Mechanistic Details of Early Steps in Coenzyme Q Biosynthesis Pathway in Yeast.
Coenzyme Q (Q) is a redox lipid that is central for the energetic metabolism of eukaryotes. The biosynthesis of Q from the aromatic precursor 4-hydroxybenzoic acid (4-HB) is understood fairly well. However, biosynthetic details of how 4-HB is produced from tyrosine remain elusive. Here, we provide key insights into this long-standing biosynthetic problem by uncovering molecular details of the first and last reactions of the pathway in the yeast Saccharomyces cerevisiae, namely the deamination of tyrosine to 4-hydroxyphenylpyruvate by Aro8 and Aro9, and the oxidation of 4-hydroxybenzaldehyde to 4-HB by Hfd1. Inactivation of the HFD1 gene in yeast resulted in Q deficiency, which was rescued by the human enzyme ALDH3A1. This suggests that a similar pathway operates in animals, including humans, and led us to propose that patients with genetically unassigned Q deficiency should be screened for mutations in aldehyde dehydrogenase genes, especially ALDH3A1.
Université Grenoble Alpes, Laboratoire Technologies de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble (TIMC-IMAG), 38000 Grenoble, France; Centre National de Recherche Scientifique (CNRS), TIMC-IMAG, 38000 Grenoble, France.
Laurie-Anne
LA
Payet
CEA-Grenoble, DRF-BIG-CBM, UMR5249, 38000 Grenoble, France.
Mélanie
M
Leroux
CEA-Grenoble, DRF-BIG-CBM, UMR5249, 38000 Grenoble, France.
John C
JC
Willison
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan.
Akio
A
Kihara
Université Grenoble Alpes, Laboratoire Technologies de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble (TIMC-IMAG), 38000 Grenoble, France; Centre National de Recherche Scientifique (CNRS), TIMC-IMAG, 38000 Grenoble, France.
Ludovic
L
Pelosi
Université Grenoble Alpes, Laboratoire Technologies de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble (TIMC-IMAG), 38000 Grenoble, France; Centre National de Recherche Scientifique (CNRS), TIMC-IMAG, 38000 Grenoble, France. Electronic address: fabien.pierrel@univ-grenoble-alpes.fr.
Fabien
F
Pierrel
D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D001547:Benzaldehydes / Q000378:metabolism; D053898:Biosynthetic Pathways; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D010084:Oxidation-Reduction; D010226:Parabens / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D014451:Ubiquinone / Q000235:genetics / Q000378:metabolism*
D001547:Benzaldehydes; D010226:Parabens; D029701:Saccharomyces cerevisiae Proteins; D014451:Ubiquinone; D014443:Tyrosine; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase; C038193:4-hydroxybenzoic acid; C011483:4-hydroxybenzaldehyde