Evidence for Cholesterol Scavenging by <i>Pneumocystis</i> and Potential Modifications of Host‐Synthesized Sterols by the <i>P. carinii</i> SAM:SMT

Worsham, D. Nicole; Basselin, Mireille; Smulian, A. George; Beach, David; Kaneshiro, Edna S.

doi:10.1111/j.1550-7408.2003.tb00683.x

Cited by 12 publications

(13 citation statements)

References 5 publications

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“…We posit that this may be a survival mechanism employed by these organisms in the lung environment. While the mechanisms of sterol uptake in P. carinii have not been defined, previous studies have shown that sterols can be scavenged from the host lung (Worsham et al 2003) and we speculate that P. carinii might circumvent drugs targeting sterol biosynthesis by the uptake of exogenous sterols under these conditions. The reduced susceptibility to TMP-SMX and pentamidine isethionate by P. carinii under MA conditions is an intriguing finding with clinical relevance.…”

Section: Resultsmentioning

confidence: 81%

Microaerophilic Conditions Increase Viability and Affect Responses of Pneumocystis carinii to Drugs In Vitro

Joffrion

Collins

Cushion

2006

J Eukaryotic Microbiology

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Section: Resultsmentioning

confidence: 81%

Microaerophilic Conditions Increase Viability and Affect Responses of Pneumocystis carinii to Drugs In Vitro

Joffrion

Collins

Cushion

2006

J Eukaryotic Microbiology

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“…of cholesterol) could represent (1) sterols present in the human lung but not in the P. jirovecii organisms, (2) sterols present in the lung and taken up by P. jirovecii , or (3) sterols present in the lung taken up by P. jirovecii and subsequently metabolized by the fungus, especially by the action of SAMrSMT. As in purified rat‐derived P. carinii in which most if not all cholesterol is scavenged by the organism (Worsham et al 2003), we currently interpret cholesterol in this P. jirovecii specimen as coming from cholesterol in the human lung tissue plus cholesterol taken up by the organisms. The Δ 7 24‐alkylsterols produced by Pneumocystis are characterized by the β configuration of the group at C‐24 of the sterol side chain (Giner et al 2002) (Fig.…”

Section: Discussionmentioning

confidence: 92%

Sterol Composition of Pneumocystis jirovecii with Blocked 14α‐Demethylase Activity

Giner

Zhao

Amit

et al. 2004

J Eukaryotic Microbiology

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Several drugs that interact with membrane sterols or inhibit their syntheses are effective in clearing a number of fungal infections. The AIDS-associated lung infection caused by Pneumocystis jirovecii is not cleared by many of these therapies. Pneumocystis normally synthesizes distinct C28 and C29 24-alkylsterols, but ergosterol, the major fungal sterol, is not among them. Two distinct sterol compositional phenotypes were previously observed in P. jirovecii. One was characterized by delta7 C28 and C29 24-alkylsterols with only low proportions of higher molecular mass components. In contrast, the other type was dominated by high C31 and C32 24-alkylsterols, especially pneumocysterol. In the present study, 28 molecular species were elucidated by nuclear magnetic resonance analysis of a human lung specimen containing P. jirovecii representing the latter sterol profile phenotype. Fifteen of the 28 had the methyl group at C-14 of the sterol nucleus and these represented 96% of the total sterol mass in the specimen (excluding cholesterol). These results strongly suggest that sterol 14alpha-demethylase was blocked in these organisms. Twenty-four of the 28 were 24-alkylsterols, indicating that methylation of the C-24 position of the sterol side chain by S-adenosyl-L-methionine:sterol C-24 methyl transferase was fully functional.

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“…although Pneumocystis is a fungus it does not contain ergosterol but synthesizes unique 24-alkylsterols with a single double bond in the sterol nucleus, which is at the D 7 position (Kaneshiro et al, 1994;Urbina et al, 1997;Giner et al, 2002). as is common in other animal parasites, there is abundant cholesterol in Pneumocystis, which is synthesized by the host and scavenged by the pathogen (Worsham et al, 2003). Plant sterols originating from vegetable material in laboratory rat chow are taken up by the rat and scavenged by P. carinii Zhou et al, 2002).…”

Section: S-adenosylmethionine (Sam Adomet)mentioning

confidence: 99%

“…Plant sterols originating from vegetable material in laboratory rat chow are taken up by the rat and scavenged by P. carinii Zhou et al, 2002). Furthermore, compounds such as desmosterol, the direct precursor of cholesterol in mammals, can be taken up by Pneumocystis and modified using its own enzymes such as saM:sMT producing D 5 24-alkysterols Worsham et al, 2003).…”

Section: S-adenosylmethionine (Sam Adomet)mentioning

confidence: 99%

Biochemical research elucidating metabolic pathways inPneumocystis

Kaneshiro

2010

Parasite

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Mots clés : S-adénosyl-L-méthionine, atovaquone, buparvaquone, chorismate, erg6, erg7, erg11, sam1, gènes, lanostérol synthase, poumon, microsomes, mitochondrie, nicotine, pneumocystérol, shikimate, stigmatellin, triazoles, ubiquinones (Coenzyme Q, CoQ). Summary:Advances in sequencing the Pneumocystis carinii genome have helped identify potential metabolic pathways operative in the organism. Also, data from characterizing the biochemical and physiological nature of these organisms now allow elucidation of metabolic pathways as well as pose new challenges and questions that require additional experiments. These experiments are being performed despite the difficulty in doing experiments directly on this pathogen that has yet to be subcultured indefinitely and produce mass numbers of cells in vitro. This article reviews biochemical approaches that have provided insights into several Pneumocystis metabolic pathways. It focuses on 1) S-adenosyl-L-methionine (AdoMet; SAM), which is a ubiquitous participant in numerous cellular reactions; 2) sterols: focusing on oxidosqualene cyclase that forms lanosterol in P. carinii; SAM:sterol C-24 methyltransferase that adds methyl groups at the C-24 position of the sterol side chain; and sterol 14a-demethylase that removes a methyl group at the C-14 position of the sterol nucleus; and 3) synthesis of ubiquinone homologs, which play a pivotal role in mitochondrial inner membrane and other cellular membrane electron transport.

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Evidence for Cholesterol Scavenging by Pneumocystis and Potential Modifications of Host‐Synthesized Sterols by the P. carinii SAM:SMT

Cited by 12 publications

References 5 publications

Microaerophilic Conditions Increase Viability and Affect Responses of Pneumocystis carinii to Drugs In Vitro

Microaerophilic Conditions Increase Viability and Affect Responses of Pneumocystis carinii to Drugs In Vitro

Sterol Composition of Pneumocystis jirovecii with Blocked 14α‐Demethylase Activity

Biochemical research elucidating metabolic pathways inPneumocystis

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