Potential Pharmacological Chaperones for Cystathionine Beta-Synthase-Deficient Homocystinuria

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