Disulfide bridges in gel-forming mucin polymers

Gel-forming mucins, such as MUC5AC and MUC5B, are large glycoproteins that polymerize to form the structural framework of the mucus gel [1]. This polymerization occurs through the formation of intermolecular disulfide bridges between cysteine-rich domains located at the N- and C-termini of the mucin monomers [2]. These disulfide bonds are essential for the viscoelastic properties of mucus, which are necessary for effective mucociliary clearance and protection of the underlying epithelium [3]. In diseases like cystic fibrosis, COPD, and asthma, the mucus becomes excessively thick and difficult to clear due to increased mucin density and oxidative stress-induced cross-linking [4]. Mucolytic drugs, such as N-acetylcysteine (NAC), target these disulfide bridges by providing free thiol groups that reduce the covalent bonds, thereby breaking the large polymers into smaller, less viscous fragments [5]. This reduction in viscosity facilitates the clearance of mucus from the airways, though it must be balanced against the potential for airway irritation or disruption of the protective barrier [5]. Sources: [1] Thornton DJ, et al. Annu Rev Physiol. 2008;70:459-86. [2] Ridley C, et al. Biochem J. 2003;373(Pt 2):389-97. [3] Fahy JV, Dickey BF. N Engl J Med. 2010;363(23):2233-47. [4] Hansson GC. Nat Rev Gastroenterol Hepatol. 2020;17(9):539-54. [5] Sadowska AM. Paediatr Respir Rev. 2012;13(1):59-64.

Other names

Mucin disulfide bondsInter-mucin disulfide linkagesCysteine-mediated mucin cross-linksMucin polymers

Reduction of intermolecular disulfide bonds via thiol-disulfide exchange, leading to the fragmentation of high-molecular-weight mucin polymers and a subsequent decrease in mucus viscosity.