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Evidence that Biosynthesis of Individual Ubiquinone Homologs in Pneumocystis carinii is Under Homolog‐Specific Negative Feedback (Product) Control
Author(s) -
KANESHIRO EDNA S.,
BASSELIN MIREILLE,
HUNT SHAN M.
Publication year - 2003
Publication title -
journal of eukaryotic microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.067
H-Index - 77
eISSN - 1550-7408
pISSN - 1066-5234
DOI - 10.1111/j.1550-7408.2003.tb00654.x
Subject(s) - library science , citation , biological sciences , biology , computational biology , computer science
Ubiquinone (Coenzyme Q, CoQ) is present in most eukaryotic organisms. This lipid is also ubiquitously distributed within cells and is found in various cellular compartments such as the mitochondria, Golgi complex, endoplasmic reticulum, and cell surface membranes. CoQ homologs are designated by the number of monounsaturated isoprene units (C,) in the polyprenyl chain of the molecule. Pneumocystis curinii synthesizes de novo four homologs CoQ7, CoQR, CoQ,,, and CoQlo 11-31; the organism does not synthesize COQ~, [3]. In ubiquinone biosynthesis, the first dedicated step in this pathway is the transfer of a polyprenyl group to p-hydroxybenzoic acid (PHBA) (Fig. I) . The completed CoQ molecule is then produced following several reactions in which side groups are added to the aromatic ring. Atovaquone and stigmatellin, analogs of CoQ, bind to the mitochondria1 cytochrome bcl complex thus inhibiting ATP production and cellular respiration by impeding electron transport. Our group previously demonstrated that atovaquone, but not stigmatellin (CoQ analog that is not a naphthoquinone), has additional activity in P. carinii [2]; atovaquone inhibited the synthesis of all four CoQ homologs. Buprdvaquone and some other CoQ analogs also show this activity. Furthermore, two distinct subcellular fractions, the mitochondria and microsomes, were shown to synthesize all four homologs. Evidence for CoQ synthesis occurring in both of these cell compartments was shown by the differential response to atovaquone and bupravaquone; microsomal CoQ synthesis was inhibited but mitochondrial synthesis was not. To address the mechanism by which naphthoquinone CoQ analogs inhibit non-mitochondria1 CoQ synthesis, we proposed that the compounds exerted activity in a negative feedback loop that is normally controlled by the final CoQ product. In the present study, we test P. carinii CoQ homologs as end-product inhibitors in regulating CoQ synthesis. These studies also provide insight into whether P. carinii could have more than one PHBA: polyprenyl transferase enzyme.