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Scientists Construct Pathway-selectively Energy Transfer System

Jan 08, 2020

Recently, a research group led by Prof. ZHAO Zongbao from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS) constructed a non-natural cofactor and formate driven system with pathway-selective energy transfer. This work was published in Angewandte Chemie International Edition.
Nicotinamide adenosine dinucleotide (NAD) and its reduced form are linked to hundreds of cellular reactions, and fluctuation of NAD (H) level causes global disturbance to cellular metabolism. To overcome the limitations of the regulation of natural cofactors, the group led by Prof. ZHAO Zongbao has been working on the research area of non-natural cofactors.
In previous works, bioorthogonal redox catalytic system was constructed with non-natural cofactor dependent oxidoreductase mutants via directed revolution (J. Am. Chem. Soc., 2011, 133, 20857). In addition, cofactor preference of phosphite dehydrogenase was engineered and the molecular basis of cofactor preference was elucidated (ACS Catal., 2019, 9, 1883). Moreover, researchers also constructed non-natural organic acids synthesis system driven by phosphite, selectively transferring energy to the metabolic pathways of bacteria (ACS Catal., 2017, 7, 1977).
In the current study, the researchers obtained a nicotinamide cytosine dinucleotide (NCD) dependent formate dehydrogenase (FDH*) through directed evolution, and built a new bioorthogonal system with NCD dependent FDH* and malic enzyme (ME*).
Results showed that pyruvate was reductive carboxylated with carbon unit and reducing power from formate. Further, the researchers constructed a malate synthesis system driven by formate and NCD in microbe.
The study reversed the natural direction of metabolic node of malate, showing great value for redesign of metabolic pathways and selective regulation of the substance and energy metabolism. It was supported by the National Natural Science Foundation of China and Dalian Institute of Chemical Physics.

 
Non-natural cofactor and formate driven reductive carboxylation of pyruvate. FDH*: formate dehydrogenase mutant; ME*: malic enzyme mutant; NCD: nicotinamide cytosine dinucleotide. (Image by GUO Xiaojia) 

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CHEN Si

Dalian Institute of Chemical Physics

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Non‐natural Cofactor and Formate Driven Reductive Carboxylation of Pyruvate

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