UNPRODUCTIVE FOLDING OF THE HUMAN G6PD-DEFICIENT VARIANT A(-)

Human glucose-6-phosphate dehydrogenase (G6PD) deficiency almost invar iably results from the presence of missense mutations in the X-Linked gene encoding G6PD. The common African deficient variant G6PD A(-) dif fers 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 ac tivity in red cells, leading to a variety of clinical manifestations, A group of deficient variants, including A(-), have near-normal affini ty for the substrates G6P and NADP. In these cases, deficiency is caus ed by a decreased number of catalytically active molecules per cell du e to intracellular instability of the mutated G6PD, although the mecha nism for this in vivo instability is unknown. Here we report that in v itro folding of the A(-) variant mainly renders partially folded polyp eptides that do not undergo the dimerization required for activity, Un der the same conditions, the nondeficient variants B and A undergo fol ding to produce active dimers with normal mobilities in native gels an d normal kinetic properties. The loss of intrinsic folding determinant s in the A(-) variant may underlie the mechanism of its in vivo instab ility.