Abstract
Gain-of-function mutations in the GLUD1 gene, encoding for glutamate dehydrogenase (GDH), result in the hyperinsulinism/hyperammonemia HI/HA syndrome. HI/HA patients present with harmful hypoglycemia secondary to protein-induced HI and elevated plasma ammonia levels. These symptoms may be accompanied by seizures and mental retardation. GDH is a mitochondrial enzyme that catalyzes the oxidative deamination of glutamate to α-ketoglutarate, under allosteric regulations mediated by its inhibitor GTP and its activator ADP. The present study investigated the functional properties of the GDH-G446V variant (alias c.1496G > T, p.(Gly499Val) (NM_005271.4)) in patient-derived lymphoblastoid cells. The calculated energy barrier between the opened and closed state of the enzyme was 41% lower in GDH-G446V compared to wild-type GDH, pointing to altered allosteric regulation. Computational analysis indicated conformational changes of GDH-G446V in the antenna region that is crucial for allosteric regulators. Enzymatic activity measured in patient-derived lymphoblastoid cells showed impaired allosteric responses of GDH-G446V to both regulators GTP and ADP. In particular, as opposed to control lymphoblastoid cells, GDH-G446V cells were not respon...Continue Reading
References
Dec 1, 1990·Archives of Biochemistry and Biophysics·E Lenartowicz
May 8, 1998·The New England Journal of Medicine·C A StanleyM Poncz
Jun 28, 2000·Diabetes·C A StanleyM Poncz
Mar 20, 2001·Journal of Molecular Biology·T J SmithC A Stanley
Oct 22, 2008·Journal of Paediatrics and Child Health·Kar-Ki ChikKwok-Leung Ng
Feb 19, 2009·Journal of Neuroscience Research·L SieE K Tan
May 16, 2009·Journal of Computational Chemistry·B R BrooksM Karplus
Aug 20, 2009·European Journal of Endocrinology·Ritika R KapoorKhalid Hussain
Oct 12, 2010·Reviews in Endocrine & Metabolic Disorders·Andrew A Palladino, Charles A Stanley
May 24, 2011·Neurochemistry International·Melis KaracaPierre Maechler
Aug 10, 2012·Molecular Biology of the Cell·Laurène VetterliPierre Maechler
Aug 1, 2014·Annals of Pediatric Endocrinology & Metabolism·Tohru Yorifuji
Apr 3, 2016·Molecular Pharmacology·Mario J BorgniaJacqueline L S Milne
Oct 19, 2016·Pediatric Diabetes·Diva D De Leon, Charles A Stanley
Nov 23, 2016·Diabetes Care·UNKNOWN International Hypoglycaemia Study Group
Jul 26, 2017·Diabetes Research and Clinical Practice·Pierre Maechler
Sep 16, 2017·Human Molecular Genetics·Mariagrazia GrimaldiPierre Maechler
Mar 16, 2019·Frontiers in Endocrinology·Sonya GalchevaKhalid Hussain
Citations
Jan 26, 2021·Human Genomics·Karolina LuczkowskaPierre Maechler
Aug 28, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xiaoyu LiaoRui Liu
Aug 19, 2021·Endocrinology·Michael A KalwatMelanie H Cobb