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Proc Natl Acad Sci U S A. 2015 May 26;112(21):6601-6. doi: 10.1073/pnas.1424638112. Epub 2015 May 11.

N-lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids.

Author information

1
Divisions of Molecular Oncology.
2
Cell Biology II, and.
3
Biochemistry, and.
4
Proteomics Facility, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and.
5
Laboratory of Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
6
Divisions of Molecular Oncology, k.vd.wetering@nki.nl.

Abstract

Despite technological advances in metabolomics, large parts of the human metabolome are still unexplored. In an untargeted metabolomics screen aiming to identify substrates of the orphan transporter ATP-binding cassette subfamily C member 5 (ABCC5), we identified a class of mammalian metabolites, N-lactoyl-amino acids. Using parallel protein fractionation in conjunction with shotgun proteomics on fractions containing N-lactoyl-Phe-forming activity, we unexpectedly found that a protease, cytosolic nonspecific dipeptidase 2 (CNDP2), catalyzes their formation. N-lactoyl-amino acids are ubiquitous pseudodipeptides of lactic acid and amino acids that are rapidly formed by reverse proteolysis, a process previously considered to be negligible in vivo. The plasma levels of these metabolites strongly correlate with plasma levels of lactate and amino acid, as shown by increased levels after physical exercise and in patients with phenylketonuria who suffer from elevated Phe levels. Our approach to identify unknown metabolites and their biosynthesis has general applicability in the further exploration of the human metabolome.

KEYWORDS:

ABCC5; MRP5; physical exercise; unknown metabolites; untargeted metabolomics

PMID:
25964343
PMCID:
PMC4450436
DOI:
10.1073/pnas.1424638112
[Indexed for MEDLINE]
Free PMC Article

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