Melenovská P, Kopecká J, Krijt J, Hnízda A, Raková K, Janošík M, Wilcken B, Kožich V. Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate. J Inherit Metab Dis. 2014 Oct 21. [Epub ahead of print]
Mutations in the CBS gene cause classical homocystinuria (cystathionine beta-synthase deficiency). For patients who do not respond to pyridoxine, CBS deficiency requires pharmacological treatment with betaine and folates, as well as highly demanding nutritional management. Previous research has shown that many of the pathogenic mutations in CBS cause protein misfolding, and that correct folding of the enzyme requires the co-translational presence of heme or related metalloporphyrins.
Melenovská et al test three compounds with chaperone-like activity, and describe the rescue of some CBS mutations by heme arginate in mammalian cells and human fibroblasts. Interestingly, while some of the heme-responsive mutations are thought to disrupt the heme-binding pocket of the enzyme, others are located distally to it; the authors postulate that, for these mutants, oversaturation with heme may induce favourable allosteric changes.
Unfortunately, as the authors note, the direct clinical applications of these findings are limited, as heme arginate requires intravenous administration and carries a significant risk of toxicity. On the other hand, these findings do point to the heme-binding pocket of the CBS enzyme as a promising target for chaperone therapy.