Ce. Naylor et al., GLUCOSE-6-PHOSPHATE-DEHYDROGENASE MUTATIONS CAUSING ENZYME DEFICIENCYIN A MODEL OF THE TERTIARY STRUCTURE OF THE HUMAN ENZYME, Blood, 87(7), 1996, pp. 2974-2982
Human glucose 6-phosphate dehydrogenase (G6PD) has a particularly larg
e number of variants resulting from point mutations; some 60 mutations
have been sequenced to date. Many variants, some polymorphic, are ass
ociated with enzyme deficiency. Certain variants have severe clinical
manifestations; for such variants, the mutant enzyme almost always dis
plays a reduced thermal stability. A homology model of human G6PD has
been built, based on the three-dimensional structure of the enzyme fro
m Leuconostoc mesenteroides. The model has suggested structural reason
s for the diminished enzyme stability and hence for deficiency. It has
shown that a cluster of mutations in exon 10, resulting in severe cli
nical symptoms, occurs at or near the dimer interface of the enzyme, t
hat the eight-residue deletion in the variant Nara is at a surface loo
p, and that the two mutations in the A- variant are close together in
the three-dimensional structure. (C) 1996 by The American Society of H
ematology.