Metabolomics, pathway regulation, and pathway discovery

Abstract

Metabolomics is a data-based research strategy, the aims of which are to identify biomarker pictures of metabolic systems and metabolic perturbations and to formulate hypotheses to be tested. It involves the assay by mass spectrometry or NMR of many metabolites present in the biological system investigated. In this minireview, we outline studies in which metabolomics led to useful biomarkers of metabolic processes. We also illustrate how the discovery potential of metabolomics is enhanced by associating it with stable isotopic techniques.

FIGURE 1.

A, Golden Rule of scientific investigation. B, strategy and outcomes of metabolomic studies.

FIGURE 2.

Parallel syntheses of glutathione and ophthalmate by the same enzymes. GCS, γ-glutamylcysteine synthetase; GS, glutathione synthetase; 2AB, 2-aminobutyrate.

FIGURE 3.

A, formation of adducts by spontaneous reaction of pyruvate (PYR) and aminooxyacetate (AOA). B, mercaptopicolinate (MPA) and pyruvate.

FIGURE 4.

A, scheme of the citric acid cycle and lipogenesis via ATP-citrate lyase. The scheme emphasizes (i) the reversibility of the conversion of citrate to isocitrate (ICIT) and α-ketoglutarate via aconitase and isocitrate dehydrogenase (ICDH) and (ii) the set of reactions by which carbons 4 and 5 of glutamine are used for fatty acid (FA) and sterol synthesis in some mammalian cells (red arrows). B, scheme of the catabolism of 4-hydroxy acids with at least five carbons using 4-hydroxy[3,4-¹³C₂]nonanoate as an example (modified from Ref. 33). Carbons 3 and 4 of the substrate are colored red and green, respectively, to facilitate the tracing of their fates through pathways A and B. Pathway A includes 4-phosphononanoyl-CoA. Note that the doubly labeled substrate forms acetyl-CoA, part of which is doubly labeled (M2) via pathway A and singly labeled (M1) via pathway B. Formate, derived from carbon 3 of the substrate, is formed via pathway B.