Sunflower trypsin inhibitor-1: chemical v. biological synthesis

Diverse gene-encoded cyclic peptides are produced by species from all three domains of life. The 14-residue, head-to-tail cyclized plant peptide, SFTI-1 (Sunflower Trypsin Inhibitor 1) [1] (Figure 1) has attracted much attention due to its great stability and capability to potently inhibit trypsin (Ki 0.1 nM) as well as the epithelial serine protease matriptase (Ki 0.92 nM) [2], giving it exciting promise as a drug lead and a protein engineering scaffold [2]. Although peptides such as SFTI-1 are routinely produced by chemical synthesis, the biological mechanisms that enable biosynthesis of ribosomally synthesized cyclic peptides are largely unknown. Recently Mylne et al. described the biosynthetic origin of SFTI-1 and a related peptide SFT-L1 [3]. Both emerge from seed storage protein precursors PawS1 and PawS2, respectively, using each seed protein’s own maturing protease for their release [3]. We used transgenic constructs in the model plant Arabidopsis thaliana combined with proteomics and MALDI mass spectrometry to study this unusual dual-fate for PawS1 and identified the residues that are critical for SFTI-1 maturation and cyclisation [3]. Here we compare best practice for chemical synthesis of SFTI-1 with how plants biologically create the same product.