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51.
Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer 总被引:2,自引:2,他引:0
The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase
isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2
60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited
by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal
regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2,
which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK
inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose
in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate.
Received 25 August 2006; received after revision 20 November 2006; accepted 20 December 2006 相似文献
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Gout AM;ADPKD Gene Variant Consortium Ravine D Harris PC Rossetti S Peters D Breuning M Henske EP Koizumi A Inoue S Shimizu Y Thongnoppakhun W Yenchitsomanus PT Deltas C Sandford R Torra R Turco AE Jeffery S Fontes M Somlo S Furu LM Smulders YM Mercier B Ferec C Burtey S Pei Y Kalaydjieva L Bogdanova N McCluskey M Geon LJ Wouters CH Reiterova J Stekrová J San Millan JL Aguiari G Del Senno L 《Nature genetics》2007,39(4):427-428
59.
Dreschers S Dumitru CA Adams C Gulbins E 《Cellular and molecular life sciences : CMLS》2007,64(2):181-191
Rhinoviruses, which cause common cold, belong to the Picornaviridae family, small non-enveloped viruses (diameter 15-30 nm) containing a single-stranded RNA genome (about 7 kb). Over 100 different rhinoviral serotypes have been identified thus far, establishing rhinoviruses as the most diverse group of Picornaviridae. Based on receptor binding properties, rhinoviruses are divided into two classes: the major group binding to intracellular adhesion molecule-1 and the minor group binding to the very low density lipoprotein receptors. Interactions between virus and the receptor molecules cause a conformational change in the capsid, which is a prerequisite for viral uptake. Rhinoviruses trigger a chemokine response upon infection that may lead to exacerbation of the symptoms of common cold, i.e. asthma and inflammation. The following review aims to summarize the knowledge about rhinoviral infections and discusses therapeutical approaches against this almost perfectly adapted pathogen. 相似文献
60.
Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome 总被引:7,自引:0,他引:7
Arts HH Doherty D van Beersum SE Parisi MA Letteboer SJ Gorden NT Peters TA Märker T Voesenek K Kartono A Ozyurek H Farin FM Kroes HY Wolfrum U Brunner HG Cremers FP Glass IA Knoers NV Roepman R 《Nature genetics》2007,39(7):882-888
Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-L?ken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder. 相似文献