Creating enzymes and self-sufficient cells for biosynthesis of the non-natural cofactor nicotinamide cytosine dinucleotide

Xueying Wang, Yanbin Feng, Xiaojia Guo, Qian Wang, Siyang Ning, Qing Li, Junting Wang, Lei Wang and Zongbao K. Zhao ()
Additional contact information
Xueying Wang: CAS
Yanbin Feng: CAS
Xiaojia Guo: CAS
Qian Wang: CAS
Siyang Ning: CAS
Qing Li: CAS
Junting Wang: CAS
Lei Wang: CAS
Zongbao K. Zhao: CAS

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract Nicotinamide adenine dinucleotide (NAD) and its reduced form are indispensable cofactors in life. Diverse NAD mimics have been developed for applications in chemical and biological sciences. Nicotinamide cytosine dinucleotide (NCD) has emerged as a non-natural cofactor to mediate redox transformations, while cells are fed with chemically synthesized NCD. Here, we create NCD synthetase (NcdS) by reprograming the substrate binding pockets of nicotinic acid mononucleotide (NaMN) adenylyltransferase to favor cytidine triphosphate and nicotinamide mononucleotide over their regular substrates ATP and NaMN, respectively. Overexpression of NcdS alone in the model host Escherichia coli facilitated intracellular production of NCD, and higher NCD levels up to 5.0 mM were achieved upon further pathway regulation. Finally, the non-natural cofactor self-sufficiency was confirmed by mediating an NCD-linked metabolic circuit to convert L-malate into D-lactate. NcdS together with NCD-linked enzymes offer unique tools and opportunities for intriguing studies in chemical biology and synthetic biology.

Date: 2021
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DOI: 10.1038/s41467-021-22357-z

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