An l-2-hydroxyglutarate biosensor based on specific transcriptional regulator LhgR

Zhaoqi Kang, Manman Zhang, Kaiyu Gao, Wen Zhang, Wensi Meng, Yidong Liu, Dan Xiao, Shiting Guo, Cuiqing Ma, Chao Gao () and Ping Xu ()
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Zhaoqi Kang: State Key Laboratory of Microbial Technology, Shandong University
Manman Zhang: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Department of Radiobiology, Institute of Radiation Medicine of Chinese Academy of Medical Science and Peking Union Medical College
Kaiyu Gao: State Key Laboratory of Microbial Technology, Shandong University
Wen Zhang: Center for Gene and Immunotherapy, The Second Hospital of Shandong University
Wensi Meng: State Key Laboratory of Microbial Technology, Shandong University
Yidong Liu: State Key Laboratory of Microbial Technology, Shandong University
Dan Xiao: State Key Laboratory of Microbial Technology, Shandong University
Shiting Guo: State Key Laboratory of Microbial Technology, Shandong University
Cuiqing Ma: State Key Laboratory of Microbial Technology, Shandong University
Chao Gao: State Key Laboratory of Microbial Technology, Shandong University
Ping Xu: State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract l-2-Hydroxyglutarate (l-2-HG) plays important roles in diverse physiological processes, such as carbon starvation response, tumorigenesis, and hypoxic adaptation. Despite its importance and intensively studied metabolism, regulation of l-2-HG metabolism remains poorly understood and none of regulator specifically responded to l-2-HG has been identified. Based on bacterial genomic neighborhood analysis of the gene encoding l-2-HG oxidase (LhgO), LhgR, which represses the transcription of lhgO in Pseudomonas putida W619, is identified in this study. LhgR is demonstrated to recognize l-2-HG as its specific effector molecule, and this allosteric transcription factor is then used as a biorecognition element to construct an l-2-HG-sensing FRET sensor. The l-2-HG sensor is able to conveniently monitor the concentrations of l-2-HG in various biological samples. In addition to bacterial l-2-HG generation during carbon starvation, biological function of the l-2-HG dehydrogenase and hypoxia induced l-2-HG accumulation are also revealed by using the l-2-HG sensor in human cells.

Date: 2021
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DOI: 10.1038/s41467-021-23723-7

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