{"doi":"10.1016/j.jbc.2021.100643","title":"Defining intermediates and redundancies in coenzyme Q precursor biosynthesis","abstract":"Coenzyme Q (CoQ), a redox-active lipid essential for oxidative phosphorylation, is synthesized by virtually all cells, but how eukaryotes make the universal CoQ head group precursor 4-hydroxybenzoate (4-HB) from tyrosine is unknown. The first and last steps of this pathway have been defined in Saccharomyces cerevisiae, but the intermediates and enzymes involved in converting 4-hydroxyphenylpyruvate (4-HPP) to 4-hydroxybenzaldehyde (4-HBz) have not been described. Here, we interrogate this pathway with genetic screens, targeted LC-MS, and chemical genetics. We identify three redundant aminotransferases (Bna3, Bat2, and Aat2) that support CoQ biosynthesis in the absence of the established pathway tyrosine aminotransferases, Aro8 and Aro9. We use isotope labeling to identify bona fide tyrosine catabolites, including 4-hydroxyphenylacetate (4-HPA) and 4-hydroxyphenyllactate (4-HPL). Additionally, we find multiple compounds that rescue this pathway when exogenously supplemented, most notably 4-hydroxyphenylacetaldehyde (4-HPAA) and 4-hydroxymandelate (4-HMA). Finally, we show that the Ehrlich pathway decarboxylase Aro10 is dispensable for 4-HB production. These results define new features of 4-HB synthesis in yeast, demonstrate the redundant nature of this pathway, and provide a foundation for further study. Coenzyme Q (CoQ), a redox-active lipid essential for oxidative phosphorylation, is synthesized by virtually all cells, but how eukaryotes make the universal CoQ head group precursor 4-hydroxybenzoate (4-HB) from tyrosine is unknown. The first and last steps of this pathway have been defined in Saccharomyces cerevisiae, but the intermediates and enzymes involved in converting 4-hydroxyphenylpyruvate (4-HPP) to 4-hydroxybenzaldehyde (4-HBz) have not been described. Here, we interrogate this pathway with genetic screens, targeted LC-MS, and chemical genetics. We identify three redundant aminotransferases (Bna3, Bat2, and Aat2) that support CoQ biosynthesis in the absence of the established pathway tyrosine aminotransferases, Aro8 and Aro9. We use isotope labeling to identify bona fide tyrosine catabolites, including 4-hydroxyphenylacetate (4-HPA) and 4-hydroxyphenyllactate (4-HPL). Additionally, we find multiple compounds that rescue this pathway when exogenously supplemented, most notably 4-hydroxyphenylacetaldehyde (4-HPAA) and 4-hydroxymandelate (4-HMA). Finally, we show that the Ehrlich pathway decarboxylase Aro10 is dispensable for 4-HB production. These results define new features of 4-HB synthesis in yeast, demonstrate the redundant nature of this pathway, and provide a foundation for further study. Coenzyme Q (ubiquinone or CoQ) is a ubiquitous redox-active lipid that functions as an essential component of the respiratory chain and acts as a potent lipophilic antioxidant (1Lester R.L. Crane F.L. The natural occurrence of coenzyme Q and related compounds.J. Biol. Chem. 1959; 234: 2169-2175Abstract Full Text PDF PubMed Google Scholar, 2Turunen M. Olsson J. Dallner G. Metabolism and function of coenzyme Q.Biochim. Biophys. Acta. 2004; 1660: 171-199Crossref PubMed Scopus (723) Google Scholar). CoQ is also an important redox cofactor for diverse processes, including pyrimidine synthesis and sulfide oxidation (3Munier-Lehmann H. Vidalain P.O. Tangy F. Janin Y.L. On dihydroorotate dehydrogenases and their inhibitors and uses.J. Med. Chem. 2013; 56: 3148-3167Crossref PubMed Scopus (116) Google Scholar, 4Ziosi M. Di Meo I. Kleiner G. Gao X.H. Barca E. Sanchez-Quintero M.J. Tadesse S. Jiang H. Qiao C. Rodenburg R.J. Scalais E. Schuelke M. Willard B. Hatzoglou M. Tiranti V. et al.Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway.EMBO Mol. Med. 2017; 9: 96-111Crossref PubMed Scopus (34) Google Scholar). Consistent with these crucial cellular roles, defects in CoQ biosynthesis are associated with diverse human diseases, including cerebellar ataxia, nephrotic syndrome, and encephalomyopathy (5Acosta M.J. Vazquez F","journal":"Journal of Biological Chemistry","year":2021,"id":186942,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":566563,"name":"Adam Jochem","orcid":null,"position":1,"is_corresponding":false},{"id":745803,"name":"Sheila Johnson","orcid":"0000-0001-5062-7934","position":2,"is_corresponding":false},{"id":746507,"name":"Thiruchelvi R. Reddy","orcid":null,"position":3,"is_corresponding":false},{"id":322137,"name":"Jason D. Russell","orcid":null,"position":4,"is_corresponding":false},{"id":71208,"name":"Joshua J. Coon","orcid":"0000-0002-0004-8253","position":5,"is_corresponding":false},{"id":253457,"name":"David J. Pagliarini","orcid":"0000-0002-0001-0087","position":6,"is_corresponding":false},{"id":566562,"name":"Kyle Robinson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T23:48:51.315888Z","pmid":"33862086","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}