Cysteamine revisited: repair of arginine to cysteine mutations

Abstract

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.

Keywords: Aminothiols; Cysteamine; Cysteine residue modification; Repair Arg to Cys mutations.

Figure 1. Strategy of cysteine residues modification in proteins by aminothiols

Postulated compounds formed by L-cysteine (orange) and aminothiol compounds interactions: A) cysteamine and B) MEG (mercaptoethylguanidine). L-lysine (C) and L-arginine (D) structures. The guanidine moiety is highlighted in green. Figure adapted from Mendes et al 2015.

Figure 2. Biosynthesis and fates of cysteamine

Endogenous production of cysteamine occurs during degradation of coenzyme A, when pantothenic acid is formed. Vanin catalyzes the hydrolysis of pantetheine into pantothenic acid and cysteamine. Cysteamine is highlighted in a blue rectangle. Cysteamine as well as cysteine can be converted into hypotaurine, which is oxidized into taurine. Less than 3% of cysteamine administrated has been postulated to be converted into S-methylcysteamine by a methyltransferase, and consequently metabolized into methanethiol and acetamide by cytochrome P450. Successively, another methyltransferase converts methanethiol into dimethylsulfide (Gahl et al 1985).

Figure 3. The mechanisms of actions of cysteamine in various diseases

Under different conditions cysteamine can exert a wide range of actions: as an antioxidant; changing gene expression; changing enzymatic activity and targeting Arg to Cys mutants (highlighted in an orange rectangle). NAFLD (non-alcoholic fatty liver disease); BDNF (brain-derived neurotrophic factor); Atg5 (autophagy related 5). Figure adapted from Besouw et al 2013.