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Metabolomics annotates ABHD3 as a physiologic regulator of medium-chain phospholipids

Nature Chemical Biology volume 7, pages 763–765 (2011)Cite this article

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Abstract

All organisms, including humans, possess a huge number of uncharacterized enzymes. Here we describe a general cell-based screen for enzyme substrate discovery by untargeted metabolomics and its application to identify the protein α/β-hydrolase domain–containing 3 (ABHD3) as a lipase that selectively cleaves medium-chain and oxidatively truncated phospholipids. Abhd3−/− mice possess elevated myristoyl (C14)-phospholipids, including the bioactive lipid C14-lysophosphatidylcholine, confirming the physiological relevance of our substrate assignments.

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Figure 1: Metabolomic profiling of an enzyme library identifies metabolites altered by ABHD3 overexpression.
Figure 2: Abhd3−/− mice possess elevated C14-PCs.

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Acknowledgements

We gratefully acknowledge D. Bachovchin and S. Ji (both at The Scripps Research Institute) for providing the serine hydrolase expression plasmids, A. Saghatelian for the fatty acyl–CoA extraction protocol, and S. Palmer for the Matlab script used to generate Figure 2a. This work was supported by the US National Institutes of Health (CA132630) and the Skaggs Institute for Chemical Biology.

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Authors and Affiliations

  1. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA

    Jonathan Z Long, Justin S Cisar, David Milliken, Sherry Niessen, Chu Wang & Benjamin F Cravatt

  2. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA

    Jonathan Z Long, Justin S Cisar, David Milliken, Sherry Niessen, Chu Wang & Benjamin F Cravatt

  3. Center for Physiological Proteomics, The Scripps Research Institute, La Jolla, California, USA

    Sherry Niessen

  4. Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA

    Sunia A Trauger & Gary Siuzdak

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  1. Jonathan Z Long
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  8. Benjamin F Cravatt
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Contributions

J.Z.L. and B.F.C. designed the experiments, analyzed the data and wrote the manuscript. J.Z.L. and J.S.C. synthesized C14 PCs. J.Z.L. and D.M. performed the experiments. S.N. generated and analyzed the untargeted proteomic data. C.W. generated the R script used for screening chromatograms from cellular metabolomes. S.A.T. and G.S. assisted in metabolite identification and tandem MS experiments.

Corresponding author

Correspondence to Benjamin F Cravatt.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Results (PDF 4680 kb)

Supplementary Table 1

Spectral counts using untargeted MS-based proteomics, as described in the Supplementary Methods, of all proteins detected in brain membranes of Abhd3+/+ or Abhd3−/− mice. (XLS 642 kb)

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Long, J., Cisar, J., Milliken, D. et al. Metabolomics annotates ABHD3 as a physiologic regulator of medium-chain phospholipids. Nat Chem Biol 7, 763–765 (2011). https://doi.org/10.1038/nchembio.659

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