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Evidence for Cholesterol Scavenging by Pneumocystis and Potential Modifications of Host‐Synthesized Sterols by the P. carinii SAM:SMT
Author(s) -
WORSHAM D. NICOLE,
BASSELIN MIREILLE,
SMULIAN A. GEORGE,
BEACH DAVID H.,
KANESHIRO EDNA S.
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.tb00683.x
Subject(s) - george (robot) , library science , biological sciences , gerontology , medicine , new england , history , biology , art history , political science , computer science , politics , computational biology , law
Pneumoc,ysti.v carinii and P. jirovecii contain a large number of 24-alkylsterols [ 1-51. S-Adenosy1Lmethionine:sterol C-24 methyl transferase (SAM:SMT) is the enzyme that catalyzes the transfer of methyl groups from SAM to the C-24 position of the sterol side chain. SAM:SMT is an attractive target for chemotherapeutic attack against the pathogen since mammals do not have this enzyme and hence do not synthesize 24-alkylsterols. This feature allows for possible organism-specific therapy with little or no toxicity to the host. Most other fungal SAM:SMT enzymes transfer a single methyl group to the C-24 position of zymosterol to produce C2x sterols. Similar to the situation in some plants, the I? carinii SAM:SMT can transfer one or two methyl groups to the sterol side chain to produce both C2s and C29 sterols. Unlike SAM:SMT from most other fungal pathogens infecting mammals, the enzyme in I! carinii prefers lanosterol instead of zymosterol as substrate [2,4,5) and synthesizes a number of C3, and C3* lanosterol derivatives 1231. Since sterols found in parasites are either scavenged from the host and inserted unchanged into membranes, synthesized de novo, or scavenged and then modified by the organism, we are investigating whether the SAM:SMT enzyme productively binds sterols known to be normally present in mammalian lungs and are available for scavenging by Pneumocystis. We are also expanding our efforts in purifying the R carinii recombinant SAM:SMT protein, which will allow us to analyze the reactions using purified enzyme and substrates. This will provide definitive evidence whether or not products were not formed by reactions other than those catalyzed by SAM:SMT.