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Unproductive folding of the human G6PD‐deficient variant A −
Author(s) -
GómezGallego Felix,
GarridoPertierra Amando,
Mason Philip J.,
Bautista José M.
Publication year - 1996
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.10.1.8566536
Subject(s) - missense mutation , in vivo , chemistry , folding (dsp implementation) , intracellular , dehydrogenase , gene , mutation , amino acid , genetics , biochemistry , microbiology and biotechnology , enzyme , biology , electrical engineering , engineering
Human ghicose‐6‐phosphate dehydrogenase (G6PD) deficiency almost invariably results from the presence of missense mutations in the X‐linked gene encoding G6PD. The common African deficient variant G6PD A∗ differs from the normal G6PD B by two amino acid substitutions. Only one of these mutations is found on its own, resulting in the nondeficient variant G6PD A. Deficiency is always associated with decreased G6PD activity in red cells, leading to a variety of clinical manifestations. A group of deficient variants, including A“, have near‐normal affinity for the substrates G6P and NADP. In these cases, deficiency is caused by a decreased number of catalytically active molecules per cell due to intracellular instability of the mutated G6PD, although the mechanism for this in vivo instability is unknown. Here we report that in vitro folding of the A∗ variant mainly renders partially folded polypeptides that do not undergo the dimeri‐ zation required for activity. Under the same conditions, the nondeficient variants B and A undergo folding to produce active dimers with normal mobilities in native gels and normal kinetic properties. The loss of intrinsic folding determinants in the A∗ variant may underlie the mechanism of its in vivo instability.—Gómez‐Gallego, F., Garrido‐Pertierra, A., Mason, P. J., Bautista, J. M. Unproductive folding of the human G6PD‐deficient variant A − . FASEB J . 10, 153‐158 (1996)