol, respectively,
in continuous gas fermentation. Therefore, this work represents remarkable
progress in microbial production of bulk chemicals using C1 gases.
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