Light-driven progesterone production by InP–(M. neoaurum) biohybrid system

Progesterone is one of the classical hormone drugs used in medicine for maintaining pregnancy. However, its manufacturing process, coupled with organic reagents and poisonous catalysts, causes irreversible environmental pollution. Recent advances in synthetic biology have demonstrated that the micro...

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Published in:Bioresources and bioprocessing 2022-09, Vol.9 (1), p.93-14, Article 93
Main Authors: Liu, Kun, Wang, Feng-Qing, Liu, Ke, Zhao, Yunqiu, Gao, Bei, Tao, Xinyi, Wei, Dongzhi
Format: Article
Language:English
Subjects:
Biochemical Engineering
Biosynthesis
Catalysts
Chemical reactions
Chemistry
Chemistry and Materials Science
Chimeras
Cytochrome P450
Cytochromes P450
Drugs
Electron transfer
Environmental Engineering/Biotechnology
Enzymes
Hybrid systems
Industrial and Production Engineering
InP nanoparticles
Metabolism
Microorganisms
NADPH/NADP
Nanoparticles
Natural products
P450
Phytosterols
Progesterone
Reagents
Reductases
Steroids
Sterols
Synthetic biology
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Summary:Progesterone is one of the classical hormone drugs used in medicine for maintaining pregnancy. However, its manufacturing process, coupled with organic reagents and poisonous catalysts, causes irreversible environmental pollution. Recent advances in synthetic biology have demonstrated that the microbial biosynthesis of natural products, especially difficult-to-synthesize compounds, from building blocks is a promising strategy. Herein, overcoming the heterologous cytochrome P450 enzyme interdependency in Mycolicibacterium neoaurum successfully constructed the CYP11A1 running module to realize metabolic conversion from waste phytosterols to progesterone. Subsequently, progesterone yield was improved through strategies involving electron transfer and NADPH regeneration. Mutant CYP11A1 (mCYP11A1) and adrenodoxin reductase (ADR) were connected by a flexible linker (L) to form the chimera mCYP11A1-L-ADR to enhance electron transfer. The chimera mCYP11A1-L-ADR, adrenodoxin (ADX), and ADR-related homolog ARH1 were expressed in M. neoaurum , showed positive activity and produced 45 mg/L progesterone. This electron transfer strategy increased progesterone production by 3.95-fold compared with M. neoaurum expressing mCYP11A1, ADR, and ADX. Significantly, a novel inorganic–biological hybrid system was assembled by combining engineered M. neoaurum and InP nanoparticles to regenerate NADPH, which was increased 84-fold from the initial progesterone titer to 235 ± 50 mg/L. In summary, this work highlights the green and sustainable potential of obtaining synthetic progesterone from sterols in M. neoaurum . Graphical Abstract
ISSN:2197-4365
2197-4365
DOI:10.1186/s40643-022-00575-7