Sterol metabolism in the opportunistic pathogen Pneumocystis: Advances and new insights

Abstract

Pneumocystis can transiently colonize healthy individuals without causing adverse symptoms, and most people test positive for exposure to this organism early in life. However, it can cause Pneumocystis pneumonia (PcP) in people with impaired immune systems and is a major cause of death in HIV/AIDS. Although it has close affinities to the Ascomycetes, Pneumocystis has features unlike those of any single group of fungi. For example, Pneumocystis does not synthesize ergosterol, which is consistent with the inefficacy of amphotericin B and some triazoles in clearing PcP. Pneumocystis sterols include distinct delta7 24-alkylsterols. Metabolic radiolabeling experiments demonstrated that P. carinii synthesizes sterols de novo. Cholesterol is the most abundant sterol in Pneumocystis; most, if not all, is scavenged from the mammalian host lung by the pathogen. The P. carinii erg7, erg6, and erg11 genes have been cloned, sequenced, and expressed in heterologous systems. The recombinant P. carinii S-adenosyl-L-methionine:C-24 sterol methyl transferase (SAM:SMT) has a preference for lanosterol over zymosterol as substrate, and the enzyme can catalyze the transfer of either one or two methyl groups to the C-24 position of the sterol side chain. Two different sterol compositions were detected among human-derived P. jirovecii; one was dominated by C28 and C29 sterols, and the other had high proportions of higher molecular mass components, notably the C32 sterol pneumocysterol. The latter phenotype apparently represents organisms blocked at 14alpha-demethylation of the sterol nucleus. These studies suggest that SAM:SMT is an attractive drug target for developing new chemotherapy for PcP.

Comparative Genomics of Pneumocystis Species Suggests the Absence of Genes for myo- Inositol Synthesis and Reliance on Inositol Transport and Metabolism

“…The lack of a long-term in vitro culture indicates that some crucial nutrients are missing or undersupplemented in the culture medium. Previous metabolic studies indicated that the pathogen does not synthesize ergosterol and has to scavenge cholesterol from its host to thrive (6). More recent genome-sequencing studies pointed out that the fungus has dramatic underrepresentation of amino acid synthesis pathways (7).…”

Comparative Genomics Suggests that the Fungal Pathogen Pneumocystis Is an Obligate Parasite Scavenging Amino Acids from Its Host's Lungs

“…Obligate parasitism has been suggested on the basis of their strict host specificity [5]–[7], patterns of co-evolution with hosts [5], [8], genetic flexibility of chromosome ends responsible for expression of a single antigen encoding gene [9], [10], and the fact that they scavenge cholesterol from their host to build their own membranes [11]. Scavenged cholesterol is found in the membrane together with specific sterols that Pneumocystis synthesizes de novo [12]. However, the issue of whether Pneumocystis species also have a free-living form in nature remains controversial.…”

EC2KEGG: a command line tool for comparison of metabolic pathways

“…Moreover, the fungus contains the incomplete steroid biosynthesis pathway, missing Erg2, Erg3, and Erg5 enzymes downstream of the pathway. This indicates that it cannot synthesize ergosterol from precursors and has to scavenge cholesterol from its host, which has been previously pointed out in other studies [10,11], and may explain the fact that the pathogen is not susceptible to antifungal drugs targeting this pathway, such as azole-based therapeutics. The detailed per pathway information derived using EC2KEGG with entailed highlighted KEGG Pathway maps can be found at http://pgp.cchmc.org/.…”