S-Adenosylmethionine and Pneumocystis

Merali, Salim; Clarkson, Allen B.

doi:10.1111/j.1574-6968.2004.tb09694.x

Cited by 25 publications

(29 citation statements)

References 32 publications

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“…Kinetic data for the inhibition of AdoMet transport by sinefungin are lacking, but because the observed inhibition occurred after 30 seconds and sinefungin is known to compete with the PET8-mediated transport of AdoMet (22), we are confident that sinefungin directly inhibits the uptake of Pneumocystis AdoMet by blocking transport rather than indirectly, though interference with AdoMetdependent reactions. Our data showing that 100 mM of sinefungin block the uptake of AdoMet by 90% confirm our earlier result using that concentration (12). More importantly, this concentration also completely blocks growth in culture, a finding that supports AdoMet transport as a drug target.…”

Section: Discussionsupporting

confidence: 81%

“…The antibiotic sinefungin is active against P. carinii in culture (12), is known to compete with AdoMet for S. cerevisiae PET8 transport (23), and is the only compound we found able to block the uptake of AdoMet by Pneumocystis. Kinetic data for the inhibition of AdoMet transport by sinefungin are lacking, but because the observed inhibition occurred after 30 seconds and sinefungin is known to compete with the PET8-mediated transport of AdoMet (22), we are confident that sinefungin directly inhibits the uptake of Pneumocystis AdoMet by blocking transport rather than indirectly, though interference with AdoMetdependent reactions.…”

Section: Discussionmentioning

confidence: 90%

“…Although Pneumocystis may express MAT activity at some stage of its life cycle, this activity has been undetectable in Pneumocystis isolated from infected animals, even when sensitive assays and procedures to eliminate possible interference are used (9). The dependence of Pneumocystis on host AdoMet is supported by evidence from experimental animals: PCP reduces pulmonary AdoMet and depletes plasma AdoMet, the selective reduction of pulmonary AdoMet attenuates the infection, and an infusion of AdoMet exacerbates the disease (9,12,13). For humans with PCP, plasma AdoMet is depleted and recovers rapidly upon the initiation of treatment (12,14,15).…”

mentioning

confidence: 70%

“…cDNA Synthesis P. carinii was isolated from lungs that had been removed from infected rats and stored frozen, as previously described (12,17). RNA was isolated from P. carinii cells, using the TRIZOL reagent according to the manufacturer's instructions (Invitrogen, Carlsbad, CA), and was then treated with RQ1 RNase-free DNase (Promega, San Luis Obispo, CA) to destroy any trace of genomic DNA.…”

Section: Methodsmentioning

confidence: 99%

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Pneumocystis S-Adenosylmethionine Transport

Pérez-Leal

Moncada

Clarkson

et al. 2011

Am J Respir Cell Mol Biol

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

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Pneumocystis S-Adenosylmethionine Transport

Pérez-Leal

Moncada

Clarkson

et al. 2011

Am J Respir Cell Mol Biol

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“…However, in some Rickettsia strains, the MAT gene is inactivated by a mutation (10), and in the fungus Pneumocystis carinii, no MAT activity has been detected (11). These organisms have the rare distinction of meeting their AdoMet needs by importing it (12). The Rickettsia transporter is part of the drug/ metabolite transporter superfamily (10), and the identity of the Pneumocystis transporter is not known.…”

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confidence: 99%

High Affinity S-Adenosylmethionine Plasma Membrane Transporter of Leishmania Is a Member of the Folate Biopterin Transporter (FBT) Family

Dridi¹,

Ouameur²,

Ouellette

2010

Journal of Biological Chemistry

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S-Adenosylmethionine (AdoMet) is an important methyl group donor that plays a central role in many essential biochemical processes. The parasite Leishmania can both synthesize and transport AdoMet. Leishmania cells resistant to the antifolate methotrexate due to a rearrangement in folate biopterin transporter (FBT) genes were cross-resistant to sinefungin, an AdoMet analogue. FBT gene rearrangements were also observed in Leishmania major cells selected for sinefungin resistance. One of the rearranged FBT genes corresponded to the main AdoMet transporter (AdoMetT1) of Leishmania as determined by gene transfection and gene inactivation experiments. AdoMetT1 was determined to be a high affinity plasma membrane transporter expressed constitutively throughout the growth phases of the parasite. Leishmania cells selected for resistance or naturally insensitive to sinefungin had lower expression of AdoMetT1. A new function in one carbon metabolism, also a pathway of interest for chemotherapeutic interventions, is described for a novel class of membrane proteins found in diverse organisms.The parasite Leishmania is distributed globally and causes a variety of clinical symptoms ranging from self-healing cutaneous lesions to visceral infections that are usually fatal if left untreated (1, 2). Current first-line chemotherapy against leishmaniasis relies on a rather limited arsenal of drugs, including pentavalent antimonials, liposomal amphotericin B, or miltefosine (2). These drugs are associated with side effects, high costs, and drug resistance, and therefore, the search for new drugs and targets to control this parasite is warranted (3, 4).S-Adenosylmethionine (AdoMet or SAM) 5 is an important biological sulfonium compound recognized as the universal methyl donor for methylation of lipids, proteins, nucleic acids, and xenobiotics in living cells (5). AdoMet is also a donor of propylamine groups for the synthesis of polyamines and participates in the reverse trans-sulfuration pathway where AdoMet is converted into cysteine and glutathione and in Leishmania in the spermidine-glutathione conjugate trypanothione (6, 7). AdoMet is also used as a source of methylene groups, amino groups, and ribosyl groups in the synthesis of fatty acids, biotin, and the modified nucleoside epoxyqueusine of tRNAs (reviewed in Ref. 8).Most cells are capable of synthesizing AdoMet from L-methionine and ATP, in a process requiring the enzyme methionine adenosyltransferase (MAT). The gene coding for this enzyme is present in most sequenced organisms (reviewed in Ref. 9). However, in some Rickettsia strains, the MAT gene is inactivated by a mutation (10), and in the fungus Pneumocystis carinii, no MAT activity has been detected (11). These organisms have the rare distinction of meeting their AdoMet needs by importing it (12). The Rickettsia transporter is part of the drug/ metabolite transporter superfamily (10), and the identity of the Pneumocystis transporter is not known. Transport of AdoMet across the plasma membrane does not occur to a signifi...

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S‐Adenosylmethionine

Markham¹

2010

Encyclopedia of Life Sciences

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S ‐adenosylmethionine is one of the few sulfonium ions found in nature and it plays essential roles in the metabolism of all known organisms. The positively charged sulfonium centre endows S ‐adenosylmethionine with a chemical versatility matched by few other biochemicals, perhaps exceeding even adenosine triphosphate (ATP). S ‐adenosylmethionine is used in a multitude of metabolic pathways, and the types of chemical reactions in which it partakes are highly varied, ranging from alkylation to free‐radical formation. S ‐sdenosylmethionine is methyl donor in many biosynthetic reactions, whereas methylation of both deoxyribonucleic acid (DNA) and proteins is part of the epigenetic control of cell growth and development. In other pathways, the propylamine moiety is incorporated into the pervasive polyamines spermidine and spermine. Unusual reactions consume S ‐adenosylmethionine in the formation of plant growth factor ethylene, of cyclopropane fatty acids and in sulfur insertion in the biosynthesis of biotin, lipoic acid and thiamine. S ‐adenosylmethionine appears to be one of the molecules required for life. Key concepts: S ‐adenosylmethionine is a branch point compound with components from purine, amino acid and reduced sulfur metabolism, and thus is potentially able to coordinate these three areas of metabolism. S ‐adenosylmethionine appears to be required for life. The sulfonium centre of S ‐adenosylmethionine is able to transfer any of the three attached alkyl groups, providing a metabolic versatility matched by few other biological molecules. S ‐adenosylmethionine is a progenitor of free radicals that occur as protein‐bound reaction intermediates in unusual chemical transformations catalysed by the ‘Radical SAM’: family of enzymes. S ‐adenosylmethionine metabolism is commonly disrupted in liver disease, and hereditary defects have been found in a few patients with abnormal sulfur metabolism. S ‐adenosylmethionine is under investigation as a potential drug in treatment of depression, arthritis and liver disease.

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S-Adenosylmethionine and Pneumocystis

Cited by 25 publications

References 32 publications

Pneumocystis S-Adenosylmethionine Transport

Pneumocystis S-Adenosylmethionine Transport

High Affinity S-Adenosylmethionine Plasma Membrane Transporter of Leishmania Is a Member of the Folate Biopterin Transporter (FBT) Family

S‐Adenosylmethionine

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