FIGURE 1.
S. cerevisiae Q6 biosynthetic pathway. Accumulation of Q6 biosynthetic intermediates is caused by the overexpression of Coq8 in Δcoq strains. The classic Q biosynthetic pathway is shown in path 1 emanating from 4-HB. Coq1 (not shown) synthesizes the hexaprenyl-diphosphate tail that is transferred by Coq2 to 4-HB to form HHB. R represents the hexaprenyl tail present in all intermediates from HHB to Q6. Alternatively, in path 2, pABA is prenylated by Coq2 to form HAB. Both HHB and HAB are early Q6 intermediates, readily detected in each of the coq null strains (Δcoq3-Δcoq9). The numbering of the aromatic carbon atoms used throughout this study is shown on the reduced form of Q6, Q6H2. Coq8 OE in certain Δcoq strains leads to the accumulation of the following compounds: 4-AP, 3-hexaprenyl-4-aminophenol; 4-HP, 3-hexaprenyl-4-hydroxyphenol; HHAB, 3-hexaprenyl-4-amino-5-hydroxybenzoic acid; HMAB, 3-hexaprenyl-4-amino-5-methoxybenzoic acid; DDMQ6H2, is the reduced form of demethyl-demethoxy-Q6; IDMQ6, 4-imino-demethoxy-Q6; IDMQ6H2, 4-amino-demethoxy-Q6H2; DMQ6, demethoxy-Q6; DMQ6H2, demethoxy-Q6H2. IDDMQ6H2, 2-demethyl-4-amino-demethoxy-Q6H2, and DHHB, 3-hexaprenyl-4,5-dihydroxybenzoic acid, are shown in parentheses to indicate that they have not been detected in this study. Black dotted arrows (from path 2 to path 1) designate the replacement of the C4-amine with a C4-hydroxyl and correspond to the C4-deamination/deimination reaction. A putative mechanism to replace the C4-imino group with the C4-hydroxy group is shown in blue brackets for IDMQ6 but could also occur on 2-demethyl-4-amino-demethoxy-Q6 (IDDMQ6) (not shown). 4-AP and 4-HP, which are formed upon inhibition of the C5-hydroxylation catalyzed by Coq6, are shown in red. Analogues of 4-HB and pABA allowing the bypass of certain steps in Q biosynthesis are indicated in green. Steps defective in the Δcoq9 strain are designated with a red asterisk.