Targeted Proteomic Approaches for Natural Product Biosynthetic Pathway Discovery

In research funded by the National Institutes of Health, we are currently developing a novel infrared laser approach to natural product biosynthetic pathway discovery, involving selective dissociation of active-site peptides containing the phosphopantetheine (Ppant) prosthetic group, which has high IR absorptivity.  A combination of innovative MS/MS approaches is essential for complete de novo sequencing of such peptides from non-sequenced organisms such as dinoflagellates that produce the elusive but highly clinically relevant brevetoxins and the anti-toxin brevenal, currently in development for treatment of respiratory diseases such as asthma and cystic fibrosis.  We have recently demonstrated that selective infrared multiphoton dissociation (IRMPD) also occurs for cystine oxidized peptides. Our selective IRMPD approach allows facile differentiation of S-sulfonated peptides from unmodified peptides, enabling the facile discovery of this important modification.