FIGURE 15.

The CoQ biosynthesis pathway in the yeast S. cerevisiae and humans. The proteins are in blue (S. cerevisiae) or green (humans). Dotted arrows designate multiple-step reactions, and the steps that are specific to yeast are shown in blue. R indicates the poly-isoprenoid tail. The synthesis of the isoprenoid depends on the mevalonate pathway, which produces the biosynthetic precursors of isoprenoids. Coq1 in yeast and a heterotetrameric protein formed by PDSS1 and PDSS2 in humans determine the number of isoprene units in the polyisoprene tail. The main ring precursor used by both yeast and humans is 4-hydroxybenzoic acid (4-HB), synthesized from tyrosine in the cytosol. The first and last steps of this pathway have been defined in the yeast, where 5 aminotransferases, Aro8, Aro9, Bat2, Bna3, and Aat2, redundantly convert tyrosine to 4-hydroxyphenylpyruvate (4-HPP) and the last step is catalyzed by Hfd1. After its transport into mitochondria, Coq2/COQ2 attaches the isoprenoid tail to 4-HB. Subsequent to this step, the CoQ ring undergoes several sequential modifications before yielding CoQ. The intermediates detected in yeast are shown. A recent study using a human embryonic kidney cell line (HEK293) showed that the decarboxylation and hydroxylation of position C1 occur in a single oxidative decarboxylation step and it is catalyzed by COQ4. The reaction catalyzed by COQ4 preferentially occurs before the C5 hydroxylation by COQ6; however, the alternative sequence of reactions, that is COQ6 and COQ3 may act before COQ4, is also possible (488). Yeast can also utilize para-aminobenzoic acid (pABA) for CoQ synthesis, which is made from chorismate in 2 steps catalyzed by Abz1 and Abz2. The nitrogen-containing intermediates generated from its utilization are also depicted. Coq6 and Coq9 are able to deaminate the ring C4 position on the intermediate derived from pABA. Whether and where Coq4 is involved before the deamination step remains to be demonstrated. pABA is also an intermediate in the synthesis of folate in the yeast. Two additional compounds that can also serve as ring precursors both in S. cerevisiae and mammals are shown at top: para-coumaric acid and resveratrol. The absence of Coq6 activity leads to the accumulation of 3-hexaprenyl-4-aminophenol (4-AP) and 3-hexaprenyl-4-hydroxyphenol (4-HP) when yeast cells are grown in pABA and 4-HB, respectively. The Coq/COQ proteins with unclear molecular functions are listed in a box. CoQ and intermediates are shown in their reduced forms. DDMQH₂, 3-hexaprenyl-5-methoxy-1,4-benzenediol; DMeQH₂, 2-methyl-3-hexaprenyl-5-methoxy-1,4,6-benzenetriol; DMQH₂, 2-methyl-3-hexaprenyl-5-methoxy-1,4-benzenediol; FPP, farnesyl diphosphate; GPP, geranyl pyrophosphate; HAB, 3-hexaprenyl-4-aminobenzoic acid; 4-HBz, 4-hydroxbenzaldehyde; HHAB, 4-amino-3-hexaprenyl-5-hydroxybenzoic acid; HHB, 3-hexaprenyl-4-HB; IPP, isopentenyl pyrophosphate. See glossary for other abbreviations.