Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme
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 inacti...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-02-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422100002X |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ju-Yi Hsieh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T13:22:18Z |
| format | Article |
| id | doaj.art-4346595fc4e4492a8c26e89d16339be5 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-20T13:22:18Z |
| publishDate | 2021-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-4346595fc4e4492a8c26e89d16339be52022-12-21T19:39:21ZengElsevieriScience2589-00422021-02-01242102034Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzymeJu-Yi Hsieh0Hao-Ping Yang1Sunil Kumar Tewary2Hui-Chen Cheng3Yi-Liang Liu4Shih-Chieh Tai5Wei-Lin Chen6Chien-Hui Hsu7Ting-Jhen Huang8Chuan-Jung Chou9Yu-Nan Huang10Ching-Tien Peng11Meng-Chiao Ho12Guang-Yaw Liu13Hui-Chih Hung14Department of Life Sciences, National Chung Hsing University, Taichung, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung, Taiwan; Ph.D. Program in Microbial Genomics, National Chung Hsing University and Academia Sinica, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung, Taiwan; Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung, Taiwan; Division of Pediatric Hematology and Oncology, China Medical University Children's Hospital, Taichung, TaiwanDivision of Pediatric Hematology and Oncology, China Medical University Children's Hospital, Taichung, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan; Corresponding authorInstitute 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 authorDepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S258900422100002XBiological SciencesGeneticsCell BiologyStructural BiologyCancer |
| spellingShingle | 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 Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme iScience Biological Sciences Genetics Cell Biology Structural Biology Cancer |
| title | Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme |
| title_full | Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme |
| title_fullStr | Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme |
| title_full_unstemmed | Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme |
| title_short | Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme |
| title_sort | single nucleotide variants lead to dysregulation of the human mitochondrial nad p dependent malic enzyme |
| topic | Biological Sciences Genetics Cell Biology Structural Biology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S258900422100002X |
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