Structure and Oxidative Folding of AAI, the Major Alfa-Amylase Inhibitor From Amaranth Seeds

• Published in: Frontiers in chemistry 2020-03, Vol.8, p.180-180
• Main Authors: Juhász, János, Gáspári, Zoltán, Pongor, Sándor
• Format: Article
• Language: English
• Subjects: AAI; Amaranth alpha-amylase inhibitor; Amaranthus hypocondriacus; Chemistry; folding intermediate; oxidative folding; vicinal disulfide
• ISSN: 2296-2646; 2296-2646
• DOI: 10.3389/fchem.2020.00180

AAI, the major alpha-amylase inhibitor (AAI) present in the seeds of the Mexican crop plant is a 32-residue-long polypeptide with three disulfide bridges. Its structure is most closely related to the plant amylase inhibitor subfamily of knottins characterized by a topological knot formed by one disulfide bridge threading through a loop formed by the peptide chain as well as a short three-stranded beta sandwich core. AAI is specific against insect amylases and does not act on corresponding human or mammalian enzymes. It was found that the oxidative folding of AAI seems to follow a hirudine-like pathway with many non-native intermediates, but notably it proceeds through a major folding intermediate (MFI) that contains a vicinal disulfide bridge. Based on a review of the pertinent literature, the known vicinal disulfides in native proteins as well as well as the network of disulfide interchanges, we propose that MFI is a kinetic trap corresponding to a compact molten globule-like state which constrains the peptide chain to a smaller number of conformations that in turn can be rapidly funneled toward the native state.