Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1995-5-23
pubmed:abstractText
Dihydroorotate dehydrogenase (DHOD) is a pyrimidine biosynthetic enzyme which is usually directly linked to the mitochondrial respiratory chain. Antimalarial naphthoquinones such as atovaquone (566c80) inhibit malarial DHOD by inhibiting electron transport. Since atovaquone also has therapeutic activity against Pneumocystis carinii, the P. carinii DHOD may also be an important drug target. Organisms were obtained from immunosuppressed rats, incubated for 24 h in a short-term in vitro culture system, and then lysed. P. carinii lysates catalyzed the generation of orotate from dihydroorotate at a rate of 852 pmol/mg of protein per min. Control preparations made from uninfected mice showed much less total enzymatic activity and enzyme specific activity. As expected, P. carinii DHOD activity was susceptible to respiratory inhibitors such as cyanide, antimycin A, and salicylhydroxamic acid (SHAM). Susceptibility to SHAM suggests the presence of an alternative oxidase. In contrast, neither pentamidine nor 5-hydroxy-6-demethylprimaquine (5H6DP), a quinone metabolite of primaquine, inhibited the enzyme. Atovaquone inhibited DHOD by 76.3% at 100 microM and 36.5% at 10 microM. A similar degree of inhibition was found when the organisms were preincubated with the drug. Atovaquone inhibited P. carinii growth in vitro at a somewhat lower concentration (between 0.3 and 3 microM). In contrast, Plasmodium falciparum growth and enzyme activity are susceptible to nanomolar concentrations of atovaquone. Thus, while it is possible that atovaquone acts by inhibiting the P. carinii electron transport chain, the possibility of another drug target cannot be excluded.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-1314606, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-1348618, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-1491058, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-1667935, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-1818143, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-184741, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-211392, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-216313, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-2164790, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-2319567, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-2386542, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-2468767, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-2675756, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-3875445, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-3920634, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-5419455, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-5491874, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-6087880, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-6378110, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-8050525, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-8222520, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-8257140, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-8398811, http://linkedlifedata.com/resource/pubmed/commentcorrection/7726490-8479795
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0066-4804
pubmed:author
pubmed:issnType
Print
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
325-8
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
1995
pubmed:articleTitle
Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase.
pubmed:affiliation
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.