Discovery metabolite profiling

Fig. 5 Discovery metabolite profiling of brain tissue, where mass ion intensity ratios (FAAH / / FAAH+/+) of metabolites are presented on three-dimensional surface plots. Global view of the relative levels of metabolites in FAAH / and FAAH+/+ brains, plotted over a mass range of 200-1,200 m/z and liquid chromatography retention times of 0-105 min (plot shown for negative ionization mode). FAAH / brains possessed highly elevated levels of A-acyl ethanolamines (NAEs) (lipid group 4) and an unknown class of lipids (group 5), identified as A-acyl taurines (NATs). Other lipids, e.g., free fatty acids (group 1), phospholipids (group 2), and ceramides (group 3) were unaltered in these samples...

But are there other endogenous substrates for this enzyme A method based on separation techniques and mass spectrometry has been developed to identify endogenous substrates of enzymes by analysis of metabolomes from wild-type and enzyme-inactivated organisms [316], Indeed, the accumulation of metabolites resulting from the inactivation of the enzyme would be considered candidate endogenous substrates for this enzyme. This method based on comparative metabolomics is called discovery metabolites profiling (DMP). 

One of the best tools for metabolite profiling is the hybrid QTRAP MS/MS system (Applied Biosystems).119-121 While the hybrid QTRAP MS/MS was initially considered a premier tool for metabolite identification, it has more recently been seen as a tool for quantitation and metabolite profiling. Li et al.122 described the use of a hybrid QTRAP MS/MS system for discovery PK assays plus metabolite profiling in the same analytical procedure. Because QTRAP MS/MS may be used as a triple quadrupole MS system, it can be used as part of a quantitative HPLC/MS/MS system. Because QTRAP MS/MS also has linear ion trap capabilities, it can be used for metabolite screening and characterization—essentially it combines the capabilities of a triple quadrupole mass spectrometer and a linear ion trap mass spectrometer. 

R. Xu, E. Duchoslav, A. Aparicio, E. B. Jones, and D. B. Kassel, Streamlined approaches to metabolic stability assessment and metabolite profiling in drug discovery, in 51st ASMS Conference on Mass Spectrometry and Allied Topics, Montreal, Canada, Book of Abstracts, ASUS, 2003. 

Phenotypic taxonomy and metabolite profiling in microbial drug discovery,... 

Superior full-scan duty cycle of the ion trap allowed Kantharaj et al. [63,309,310] to acquire on-the-fly MS/MS data for all the ions formed over a predetermined threshold (data-dependent MS/MS scan). For discovery compounds, which showed more than 20% metabolic turnover after 15 min of incubation, metabolite profiling evaluation was performed by interpreting the data-dependent MS/MS scans. Interpretation of the MS/MS scans involved comparison of the parent ion fragments with that of the metabolites. Once the structural elucidation was complete, data were discussed with the discovery teams and/or medicinal chemists to modify the structure for metabolic stability. 

In the drug discovery stage, most drug metabolite profiling studies are conducted with nonradiolabeled lead compounds by using LC/UV/MS... 

LC—MS in Endogenous Metabolite Profiling and Small-Molecule Biomarker Discovery... 

Optimization in Drug Discovery, ed. Z. Yan and G.W. Caldwell, Humana Press Inc., Totowa, N.J., 2004 R 240 W.-N. Wu and L.A. McKown, In vitro Drug Metabolite Profiling Using Hepatic S9 and Human Liver Microsomes , p. 163... 

---