Cysteamine revisited: repair of arginine to cysteine mutations.
Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.
['Gallego-Villar|L|L|', 'Hannibal|Luciana|L|', 'Häberle|J|J|', 'Thöny|B|B|', 'Ben-Omran|T|T|', 'Nasrallah|G K|GK|', 'Dewik|Al-N|AN|', 'Kruger|W D|WD|', 'Blom|H J|HJ|']
D000818:Animals D053318:Apolipoprotein E3 D001120:Arginine D001123:Argininosuccinate Lyase D003541:Cystathionine beta-Synthase D003543:Cysteamine D003545:Cysteine D003554:Cystinosis D006706:Homeostasis D006801:Humans D006863:Hydrogen-Ion Concentration D008968:Molecular Conformation D009154:Mutation D020125:Mutation, Missense D010084:Oxidation-Reduction D013438:Sulfhydryl Compounds D013925:Thromboplastin
Cysteamine Aminothiols Cysteine residue modification Repair Arg to Cys mutations