Ubiquinone (coenzyme Q) biosynthesis in bacteria and mitochondria

De novo biosynthesis of ubiquinone (coenzyme Q) from 4-hydroxybenzoate and a long-chain all-trans-polyprenyl diphosphate in bacteria and in the mitochondria of eukaryotes. A dedicated trans-prenyltransferase sets the tail length (homomeric IspB or Coq1, or a heterotetrameric Dps1/Dlp1 or PDSS1/PDSS2 enzyme). The aromatic head group comes from chorismate via UbiC in bacteria, and from tyrosine in fungi, where aminotransferases form 4-hydroxyphenylpyruvate and an aldehyde dehydrogenase (Hfd1) oxidizes 4-hydroxybenzaldehyde to 4-hydroxybenzoate. UbiA-family prenyltransferases (UbiA in the bacterial membrane, Coq2 in the mitochondrial inner membrane) attach the tail. The ring then undergoes one decarboxylation, three hydroxylations, two O-methylations and one C-methylation, in lineage-specific order: bacteria decarboxylate first with prFMN-dependent UbiD (cofactor from UbiX) and use UbiI/UbiH/UbiF or Coq7 hydroxylases, whereas the mitochondrial CoQ synthome hydroxylates C5 with Coq6, O-methylates with Coq3, performs a C1 oxidative decarboxylation with Coq4, then C-methylates (Coq5), hydroxylates C6 (Coq7) and O-methylates again (Coq3). Accessory factors (UbiJ, UbiK and UbiB in bacteria; Coq8, Coq9 and the mitochondrial ferredoxin system in eukaryotes) organize the hydrophobic intermediates or supply electrons. Oxygen-independent UbiT/UbiU/UbiV implementations, C5-C20 prenyl diphosphate synthesis, and coenzyme Q transport and use are outside the module.

This module is intentionally narrower than KEGG map00130: it represents aerobic ubiquinone biosynthesis, not all terpenoid quinones. Homogentisate production, generic NAD(P)H:quinone oxidoreductases, acyl-CoA thioesterases, menaquinone synthesis, and downstream quinone use are outside the boundary. GENERALIZE with YeastPathways (2026-10): the module was broadened from a bacterial pathway to bacteria plus mitochondria rather than creating a separate eukaryotic sibling, because the tail synthase, the UbiA/Coq2 prenyltransferase, the UbiG/Coq3 and UbiE/Coq5 methyltransferases, the Coq6/UbiI-type flavin hydroxylase and the Coq7 hydroxylase are homologous across the two lineages; only the head-group supply, the decarboxylase and the reaction order differ. Those differences are modeled as exclusive lineage variants at the head-group, prenylation (compartment), ring-modification and accessory levels, so the bacterial content is kept intact inside the bacterial variants. The human-scoped MODULE:coenzyme_q10_biosynthesis remains a concrete human instance of the eukaryotic variant. The chain-length-determining polyprenyl diphosphate synthase (Coq1, IspB, Dps1/Dlp1, PDSS1/PDSS2) is now an optional part, because MODULE:isoprenoid_diphosphate_biosynthesis stops at GGPP and defers Coq1 here; ERG20 and BTS1 stay in that module. YeastCyc corrections: COQ4 fills the unassigned decarboxylation (RXN3O-73) and also performs the C1 hydroxylation that YeastCyc assigns to COQ6 (RXN3O-12) (PMID:38295803); CAT5 is COQ7; COQ8, COQ9 and the YAH1/ARH1 ferredoxin system are missing from the YeastCyc gene list; the coumarate route of PWY3O-1109 has no genes and is replaced by the Aro8/Aro9 and Hfd1 steps (PMID:27693056). All YeastPathways activities are placed in the cytosol, whereas the CoQ enzymes are mitochondrial. GO-CAM disagreements: PWY3O-19 types both COQ6 activities with the bacterial UbiH term GO:0008681; PWY3O-862 types COQ1 and COQ6 only with GO:0003674; HEXPPSYN-PWY-2 types COQ1 as a heptaprenyl diphosphate synthase. The PomBase model 662af8fa00000408 assigns the C1 hydroxylation (GO:0120538) to coq6 after coq4 decarboxylation, whereas Pelosi et al. (PMID:38295803) assign both C1 reactions to COQ4; it also includes coq10 (CoQ binding after synthesis), coq11, coq12 and a ptc7 phosphatase that are not modeled as annotons here. The human mitochondrial pathway (PDSS1/2, COQ2-COQ9, COQ8A/B) is modelled separately in MODULE:coenzyme_q10_biosynthesis; there COQ2, COQ5 and COQ3 are the UbiA, UbiE and UbiG orthologs, COQ7 is the Coq7-family late hydroxylase, COQ8A/B are UbiB-family members, and C1 decarboxylation is performed by the zinc enzyme COQ4 rather than by UbiD/UbiX. FAMILY SCOPE (2026-11): three annotons use a PANTHER family whose review leaves the annoton's activity UNRESOLVED at family level, because no PANTHER subfamily separates the ubiquinone members: PTHR12001 SF69 mixes C30 (COQ1), C40 (E. coli IspB) and C50 (dps1) synthases, so GO:0106350 is member-level; PTHR30108 SF17 holds UbiD together with Fdc1, BsdC and HudA, so GO:0008694 is member-level; and PTHR10566 ATP hydrolysis is shown only for E. coli UbiB. The activities rest on the member gene reviews, and the resulting FAMILY_FUNCTION_UNREVIEWED warnings are expected. P. putida KT2440 makes UQ9, so its IspB is not a representative of the C40 annoton, and KT2440 uses UbiI (VisC), UbiH and Coq7 for the three hydroxylations. The Arh1 family follows UniProt and the current PAINT seeds (PTHR48467) rather than PANTHER 19.0 classification (PTHR11938:SF91); member-index overrides record the decision. UbiK has no molecular function asserted because its activity is unknown (PMID:28559279). C1 STEP: the three COQ6 reviews disagree on GO:0120538 (ferredoxin-dependent C1 hydroxylase): REMOVE for yeast COQ6 (PMID:38295803 assigns both C1 reactions to COQ4), MARK_AS_OVER_ANNOTATED for S. pombe coq6, and ACCEPT for human COQ6 on an in vitro IDA (PMID:38425362); each review cross-references the others. The COQ4 annoton uses GO:0120539, which GO defines as a non-oxidative decarboxylation although COQ4 performs an oxidative one; a new term is proposed in the yeast COQ4 review (proposed_new_terms).