The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B-12

doi:10.1016/j.cell.2017.09.051

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	The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B-12
	Shen, Hongying 1,2,3,4; Campanello, Gregory C.6; Flicker, Daniel 1,2,3,4; Grabarek, Zenon 1,2,3; Hu, Junchi 5; Luo, Cheng5 ; Banerjee, Ruma 6; Mootha, Vamsi K.1,2,3,4
刊名	CELL
	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.
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关键词	METHYLMALONYL-COA MUTASE ; CHLOROFLEXUS-AURANTIACUS ; SUCCINATE-DEHYDROGENASE ; LIVER-MITOCHONDRIA ; ISOCITRATE LYASE ; DATA QUALITY ; METABOLISM ; PROTEIN ; INHIBITION ; COBALAMIN
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000414250900008
内容类型	期刊论文
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-+.