Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme
Ju-Yi Hsieh,
Hao-Ping Yang,
Sunil Kumar Tewary,
Hui-Chen Cheng,
Yi-Liang Liu,
Shih-Chieh Tai,
Wei-Lin Chen,
Chien-Hui Hsu,
Ting-Jhen Huang,
Chuan-Jung Chou,
Yu-Nan Huang,
Ching-Tien Peng,
Meng-Chiao Ho,
Guang-Yaw Liu,
Hui-Chih Hung
Affiliations
Ju-Yi Hsieh
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
Hao-Ping Yang
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan; Ph.D. Program in Microbial Genomics, National Chung Hsing University and Academia Sinica, Taiwan
Sunil Kumar Tewary
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
Hui-Chen Cheng
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
Yi-Liang Liu
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan; Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
Shih-Chieh Tai
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
Wei-Lin Chen
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
Chien-Hui Hsu
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
Ting-Jhen Huang
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
Chuan-Jung Chou
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
Yu-Nan Huang
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan; Division of Pediatric Hematology and Oncology, China Medical University Children's Hospital, Taichung, Taiwan
Ching-Tien Peng
Division of Pediatric Hematology and Oncology, China Medical University Children's Hospital, Taichung, Taiwan
Meng-Chiao Ho
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan; Corresponding author
Guang-Yaw Liu
Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan; Division of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan; Corresponding author
Hui-Chih Hung
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan; Ph.D. Program in Microbial Genomics, National Chung Hsing University and Academia Sinica, Taiwan; Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan; iEGG & Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan; Corresponding author
Summary: Human mitochondrial NAD(P)+-dependent malic enzyme (ME2) is well recognized to associate with cancer cell metabolism, and the single nucleotide variants (SNVs) of ME2 may play a role in enzyme regulation. Here we reported that the SNVs of ME2 occurring in the allosteric sites lead to inactivation or overactivation of ME2. Two ME2-SNVs, ME2_R67Q and ME2-R484W, that demonstrated inactivating or overactivating enzyme activities of ME2, respectively, have different impact toward the cells. The cells with overactivating SNV enzyme, ME2_R484W, grow more rapidly and are more resistant to cellular senescence than the cells with wild-type or inactivating SNV enzyme, ME2_R67Q. Crystal structures of these two ME2-SNVs reveal that ME2_R67Q was an inactivating “dead form,” and ME2_R484W was an overactivating “closed form” of the enzyme. The resolved ME2-SNV structures provide a molecular basis to explain the abnormal kinetic properties of these SNV enzymes.
