The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B-12
文献类型：期刊论文
| 作者 | Shen, Hongying1,2,3,4; Campanello, Gregory C.6; Flicker, Daniel1,2,3,4; Grabarek, Zenon1,2,3; Hu, Junchi5; Luo, Cheng5 ; Banerjee, Ruma6; Mootha, Vamsi K.1,2,3,4
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| 刊名 | CELL
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| 出版日期 | 2017-11-02 |
| 卷号 | 171期号:4页码:771-+ |
| ISSN号 | 0092-8674 |
| DOI | 10.1016/j.cell.2017.09.051 |
| 文献子类 | Article |
| 英文摘要 | CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B-12 levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology, and activity-based metabolomics, we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate, a recently identified human anti-microbial metabolite and immunomodulator. We report that CLYBL loss leads to a cell-autonomous defect in the mitochondrial B-12 metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B-12-dependent methylmalonyl-CoA mutase (MUT). Our work de-orphans the function of human CLYBL and reveals that a consequence of exposure to the immunomodulatory metabolite itaconate is B-12 inactivation. |
| WOS关键词 | METHYLMALONYL-COA MUTASE ; CHLOROFLEXUS-AURANTIACUS ; SUCCINATE-DEHYDROGENASE ; LIVER-MITOCHONDRIA ; ISOCITRATE LYASE ; DATA QUALITY ; METABOLISM ; PROTEIN ; INHIBITION ; COBALAMIN |
| 资助项目 | DOE Office of Science User Facility[DE-AC02-05CH11231] ; NIH Common Fund Metabolite Standards Synthesis Core (NHLBI)[HHSN268201300022C] ; NIH[R24DK080261] ; NIH[R35GM122455] ; NIH[R01DK45776] ; NSFC[21472208] ; NSFC[81625022] ; NSFC[81430084] ; NSFC[21210003] ; [F32GM114905] ; [K99GM124296] ; [F32GM113405] ; [F31DK107187] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000414250900008 |
| 出版者 | CELL PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272413]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Mootha, Vamsi K. |
| 作者单位 | 1.Broad Inst, Cambridge, MA 02141 USA; 2.Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA; 3.Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA; 4.Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA; 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 200031, Peoples R China 6.Univ Michigan, Med Sch, Dept Biol Chem, Ann Arbor, MI 48109 USA; |
| 推荐引用方式 GB/T 7714 | Shen, Hongying,Campanello, Gregory C.,Flicker, Daniel,et al. The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B-12[J]. CELL,2017,171(4):771-+. |
| APA | Shen, Hongying.,Campanello, Gregory C..,Flicker, Daniel.,Grabarek, Zenon.,Hu, Junchi.,...&Mootha, Vamsi K..(2017).The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B-12.CELL,171(4),771-+. |
| MLA | Shen, Hongying,et al."The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B-12".CELL 171.4(2017):771-+. |
入库方式： OAI收割
来源：上海药物研究所
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