7zl8
NME1 in complex with succinyl-CoA
Structural highlights
DiseaseNDKA_MOUSE This protein is found in reduced amount in tumor cells of high metastatic potential. FunctionNDKA_MOUSE Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. Possesses nucleoside-diphosphate kinase, serine/threonine-specific protein kinase, geranyl and farnesyl pyrophosphate kinase, histidine protein kinase and 3'-5' exonuclease activities. Involved in cell proliferation, differentiation and development, signal transduction, G protein-coupled receptor endocytosis, and gene expression. Required for neural development including neural patterning and cell fate determination. During GZMA-mediated cell death, works in concert with TREX1. NME1 nicks one strand of DNA and TREX1 removes bases from the free 3' end to enhance DNA damage and prevent DNA end reannealing and rapid repair (By similarity). Publication Abstract from PubMedThe synthesis of fatty acids from acetyl-coenzyme A (AcCoA) is deregulated in diverse pathologies, including cancer. Here, we report that fatty acid accumulation is negatively regulated by nucleoside diphosphate kinases 1 and 2 (NME1/2), housekeeping enzymes involved in nucleotide homeostasis that were recently found to bind CoA. We show that NME1 additionally binds AcCoA and that ligand recognition involves a unique binding mode dependent on the CoA/AcCoA 3' phosphate. We report that Nme2 knockout mice fed a high-fat diet (HFD) exhibit excessive triglyceride synthesis and liver steatosis. In liver cells, NME2 mediates a gene transcriptional response to HFD leading to the repression of fatty acid accumulation and activation of a protective gene expression program via targeted histone acetylation. Our findings implicate NME1/2 in the epigenetic regulation of a protective liver response to HFD and suggest a potential role in controlling AcCoA usage between the competing paths of histone acetylation and fatty acid synthesis. Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet.,Iuso D, Garcia-Saez I, Coute Y, Yamaryo-Botte Y, Boeri Erba E, Adrait A, Zeaiter N, Tokarska-Schlattner M, Jilkova ZM, Boussouar F, Barral S, Signor L, Couturier K, Hajmirza A, Chuffart F, Bourova-Flin E, Vitte AL, Bargier L, Puthier D, Decaens T, Rousseaux S, Botte C, Schlattner U, Petosa C, Khochbin S Sci Adv. 2023 Sep 8;9(36):eadh0140. doi: 10.1126/sciadv.adh0140. Epub 2023 Sep 6. PMID:37672589[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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