Journal
NATURE
Volume 597, Issue 7876, Pages 420-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03865-w
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Funding
- Cancer Center Support Grant at the Laura and Isaac Perlmutter Cancer Center [P30CA016087]
- Damon Runyon Cancer Research Foundation [DRG-2348-18, DRR 63-20]
- Wallonie-Bruxelles International (WBI) fellowship
- Ruth L. Kirschstein Institutional National Research Service Award [T32 CA009161, NCI F99/K00, F99 CA245822]
- Uehara Memorial Foundation Research Fellowship
- National Cancer Institute [R01CA157490, R01CA188048, P01CA117969, R35CA232124]
- ACS Research Scholar [RSG-13-298-01-TBG]
- NIH [R01GM095567]
- Lustgarten Foundation
- Stand Up to Cancer (SU2C)
- Entertainment Industry Foundation
- Mary Kay Foundation Cancer Research Grant [017-32]
- Shifrin-Myers Breast Cancer Discovery Fund at NYU
- Hearst Foundation [V2017-004]
- NCI K22 Career Transition Award [K22CA212059]
- Tara Miller Melanoma Foundation - MRA Young Investigator Award [668365]
- Harry J. Lloyd Trust
- Max Raskin
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The study reveals a previously unknown protein HPDL's involvement in the biosynthesis of CoQ10, providing crucial insights into diseases related to HPDL deficiencies and cancers with HPDL overexpression.
Oxygen is critical for a multitude of metabolic processes that are essential for human life. Biological processes can be identified by treating cells with O-18(2) or other isotopically labelled gases and systematically identifying biomolecules incorporating labeled atoms. Here we labelled cell lines of distinct tissue origins with O-18(2) to identify the polar oxy-metabolome, defined as polar metabolites labelled with O-18 under different physiological O-2 tensions. The most highly O-18-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 deficiencies(1-4) and cancers with HPDL overexpression(5).
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