title: Pneumocystis S-adenosylmethionine transport: a potential drug target.
abstract: Pneumocystis pneumonia (PCP) is a life-threatening condition in immunosuppressed patients. Current treatments are inadequate, and new drug leads are needed. This fungus depends on its host for S-adenosylmethionine (AdoMet), a critical metabolic intermediate ordinarily synthesized by individual cells as needed. Pneumocystis contains a gene coding for the AdoMet-synthesizing enzyme methionine ATP transferase (MAT), and the protein is expressed. However, the fungus lacks MAT activity, and infection causes the depletion of host plasma AdoMet. The uptake of Pneumocystis AdoMet was shown to be exquisitely specific, which suggests the transport of AdoMet as a potential drug target. Here we report on the discovery of PcPET8, a Pneumocystis gene with homology to mitochondrial AdoMet transporters. When expressed by Saccharomyces cerevisiae, it locates properly to the mitochondrion and complements a strain of S. cerevisiae lacking its native mitochondrial AdoMet transporter. The importance of AdoMet transport is demonstrated by the ability of the AdoMet analogue sinefungin to block the uptake of Pneumocystis AdoMet and inhibit growth in culture. Because PcPET8 is likely critical for Pneumocystis, the yeast construct has potential as a surrogate for testing compounds against Pneumocystis.
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Perez-Leal
authors.forename: Camilo
authors.initials: C
authors.lastname: Moncada
authors.forename: Allen B
authors.initials: AB
authors.lastname: Clarkson
authors.forename: Salim
authors.initials: S
authors.lastname: Merali
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D016503:Drug Delivery Systems; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D045363:Pneumocystis carinii / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy* / Q000201:enzymology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D011994:Recombinant Proteins; D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase; D000241:Adenosine; C006235:sinefungin