Targeting Cystathionine Beta-Synthase Misfolding in Homocystinuria by Small Ligands: State of the Art and Future Directions

<div>Classical homocystinuria (HCU) is the most common loss-of-function</div><div>inborn error of sulfur amino acids metabolism. HCU is caused by a deficiency in</div><div>enzymatic 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 mutations</div><div>do not target key catalytic residues, but rather introduce structural perturbations</div><div>leading to an enhanced tendency of the mutant CBS to misfold and either to</div><div>form non-functional aggregates or to undergo proteasome-dependent degradation.</div><div>Thus correction of CBS misfolding represents an alternative therapeutic approach</div><div>for HCU. In this review, we summarize the complex nature of CBS, its multidomain</div><div>architecture, the interplay between the three cofactors required for CBS function (heme, pyridoxal-</div><div>5’-phosphate (PLP) and S-adenosyl-L-methionine) as well as the intricate allosteric regulatory</div><div>mechanism only recently explained thanks to advances in CBS crystallography. While roughly half of</div><div>the patients responds to treatment with a PLP precursor pyridoxine, many studies suggested usefulness</div><div>of small chemicals, such as chemical and pharmacological chaperones or proteasome inhibitors,</div><div>rescuing mutant CBS activity in cellular and animal models of HCU. Non-specific chemical chaperones</div><div>and proteasome inhibitors assist in mutant CBS folding process and/or prevent its rapid degradation,</div><div>thus resulting in increased steady state levels of the enzyme and CBS activity. Recent increased</div><div>interest in the field and available structural information will hopefully yield CBS-specific compounds</div><div>by using high-throughput screening and computational modeling of novel ligands improving folding,</div><div>stability and activity of CBS.</div>