The Department of Biomedicine

BBB seminar: Aurora Martínez

Mechanisms underlying responsiveness to cofactor/vitamin supplementation therapy in certain enzyme deficiencies

Main content

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 Km (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.