Glucose 6-phosphate dehydrogenase mutations causing enzyme deficiency in a model of the tertiary structure of the human enzyme

• Published in: Blood Vol. 87; no. 7; pp. 2974 - 2982
• Main Authors: NAYLOR, C. E, ROWLAND, P, BASAK, A. K, GOVER, S, MASON, P. J, BAUTISTA, J. M, VULLIAMY, T. J, LUZZATTO, L, ADAMS, M. J
• Format: Journal Article
• Language: English
• Published: Washington, DC The Americain Society of Hematology 01-04-1996
• Subjects: Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Glucosephosphate Dehydrogenase - drug effects; Glucosephosphate Dehydrogenase - genetics; Glucosephosphate Dehydrogenase - metabolism; Humans; Models, Molecular; Molecular Sequence Data; Oxidoreductases; Point Mutation; Protein Conformation; Human; Leuconostoc mesenteroides; Glucose-6-phosphate 1-dehydrogenase; Stability; Enzyme; Tertiary structure; Homology; Molecular interaction; Streptococcaceae; Microbial origin; Bacteria; Micrococcales; Dimer; Models; Oxidoreductases; Mutation; Physicochemical properties; Aminoacid sequence
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V87.7.2974.bloodjournal8772974

Human glucose 6-phosphate dehydrogenase (G6PD) has a particularly large number of variants resulting from point mutations; some 60 mutations have been sequenced to date. Many variants, some polymorphic, are associated with enzyme deficiency. Certain variants have severe clinical manifestations; for such variants, the mutant enzyme almost always displays a reduced thermal stability. A homology model of human G6PD has been built, based on the three-dimensional structure of the enzyme from Leuconostoc mesenteroides. The model has suggested structural reasons for the diminished enzyme stability and hence for deficiency. It has shown that a cluster of mutations in exon 10, resulting in severe clinical symptoms, occurs at or near the dimer interface of the enzyme, that the eight-residue deletion in the variant Nara is at a surface loop, and that the two mutations in the A- variant are close together in the three-dimensional structure.