Citation
Jambunathan, K., Watson, D. S., Endsley, A. N., Kodukula, K., & Galande, A. K. (2012). Comparative analysis of the substrate preferences of two post-proline cleaving endopeptidases, prolyl oligopeptidase and fibroblast activation protein α. FEBS letters, 586(16), 2507-2512.
Abstract
Post-proline cleaving peptidases are promising therapeutic targets for neurodegenerative diseases, psychiatric conditions, metabolic disorders, and many cancers. Prolyl oligopeptidase (POP; E.C. 3.4.21.26) and fibroblast activation protein α (FAP; E.C. 3.4.24.B28) are two post-proline cleaving endopeptidases with very similar substrate specificities. Both enzymes are implicated in numerous human diseases, but their study is impeded by the lack of specific substrate probes. We interrogated a combinatorial library of proteolytic substrates and identified novel and selective substrates of POP and FAP. These new sequences will be useful as probes for fundamental biochemical study, scaffolds for inhibitor design, and triggers for controlled drug delivery.
Highlights
► Substrates of prolyl oligopeptidase (POP) and fibroblast activation protein α (FAP).
► Bias against charged residues at the P1’ and P2’ positions for POP-specific substrates.
► FAP-specific substrates preferred charged residues at the P1’ and P2’ positions.
► No serine or threonine residues at P1’ and P2’ positions for FAP-specific substrates.
► In synthetic format, some physiologic substrates of FAP are also cleaved by POP.
