Effects of atovaquone and diospyrin-based drugs on ubiquinone biosynthesis in Pneumocystis carinii organisms

Edna S. Kaneshiro, Dong Geun Sul, Banasri Hazra

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The naphthoquinone atovaquone is effective against Plasmodium and Pneumocystis carinii carinii. In Plasmodium, the primary mechanism of drug action is an irreversible binding to the mitochondrial cytochrome bc1 complex as an analog of ubiquinone. Blockage of the electron transport chain ultimately inhibits de novo pyrimidine biosynthesis since dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis, is unable to transfer electrons to ubiquinone. In the present study, the effect of atovaquone was examined on Pneumocystis carinii carinii coenzyme Q biosynthesis (rather than electron transport and respiration) by measuring its effect on the incorporation of radiolabeled p-hydroxybenzoate into ubiquinone in vitro. A triphasic dose-response was observed, with inhibition at 10 nM and then stimulation up to 0.2 μM, followed by inhibition at 1 μM. Since other naphthoquinone drugs may also act as analogs of ubiquinone, diospyrin and two of its derivatives were also tested for their effects on ubiquinone biosynthesis in P. carinii carinii. In contrast to atovaquone, these drugs did not inhibit the incorporation of p-hydroxybenzoate into P. carinii carinii ubiquinone.

Original languageEnglish
Pages (from-to)14-18
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume44
Issue number1
Publication statusPublished - 2000 Jan 8
Externally publishedYes

Fingerprint

Atovaquone
Pneumocystis carinii
Ubiquinone
Pharmaceutical Preparations
Naphthoquinones
Plasmodium
Electron Transport
Electron Transport Complex III
diospyrin
Respiration
Electrons

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Effects of atovaquone and diospyrin-based drugs on ubiquinone biosynthesis in Pneumocystis carinii organisms. / Kaneshiro, Edna S.; Sul, Dong Geun; Hazra, Banasri.

In: Antimicrobial Agents and Chemotherapy, Vol. 44, No. 1, 08.01.2000, p. 14-18.

Research output: Contribution to journalArticle

@article{0edad3cf0ade495ba0a4ece047ad3363,
title = "Effects of atovaquone and diospyrin-based drugs on ubiquinone biosynthesis in Pneumocystis carinii organisms",
abstract = "The naphthoquinone atovaquone is effective against Plasmodium and Pneumocystis carinii carinii. In Plasmodium, the primary mechanism of drug action is an irreversible binding to the mitochondrial cytochrome bc1 complex as an analog of ubiquinone. Blockage of the electron transport chain ultimately inhibits de novo pyrimidine biosynthesis since dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis, is unable to transfer electrons to ubiquinone. In the present study, the effect of atovaquone was examined on Pneumocystis carinii carinii coenzyme Q biosynthesis (rather than electron transport and respiration) by measuring its effect on the incorporation of radiolabeled p-hydroxybenzoate into ubiquinone in vitro. A triphasic dose-response was observed, with inhibition at 10 nM and then stimulation up to 0.2 μM, followed by inhibition at 1 μM. Since other naphthoquinone drugs may also act as analogs of ubiquinone, diospyrin and two of its derivatives were also tested for their effects on ubiquinone biosynthesis in P. carinii carinii. In contrast to atovaquone, these drugs did not inhibit the incorporation of p-hydroxybenzoate into P. carinii carinii ubiquinone.",
author = "Kaneshiro, {Edna S.} and Sul, {Dong Geun} and Banasri Hazra",
year = "2000",
month = "1",
day = "8",
language = "English",
volume = "44",
pages = "14--18",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "1",

}

TY - JOUR

T1 - Effects of atovaquone and diospyrin-based drugs on ubiquinone biosynthesis in Pneumocystis carinii organisms

AU - Kaneshiro, Edna S.

AU - Sul, Dong Geun

AU - Hazra, Banasri

PY - 2000/1/8

Y1 - 2000/1/8

N2 - The naphthoquinone atovaquone is effective against Plasmodium and Pneumocystis carinii carinii. In Plasmodium, the primary mechanism of drug action is an irreversible binding to the mitochondrial cytochrome bc1 complex as an analog of ubiquinone. Blockage of the electron transport chain ultimately inhibits de novo pyrimidine biosynthesis since dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis, is unable to transfer electrons to ubiquinone. In the present study, the effect of atovaquone was examined on Pneumocystis carinii carinii coenzyme Q biosynthesis (rather than electron transport and respiration) by measuring its effect on the incorporation of radiolabeled p-hydroxybenzoate into ubiquinone in vitro. A triphasic dose-response was observed, with inhibition at 10 nM and then stimulation up to 0.2 μM, followed by inhibition at 1 μM. Since other naphthoquinone drugs may also act as analogs of ubiquinone, diospyrin and two of its derivatives were also tested for their effects on ubiquinone biosynthesis in P. carinii carinii. In contrast to atovaquone, these drugs did not inhibit the incorporation of p-hydroxybenzoate into P. carinii carinii ubiquinone.

AB - The naphthoquinone atovaquone is effective against Plasmodium and Pneumocystis carinii carinii. In Plasmodium, the primary mechanism of drug action is an irreversible binding to the mitochondrial cytochrome bc1 complex as an analog of ubiquinone. Blockage of the electron transport chain ultimately inhibits de novo pyrimidine biosynthesis since dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis, is unable to transfer electrons to ubiquinone. In the present study, the effect of atovaquone was examined on Pneumocystis carinii carinii coenzyme Q biosynthesis (rather than electron transport and respiration) by measuring its effect on the incorporation of radiolabeled p-hydroxybenzoate into ubiquinone in vitro. A triphasic dose-response was observed, with inhibition at 10 nM and then stimulation up to 0.2 μM, followed by inhibition at 1 μM. Since other naphthoquinone drugs may also act as analogs of ubiquinone, diospyrin and two of its derivatives were also tested for their effects on ubiquinone biosynthesis in P. carinii carinii. In contrast to atovaquone, these drugs did not inhibit the incorporation of p-hydroxybenzoate into P. carinii carinii ubiquinone.

UR - http://www.scopus.com/inward/record.url?scp=0033986822&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033986822&partnerID=8YFLogxK

M3 - Article

VL - 44

SP - 14

EP - 18

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 1

ER -