Amino acid conservation and clinical severity of human glucose-6-phosphate dehydrogenase mutations |
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Authors: | Yi-Sheng Cheng Tang K Tang Ming-Jing Hwang |
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Institution: | (1) Graduate Institute of Life Sciences, National Defense Medical Center, Academia Sinica, Taipei, Taiwan;(2) Division of Structural Biology, Academia Sinica, Taipei, Taiwan;(3) Cardiovascular Research, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan;(4) Institute of Biomedical Sciences, Academia Sinica, 128 Yen-chiou Yuan Rd., Sec. 2, 11529 Taipei, Taiwan |
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Abstract: | More than a hundred naturally occurring mutations of human glucose-6-phosphate dehydrogenase (G6PD) have been identified at the amino acid level. The abundance of distinct mutation sites and their clinical manifestations make this enzyme ideal for structure-function analysis studies. We present here a sequence and structure combined analysis by which the severity of clinical symptoms resulting from point mutations of this enzyme is correlated with quantified degrees of amino acid conservation within 23 G6PD sequences from different organisms. Our analysis verifies, on a quantitative basis, a widely held notion that clinically severer mutations of G6PD usually occur at conserved amino acids. However, marked exceptions to this general trend exist which are most notably revealed by a number of mutations associated with chronic nonspherocytic hemolytic anemia (class I variants). When mapped onto a homology-derived structural model of human G6PD, these class I mutational sites of low amino acid conservation appear to localize in two spatially distinct clusters, both of which are populated with mutations consisting mainly of clinically severer variants (i.e. class I and class II). These results of computer-assisted analyses contribute to a further understanding of the structure-function relationships of human G6PD deficiency. |
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Keywords: | Human G6PD deficiency Protein structure and sequence Computer graphics analysis |
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