Publications

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

  Banh R.S., Kim E.S., Spillier Q., Biancur D.E., Yamamoto K., Sohn A.S.W., Shi G., Jones D.R., Kimmelman A.C., Pacold M.E.

  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 w ... >> More

  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 deficiencies^1-4 and cancers with HPDL overexpression⁵. << Less

  Nature 597:420-425(2021) [PubMed] [EuropePMC]

• Biosynthesis of L-p-hydroxyphenylglycine, a non-proteinogenic amino acid constituent of peptide antibiotics.

  Hubbard B.K., Thomas M.G., Walsh C.T.

  <h4>Background</h4>The non-proteinogenic amino acid p-hydroxyphenylglycine is a crucial component of certain peptidic natural products synthesized by a non-ribosomal peptide synthetase mechanism. In particular, for the vancomycin group of antibiotics p-hydroxyphenylglycine plays a structural role ... >> More

  <h4>Background</h4>The non-proteinogenic amino acid p-hydroxyphenylglycine is a crucial component of certain peptidic natural products synthesized by a non-ribosomal peptide synthetase mechanism. In particular, for the vancomycin group of antibiotics p-hydroxyphenylglycine plays a structural role in formation of the rigid conformation of the central heptapeptide aglycone in addition to being the site of glycosylation. Initial labeling studies suggested tyrosine was a precursor of p-hydroxyphenylglycine but the specific steps in p-hydroxyphenylglycine biosynthesis remained unknown. Recently, the sequencing of the chloroeremomycin gene cluster from Amycolatopsis orientalis gave new insights into the biosynthetic pathway and allowed for the prediction of a four enzyme pathway leading to L-p-hydroxyphenylglycine from the common metabolite prephenate.<h4>Results</h4>We have characterized three of the four proposed enzymes of the L-p-hydroxyphenylglycine biosynthetic pathway. The three enzymes are encoded by open reading frames (ORFs) 21, 22 and 17 (ORF21: [PCZA361.1, O52791, CAA11761]; ORF22: [PCZA361. 2, O52792, CAA11762]; ORF17: [PCZA361.25, O52815, CAA11790]), of the chloroeremomycin biosynthetic gene cluster and we show they have p-hydroxymandelate synthase, p-hydroxymandelate oxidase and L-p-hydroxyphenylglycine transaminase activities, respectively.<h4>Conclusions</h4>The L-p-hydroxyphenylglycine biosynthetic pathway shown here is proposed to be the paradigm for how this non-proteinogenic amino acid is synthesized by microorganisms incorporating it into peptidic natural products. This conclusion is supported by the finding of homologs for the four L-p-hydroxyphenylpyruvate biosynthetic enzymes in four organisms known to synthesize peptidic natural products that contain p-hydroxyphenylglycine. Three of the enzymes are proposed to function in a cyclic manner in vivo with L-tyrosine being both the amino donor for L-p-hydroxyphenylglycine and a source of p-hydroxyphenylpyruvate, an intermediate in the biosynthetic pathway. << Less

  Chem. Biol. 7:931-942(2000) [PubMed] [EuropePMC]

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