Role of cystathionine beta-synthase stability in pathogenesis of homocystinuria

Human cystathionine beta-synthase (CBS) is crucial in sulfur amino acid metabolism. Dysregulation of CBS has major effects, with overexpression in cancer and Down Syndrome leading to excess hydrogen sulfide and deficiency causing homocystinuria (HCU) due to homocysteine buildup. Understanding CBS biology is vital for grasping related diseases and processes like oxidative stress and aging.

CBS has a multi-domain structure with a heme-binding domain, a central catalytic core with a pyridoxal-5’-phosphate (PLP) cofactor, and a regulatory domain for binding S-adenosylmethionine (SAM) and forming oligomers. Changes in CBS structure upon SAM binding are still not fully understood, especially in multimeric CBS and its effects on enzyme activation and turnover.

Common missense CBS mutations causing HCU don't affect catalytic sites but lead to misfolded, unstable proteins. These misfolded proteins are often degraded by the ubiquitin-proteasome system (UPS). Proteasome inhibitors can rescue some CBS variants, suggesting alternative pathways might maintain different CBS mutants. Understanding these pathways can help target CBS misfolding for HCU treatment.

My PhD thesis aims to clarify the role of CBS oligomerization in protein stabilization, uncover mechanisms of CBS turnover in health and disease, and explore proteostasis in HCU. This could lead to new pharmacological methods to rescue mutant CBS folding, stability, and activity.