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| 1 | The Study of Carbamoyl Phosphate Synthetase 1 Deficiency Sheds Light on the Mechanism for Switching On/Off the Urea Cycle显示文摘Carbamoyl phosphate synthetase 1(CPS1) deficiency(CPS1D) is an inborn error of the urea cycle having autosomal(2q34) recessive inheritance that can cause hyperammonemia and neonatal death or mental retardation. We analyzed the effects on CPS1 activity, kinetic parameters and enzyme stability of missense mutations reported in patients with CPS1 deficiency that map in the 20-k Da C-terminal domain of the enzyme. This domain turns on or off the enzyme depending on whether the essential allosteric activator of CPS1, N-acetylL-glutamate(NAG), is bound or is not bound to it. To carry out the present studies, we exploited a novel system that allows the expression in vitro and the purification of human CPS1, thus permitting site-directed mutagenesis. These studies have clarified disease causation by individual mutations, identifying functionally important residues, and revealing that a number of mutations decrease the affinity of the enzyme for NAG. Patients with NAG affinity-decreasing mutations might benefit from NAG site saturation therapy with N-carbamyl-Lglutamate(a registered drug, the analog of NAG). Our results, together with additional present and prior site-directed mutagenesis data for other residues mapping in this domain, suggest an NAG-triggered conformational change in the b4-a4 loop of the C-terminal domain of this enzyme. This change might be an early event in the NAG activation process. Molecular dynamics simulations that were restrained according to the observed effects of the mutations are consistent with this hypothesis, providing further backing for this structurally plausible signaling mechanism by which NAG could trigger urea cycle activation via CPS1. | Carmen Díez-Fernández José Gallego Johannes H?berle Javier Cervera Vicente Rubio | 2015 | Journal of Genetics and Genomics2015，42，5： | 7 |
| 2 | Energy-efficient cloud computing 显示文摘 | Berl A Gelenbe E Girolamo M D | 2010 | Computer Journal2010，53，7： | 1 |
| 3 | Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension: a case for albuminuria显示文摘 | ANAVEKAR N S GANS D J BERL T | 2004 | Kidney Int Suppl2004，，92： | 1 |
| 4 | The syndrome of inappropriate antidiuresis 显示文摘 | David H Ellison M D Tomas Berl M D | 2007 | N Engl J Med2007，356，20： | 1 |
| 5 | Joint contracture following prolonged stay in the intensive care unit显示文摘 | Claver H H 6 berl PC Fergusson D | 2008 | CMAJ2008，178，6： | 1 |
| 6 | CS2: A piecewise-linear model for large strain consolidation显示文摘 | FOX P J BERLES J D | 1997 | International Journal for Numerical and Analytical Methods in Geomechanics1997，21，7： | 1 |
| 7 | Energy-efficient cloud computing显示文摘 | A Berl E C_relenbe M D Girolamo G Giuliani D H Meer M Q Dang K Pentikousis | 2010 | The Computer Jottrnal2010，53，7： | 1 |
| 8 | Clinical practice : The syndrome of inappro- priate antidiuresis显示文摘 | Ellison D H Berl T | 2007 | N Engl J Med2007，356，： | 1 |
| 9 | The syndrome of inappropriate antidiuresis显示文摘 | E]lison D H Berl T | 2007 | New England Journal of Medicine2007，356，20： | 1 |
| 10 | A piecewise-linear model for large strain consolidation 显示文摘 | FOX P J BERLES J D | 1997 | International Journal for Numerical and Analytical Methods in Geomechanics1997，，21： | 1 |
| 11 | Functional imaging of developmental and adaptive changes in neurocognition显示文摘 | Berl M M Vaidya C J Gaillard W D | 2006 | NeuroImage2006，30，2： | 1 |
| 12 | Pathological worry, anxiety disorders and the impact of co-occurrence with depressive and other anxiety disorders 显示文摘 | Starcevic V Berle D Milicevic D | 2007 | J Anxiety Disord2007，21，8： | 1 |
| 13 | A piecewise-linear model for large strain consolidation 显示文摘 | FOX P J BERLES J D | 1997 | International Journal for Numerical and Analytical Methods in Geomechanics1997，，21： | 1 |
| 14 | Disgust and obsessive-compulsive disorder: An update 显示文摘 | BERLE D PHILLIPS ES | 2006 | Psychiatry2006，69，3： | 1 |
| 15 | Obsessive-compulsive personality disorder co-occurring with obsessivecompulsive disorder:Conceptual and clinical implications显示文摘 | Starcevic V Berle D Brakoulias V | 2013 | Aust N Z J Psychiatry2013，47，1： | 1 |
| 16 | Preliminary results of a phase I/II study of HDR brachytherapy alone for T1/T2 breast cancer显示文摘 | Wazer DE Berle Graham R Wazer D Berle L | 2002 | Int J Radiat Oncol Biol Phys2002，53，4： | 1 |
| 17 | Clinical practice:The syndrome of inappropriate antidiuresis显示文摘 | Ellison D H Berl T | 2007 | N Engl J Med2007，356，： | 1 |
| 18 | Clinical practice:The syndrome of inappropriate a-ntidiuresis显示文摘 | Ellison D H Berl T | 2007 | N Enel J Med2007，356，： | 1 |
| 19 | Comparing field investigations with laboratory models to predict landfill leachate emissions显示文摘 | Fellner J D?berl G Allgaier G | 2009 | Waste Management2009，29，6： | 1 |
| 20 | CS2:A piecewise-linear model for large strain consolidation显示文摘 | Fox P J Berles J D | 1997 | International Journal for Numerical and Analytical Methods in Geomechanics1997，21，7： | 1 |
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