Pneumocystis carinii pneumonia: the status of Pneumocystis biochemistry.
Pneumocystis carinii pneumonia remains a prevalent opportunistic disease among immunocompromised individuals. Although aggressive prophylaxis has decreased the number of acute P. carinii pneumonia cases, many patients cannot tolerate the available drugs, and experience recurrence of the infection, which can be fatal. It is now generally agreed that the organism should be placed with the fungi, but the identification of extant fungal species representing its closest kins, remains debated. Most recent data indicate that P. carinii represents a diverse group of organisms. Since the lack of methods for the continuous subcultivation of this organism hampered P. carinii research, molecular cloning and nucleotide sequencing approaches led the way for understanding the biochemical nature of this pathogen. However, within the last 5 years, the development of improved protocols for isolating and purifying viable organisms from infected mammalian host lungs has enabled direct biochemical and metabolism studies on the organism. The protein moiety of the major high mol. wt surface antigen, represented by numerous isoforms, is encoded by different genes. These proteins are post-transcriptionally modified by carbohydrates and lipids. The organism has the shikimic acid pathway that leads to the formation of compounds which mammals cannot synthesise (e.g., folic acid), hence drugs that inhibit these pathways are effective against the pathogen. Ornithine decarboxylase has now been detected; rapid and complete depletion of polyamines occurs in response to difluoromethylornithine (DFMO). Instead of ergosterol (the major sterol of higher fungi), P. carinii synthesises distinct delta7, C-24-alkylated sterols. An unusual C32 sterol, pneumocysterol, has been identified in human-derived P. carinii. Another signature lipid discovered is cis-9,10-epoxy stearic acid. CoQ10, identified as the major ubiquinone homologue, is synthesised de novo by P. carinii. Atovaquone and other hydroxynaphthoquinone drugs with anti-P. carinii activity probably inhibit pathogen respiration as CoQ analogues. Unlike its effects on Plasmodium, atovaquone does not inhibit the P. carinii dihydroorotate dehydrogenase and pyrimidine metabolism.
Kaneshiro
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Department of Biological Sciences, University of Cincinnati, OH, USA. Edna.Kaneshiro@uc.edu
D000818:Animals; D001426:Bacterial Proteins / Q000032:analysis; D004798:Enzymes / Q000378:metabolism; D005798:Genes, Bacterial; D006801:Humans; D008322:Mammals; D011010:Pneumocystis / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011020:Pneumonia, Pneumocystis / Q000382:microbiology*
D001426:Bacterial Proteins; D004798:Enzymes