Mechanistic peptidomics: Factors that dictate specificity in the formation of endogenous peptides in human milk

Andres Guerrero, David C. Dallas, Stephanie Contreras, Sabrina Chee, Evan A. Parker, Xin Sun, Lauren Dimapasoc, Daniela Barile, J. Bruce German, Carlito B Lebrilla

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


An extensive mass spectrometry analysis of the human milk peptidome has revealed almost 700 endogenous peptides from 30 different proteins. Two in-house computational tools were created and used to visualize and interpret the data through both alignment of the peptide quasi-molecular ion intensities and estimation of the differential enzyme participation. These results reveal that the endogenous proteolytic activity in the mammary gland is remarkably specific and well conserved. Certain proteins-not necessarily the most abundant ones-are digested by the proteases present in milk, yielding endogenous peptides from selected regions. Our results strongly suggest that factors such as the presence of specific proteases, the position and concentration of cleavage sites, and, more important, the intrinsic disorder of segments of the protein drive this proteolytic specificity in the mammary gland. As a consequence of this selective hydrolysis, proteins that typically need to be cleaved at specific positions in order to exert their activity are properly digested, and bioactive peptides encoded in certain protein sequences are released. Proteins that must remain intact in order to maintain their activity in the mammary gland or in the neonatal gastrointestinal tract are unaffected by the hydrolytic environment present in milk. These results provide insight into the intrinsic structural mechanisms that facilitate the selectivity of the endogenous milk protease activity and might be useful to those studying the peptidomes of other biofluids.

Original languageEnglish (US)
Pages (from-to)3343-3351
Number of pages9
JournalMolecular and Cellular Proteomics
Issue number12
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Analytical Chemistry


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