BBB seminar: Aurora Martínez

Aurora Martínez
Department of Biomedicine, University of Bergen

Many inherited diseases are caused by the enhanced tendency of the mutant variant proteins to misfold and to either undergo proteasomal degradation or deleterious aggregation with plaque formation. For several of these diseases evidence has been accumulated that osmolytes and other chemical or pharmacological chaperones rescue the misfolded proteins by stimulating their renaturation in vitro and in vivo. Successful therapeutic intervention includes the stabilization of mutant receptors by molecules resembling natural agonists or antagonists. With respect to human genetic diseases involving malfunctioning enzymes, many can be remedied or ameliorated by the administration of high doses of vitamins or other components of the corresponding coenzyme/cofactor, partially restoring enzymatic activity.

We are interested in phenylketonuria (PKU) patients harbouring a subset of phenylalanine hydroxylase (PAH) mutations who have shown normalization of blood phenylalanine levels upon oral administration of the PAH cofactor tetrahydrobiopterin (BH₄). Several hypotheses have been put forward previously to explain the BH₄ responsiveness, but the molecular basis for the corrective effect(s) of BH₄ is not understood. The biochemical, kinetic and structural changes associated with fifteen BH₄-responsive mutations indicate a multifactorial basis for the responsiveness. The mutants show residual activity (>30 % of wild-type), and display various kinetic defects, including increased K_m (BH₄) and reduced cooperativity of substrate binding. For some mutants, BH₄ seems to function through stabilization and protection of the enzyme from inactivation and proteolytic degradation, thus being a true pharmacolological chaperon.