Potential Pharmacological Chaperones for Cystathionine Beta-Synthase-Deficient Homocystinuria

Classical homocystinuria (HCU) is the most common loss-of-function inborn
error of sulfur amino acid metabolism. HCU is caused by a deficiency in enzymatic
degradation of homocysteine, a toxic intermediate of methionine transformation
to cysteine, chiefly due to missense mutations in the cystathionine betasynthase
(CBS) gene. As with many other inherited disorders, the pathogenic
mutations do not target key catalytic residues, but rather introduce structural
perturbations leading to an enhanced tendency of the mutant CBS to misfold
and either to form nonfunctional aggregates or to undergo proteasome-dependent
degradation. Correction of CBS misfolding would represent an alternative therapeutic
approach for HCU. In this review, we summarize the complex nature of
CBS, its multi-domain architecture, the interplay between the three cofactors
required for CBS function [heme, pyridoxal-50-phosphate (PLP), and
S-adenosylmethionine (SAM)], as well as the intricate allosteric regulatory
mechanism only recently understood, thanks to advances in CBS crystallography.
While roughly half of the patients respond to treatment with a PLP precursor
pyridoxine, many studies suggested usefulness of small chemicals, such as
chemical and pharmacological chaperones or proteasome inhibitors, rescuing
mutant CBS activity in cellular and animal models of HCU. Non-specific chemical
chaperones and proteasome inhibitors assist in mutant CBS folding process
and/or prevent its rapid degradation, thus resulting in increased steady-state levels
of the enzyme and CBS activity. Recent interest in the field and available
structural information will hopefully yield CBS-specific compounds, by using
high-throughput screening and computational modeling of novel ligands, improving
folding, stability, and activity of CBS mutants.