An international research team led by CIC bioGUNE has advanced understanding of classical homocystinuria, a rare genetic disorder that impairs the breakdown of homocysteine, causing systemic health issues. Published in The FEBS Journal, the study focuses on the R336C mutation in the CBS enzyme. Contrary to previous beliefs that this mutation denatures the enzyme, researchers found that the enzyme's structure remains mostly intact but exhibits abnormal flexibility. This impairs communication between its cofactor (vitamin B6 derivative) and catalytic site, reducing enzymatic function.

Key findings include:

The R336C mutation causes subtle structural shifts affecting the PLP cofactor’s function.

It disrupts enzyme activity not by structural collapse but by altering its internal dynamics.

The Bateman module, crucial for enzyme regulation, becomes overly mobile, hindering substrate access.

These insights explain poor patient response to vitamin B6 therapy and suggest new treatment strategies, such as drugs to restore cofactor interaction or modulate enzyme flexibility. The study emphasizes the value of international collaboration in rare disease research and the development of personalized medicine.