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

Classical homocystinuria (HCU) is the most common loss-of-function
inborn error of sulfur amino acids 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 non-functional aggregates or to undergo proteasome-dependent degradation.
Thus correction of CBS misfolding represents an alternative therapeutic approach
for HCU. In this review, we summarize the complex nature of CBS, its multidomain
architecture, the interplay between the three cofactors required for CBS function (heme, pyridoxal-
5’-phosphate (PLP) and S-adenosyl-L-methionine) as well as the intricate allosteric regulatory
mechanism only recently explained thanks to advances in CBS crystallography. While roughly half of
the patients responds 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 increased
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.