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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2002-11-3622. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-11-3622v1 102/2/725    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hamilton, D. Articles by Batist, G. Search for Related Content PubMed PubMed Citation Articles by Hamilton, D. Articles by Batist, G. Related Collections Red Cells Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 July 2003, Vol. 102, No. 2, pp. 725-730 RED CELLS A novel missense mutation in the -glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production David Hamilton, Jian Hui Wu, Moulay Alaoui-Jamali, and Gerald Batist From the Departments of Pharmacology and Therapeutics, Medicine, and Oncology, McGill University, and Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, QC, Canada -Glutamylcysteine synthetase (-GCS) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis: the adenosine triphosphate (ATP)–dependent ligation of glutamate and cysteine. -GCS consists of a catalytic (-GCSH) and modifier (-GCSL) subunit. Hereditary deficiency of -GCS has been reported in a small number of patients and is associated with low erythrocyte levels of -GCS and GSH leading to hemolytic anemia. Here we report a novel -GCSH mutation, isolated from the cDNA of 2 related patients diagnosed with -GCS deficiency. Each was found to be homozygous for a C>T missense mutation at nucleotide 379, encoding for a predicted Arg127Cys amino acid change. Computerized structure modeling identified that the mutated amino acid lies within a cleft on the protein surface of -GCSH, and the border of this cleft was shown to contain Cys249, an evolutionarily conserved residue that has been proven to lie near the binding site of -GCSH. Transfection studies showed that the mutation is associated with decreased GSH production, and binding studies using purified recombinant protein showed that the mutant protein has markedly decreased enzymatic activity compared to wild type. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. I. Biterova and J. J. Barycki Mechanistic Details of Glutathione Biosynthesis Revealed by Crystal Structures of Saccharomyces cerevisiae Glutamate Cysteine Ligase J. Biol. Chem., November 20, 2009; 284(47): 32700 - 32708. [Abstract] [Full Text] [PDF] G. M. Nava, D. Y. Lee, J. H. Ospina, S.-Y. Cai, and H. R. Gaskins Genomic analyses reveal a conserved glutathione homeostasis pathway in the invertebrate chordate Ciona intestinalis Physiol Genomics, November 1, 2009; 39(3): 183 - 194. [Abstract] [Full Text] [PDF] M. Manu Pereira, T. Gelbart, E. Ristoff, K.C. Crain, J.M. Bergua, A. Lopez Lafuente, S.G. Kalko, E. Garcia Mateos, E. Beutler, and J.L. Vives Corrons Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to {gamma}-glutamylcysteine synthetase deficiency in a patient of Moroccan origin Haematologica, November 1, 2007; 92(11): e102 - e105. [Abstract] [Full Text] [PDF] D. Hamilton, J. H. Wu, and G. Batist Structure-Based Identification of Novel Human {gamma}-Glutamylcysteine Synthetase Inhibitors Mol. Pharmacol., April 1, 2007; 71(4): 1140 - 1147. [Abstract] [Full Text] [PDF] I.-S. Song, S. Tatebe, W. Dai, and M. T. Kuo Delayed Mechanism for Induction of {gamma}-Glutamylcysteine Synthetase Heavy Subunit mRNA Stability by Oxidative Stress Involving p38 Mitogen-activated Protein Kinase Signaling J. Biol. Chem., August 5, 2005; 280(31): 28230 - 28240. [Abstract] [Full Text] [PDF]

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