The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway

Robert S. Banh, Esther S. Kim, Quentin Spillier, Douglas E. Biancur, Keisuke Yamamoto, Albert S. W. Sohn, Guangbin Shi, Drew R. Jones, Alec C. Kimmelman and Michael E. Pacold ()
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Robert S. Banh: New York University Langone Health
Esther S. Kim: New York University Langone Health
Quentin Spillier: New York University Langone Health
Douglas E. Biancur: New York University Langone Health
Keisuke Yamamoto: New York University Langone Health
Albert S. W. Sohn: New York University Langone Health
Guangbin Shi: New York University Langone Health
Drew R. Jones: New York University Langone Health
Alec C. Kimmelman: New York University Langone Health
Michael E. Pacold: New York University Langone Health

Nature, 2021, vol. 597, issue 7876, 420-425

Abstract: Abstract Oxygen is critical for a multitude of metabolic processes that are essential for human life. Biological processes can be identified by treating cells with 18O2 or other isotopically labelled gases and systematically identifying biomolecules incorporating labeled atoms. Here we labelled cell lines of distinct tissue origins with 18O2 to identify the polar oxy-metabolome, defined as polar metabolites labelled with 18O under different physiological O2 tensions. The most highly 18O-labelled feature was 4-hydroxymandelate (4-HMA). We demonstrate that 4-HMA is produced by hydroxyphenylpyruvate dioxygenase-like (HPDL), a protein of previously unknown function in human cells. We identify 4-HMA as an intermediate involved in the biosynthesis of the coenzyme Q10 (CoQ10) headgroup in human cells. The connection of HPDL to CoQ10 biosynthesis provides crucial insights into the mechanisms underlying recently described neurological diseases related to HPDL deficiencies1–4 and cancers with HPDL overexpression5.

Date: 2021
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DOI: 10.1038/s41586-021-03865-w

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