New Insights into the Enzymatic Mechanisms Behind Rare Metabolic Disorder

An international research team has made significant advancements in understanding a rare hereditary metabolic disease called classical homocystinuria, as published in The FEBS Journal. The study focused on a specific mutation, R336C, in the enzyme cystathionine beta-synthase (CBS), which plays a crucial role in metabolizing the amino acid homocysteine. Elevated homocysteine levels can lead to various health complications affecting the vascular, nervous, ocular, and skeletal systems.

The researchers discovered that, contrary to earlier assumptions, this mutation does not dismantle the enzyme's overall structure. Instead, it causes abnormal flexibility that hampers the enzyme's function, leading to amino acid accumulation. The mutation triggers subtle, long-range structural changes that disrupt communication between the enzyme's active sites, especially near the cofactor pyridoxal phosphate (PLP), a derivative of vitamin B6 vital for enzymatic activity.

This disruption impairs the enzyme's ability to perform its biological function efficiently, as the mutated enzyme tends to favor inactive forms. Additionally, the mutation affects the intrinsic mobility of the Bateman module, a regulatory region of the enzyme that influences substrate access. Although the enzyme can assemble correctly, its altered dynamics hinder substrate entry, compounding the functional deficiency.

The study’s findings shed new light on why patients with this mutation often do not respond well to vitamin B6 supplements and suggest alternative therapeutic approaches. These include designing drugs that restore proper communication between the enzyme and the PLP cofactor or therapies aimed at correcting the enzyme's dynamic regulation.

This research was conducted with collaborators from the CIBERehd biomedical network, Qatar University, and the University of Verona. It provides crucial structural insights into how specific mutations cause enzyme dysfunction, paving the way for personalized treatment strategies for those affected by this condition.

Overall, the study highlights the importance of detailed molecular investigations in understanding rare diseases and developing targeted therapies, emphasizing the value of international scientific collaboration in advancing personalized medicine.