Key mechanisms of enzyme involved in rare metabolic disease identified

An international research team has published a study in the journal The FEBS Journal that significantly advances the knowledge of a rare hereditary metabolic disease: classical homocystinuria. The team was coordinated by the Liver Diseases and Computational Chemistry groups at the CIC bioGUNE research center, member of BRTA.

This genetically based disorder hinders the proper elimination of homocysteine, an amino acid that, when present at high concentrations, can cause complications in various organs and systems of the human body, including the vascular and nervous systems, eyes, and skeleton.

The research focused on a specific mutation, known as R336C, that affects the enzyme cystathionine beta-synthase (CBS), which is essential for metabolizing homocysteine. The study reveals that, contrary to previous assumptions, this variant preserves the enzyme’s overall structure nearly intact but displays abnormal flexibility that significantly reduces its ability to perform its biological function. This contributes to the accumulation of amino acids in the body.

One of the team’s main findings was uncovering how the mutation triggers a cascade of subtle structural changes that propagate over long distances, from its immediate surroundings to the amino acids near the cofactor pyridoxal phosphate (PLP, a derivative of vitamin B6), which is essential for enzymatic activity.

Instead of stabilizing its functional form, the mutated enzyme tends to disrupt communication between the cofactor and the catalytic site, favoring an inactive conformation. This explains the loss of catalytic efficiency without altering the protein’s overall three-dimensional structure.

Furthermore, it was observed that this mutation affects the intrinsic mobility of the so-called Bateman module, a region of the enzyme that is key to its regulation. Although the mutated enzyme can still assemble correctly, its dynamic changes tend to hinder substrate access to the cavity where the chemical reaction it is supposed to catalyze takes place.

The study, which also involved professionals from the CIBERehd biomedical research network, Qatar University, and the University of Verona, opens the door to new therapeutic strategies for individuals affected by this condition.

“This study provides one of the few three-dimensional structures of a human CBS enzyme mutant elucidated to date. The information obtained is relevant because it explains the causes of the catalytic dysfunction of the R336C variant, one of more than 200 pathogenic mutations described so far.

“Our work offers a different explanation from previous proposals that attributed the mutation to a denaturing effect (loss of three-dimensional structure) and the inability of the mutated enzyme to accommodate the PLP cofactor at its catalytic site. Our new data explains why these patients do not respond well to treatments based on pyridoxine (vitamin B6) supplementation and suggests which therapeutic strategies could be effective in carriers of this genomic alteration.

“Among the possible intervention strategies identified are the design of drugs that restore communication between the enzyme and the PLP cofactor, and personalized therapies aimed at restoring the dynamics of the Bateman module that regulates substrate access to the catalytic cavity,” explains Dr. Luis Alfonso Martínez de la Cruz, associate principal investigator of the Liver Diseases group at CIC bioGUNE.

This research highlights the importance of international scientific collaboration and the detailed study of rare diseases in continuing to advance toward more personalized and effective medicine.

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CIC bioGUNE