Inspired largely by the role of the posttranslationally modified amino acid dopa (DOPA) in mussel adhesion, catechol functional groups have become commonplace in medical adhesives, tissue scaffolds, and advanced smart polymers. Yet, the complex redox chemistry of catechol groups complicates cross-link regulation, hampering fabrication and the long-term stability/performance of mussel-inspired polymers. Here, we investigated the various fates of DOPA residues in proteins comprising mussel byssus fibers before, during, and after protein secretion. Utilizing a combination of histological staining and confocal Raman spectroscopy on native tissues, as well as peptide-based cross-linking studies, we have identified at least two distinct DOPA-based cross-linking pathways during byssus fabrication, achieved by oxidative covalent cross-linking or formation of metal coordination interactions under reducing conditions, respectively. We suggest that these end states are spatiotemporally regulated by the microenvironments in which the proteins are stored prior to secretion, which are retained after formation—in particular, due to the presence of reducing moieties. These findings provide physicochemical pathways toward greater control over properties of synthetic catechol-based polymers and adhesives.

Highlights Canagliflozin constrains cell proliferation in the absence of glucose. Canagliflozin modulates mitochondrial respiration. Canagliflozin impairs glutamine-mediated anaplerosis through the citric acid cycle. Canagliflozin mediates antiproliferative response through inhibition of glutamine metabolism.