The yeast Saccharomyces cerevisiae is a powerful experimental system to study biochemical, cell biological and molecular biological aspects of lipid synthesis. Most but not all genes encoding enzymes involved in fatty acid, phospholipid, sterol or sphingolipid biosynthesis of this unicellular eukaryote have been cloned, and many gene products have been functionally characterized. Less information is available about genes and gene products governing the transport of lipids between organelles and within membranes, turnover and degradation of complex lipids, regulation of lipid biosynthesis, and linkage of lipid metabolism to other cellular processes. Here we summarize current knowledge about lipid biosynthetic pathways in S. cerevisiae and describe the characteristic features of the gene products involved. We focus on recent discoveries in these fields and address questions on the regulation of lipid synthesis, subcellular localization of lipid biosynthetic steps, cross-talk between organelles during lipid synthesis and subcellular distribution of lipids. Finally, we discuss distinct functions of certain key lipids and their possible roles in cellular processes.

Biochemistry, Cell Biology and Molecular Biology of Lipids of Saccharomyces cerevisiae

Much has been made about J. L. W. Thudichum’s colorful, and one could say clairvoyant, naming of sphingosine “in commemoration of the many enigmas which it presented to the inquirer” in his 1884 treatise The Chemistry of the Brain(1) because many of the riddles of sphingolipids (as the broader field was later named)(2) remained unanswered for the following century. This changed radically over the past several decades as researchers explored, and ultimately established, what seemed at the time to be radical concepts: that sphingolipids are not just structural elements of cells but also participate in intra- and extracellular signaling; that not only the complex glycan headgroups, but also the lipid backbones, are highly specified metabolically and have selective biochemical functions; and that even the longest known function of these lipids, as structural components of the “fluid mosaic” of cell membrane lipids, is not so simple, and often involves the dynamic clustering of sphingolipids in nontraditional microdomains referred to as rafts. We still know only a fraction of their secrets, but this enlightenment has defined models for thinking about these compounds that remove them from their enigmatic “black box.”

Now, a major challenge is to keep up with the rapid growth in knowledge about the sphingolipidome, that is, the ensemble of all sphingolipids.(3) A major goal of the review is to help the reader more easily grasp the metabolic interrelationships that account for the tens of thousands of molecular subspecies (and perhaps more) that appear in nature, with a focus on mammals. The magnitude of this subject precludes the inclusion of all of the enzymes and metabolites, and the author apologizes for the omission of many interesting topics. To put this information in context, there is a brief background discussion of their structures and functions, which have been dealt with also in a recent Chemical Reviews article(4) on the chemicophysical features of sphingolipids and raft formation, and by excellent reviews on sphingolipid signaling5,6 and the biological functions of complex glycosphingolipids.7−10

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism.

Fungal endophytes residing in the internal tissues of living plants occur in almost every plant on earth from the arctic to the tropics. The endophyte–host relationship is described as a balanced symbiotic continuum ranging from mutualism through commensalism to parasitism. This overview will highlight selected aspects of endophyte diversity, host specificity, endophyte–host interaction and communication as well as regulation of secondary metabolite production with emphasis on advanced genomic methods and their role in improving our current knowledge of endophytic associations. Furthermore, the chemical potential of endophytic fungi for drug discovery will be discussed with focus on the detection of pharmaceutically valuable plant constituents as products of fungal biosynthesis. In addition, selected examples of bioactive metabolites reported in recent years (2008–2010) from fungal endophytes residing in terrestrial plants are presented grouped according to their reported biological activities.

Fungal endophytes: unique plant inhabitants with great promises

During the past two decades the frequencies and types of life-threatening fungal infections have increased dramatically in immunocompromised patients (7, 220, 232, 282). Several factors have contributed to this rise: the expansion of severely ill and/or immunocompromised patient populations with human immunodeficiency virus (HIV) infection, with chemotherapy-induced neutropenia, and receiving organ transplant-associated immunosuppressive therapy; more invasive medical procedures, such as extensive surgery and the use of prosthetic devices and vascular catheters; treatment with broad-spectrum antibiotics or glucocorticosteroids; parenteral nutrition; and peritoneal dialysis or hemodialysis (25, 63, 66). The major opportunistic pathogen has been Candida albicans (17, 25, 142); however, the frequency of non-C. albicans Candida species is increasing (232, 287). Invasive pulmonary aspergillosis is a leading cause of attributable mortality in bone marrow transplant recipients (209). HIV-infected patients are particularly susceptible to mucosal candidiasis, cryptococcal meningitis, disseminated histoplasmosis, and coccidioidomycosis (5, 66, 294), while Pneumocystis carinii pneumonia is a leading cause of death in HIV-infected patients in North America and Europe (121). P. carinii was considered, until recently, a protozoal parasite on the basis of its resistance to classical antifungal agents. However, it has been reclassified as being most closely related to ascomycetous fungi on the basis of rRNA and b-tubulin homologies, the presence of the typical fungal cell wall polymers glucan and chitin, and separate dihydrofolate reductase and thymidylate synthase enzymes (in protozoa, both activities reside on a single protein) (74, 163). Treatment of invasive mycoses is complicated by problems in diagnosis (285) and susceptibility testing (8, 79, 90, 230) of fungi. Opportunistic fungal infections are often treated empirically in profoundly neutropenic patients when there is fever of unknown origin refractory to broad-spectrum antibacterial agents (233, 266, 284). Treatment of deeply invasive fungal infections has consistently lagged behind bacterial chemotherapy (27, 178). Amphotericin B, still the ‘‘gold standard’’ for the treatment of most severe invasive fungal infections, was discovered in 1956 (102). One reason for the slow progress is that, like mammalian cells, fungi are eukaryotes, and thus, agents that inhibit protein, RNA, or DNA biosynthesis have greater potential for toxicity. A second reason is that, until recently, the incidence of life-threatening fungal infections was perceived as being too low to warrant aggressive research by the pharmaceutical industry. In the past decade, however, there has been a major expansion in the number of antifungal drugs available (99). Nevertheless, there are still major weaknesses in their spectra, potencies, safety, and pharmacokinetic properties. This minireview briefly discusses the antifungal agents currently in clinical use. It then considers the use of promising new biochemical targets in fungi as well as host-based, immunological approaches as evolving strategies for antifungal therapy.

Antifungal agents: chemotherapeutic targets and immunologic strategies.

Sphingofungins E and F : novel serinepalmitoyl transferase inhibitors from Paecilomyces variotii

Inhibition of serine palmitoyl-transferase activity by lipoxamycin.

Enfumafungin (1) is a hemiacetal, triterpene glycoside that was isolated from a fermentation of Hormonema sp. as a mixture of two interconverting forms. The primary structure of the major component of the mixture was determined as part of the mixture, mainly via NMR and comparison with hyalodendroside A (2), a related hemiacetal, triterpene glycoside that exists in a single form. The primary structure was confirmed, and the relative stereochemistry determined, based on a pair of methylacetal derivatives (3 and 4). Enfumafungin is an antifungal agent that acts as a specific inhibitor of glucan synthesis in cells and in vitro, and leads to morphological changes in yeasts and molds.

Isolation and Structural Determination of Enfumafungin, a Triterpene Glycoside Antifungal Agent That Is a Specific Inhibitor of Glucan Synthesis

There is disclosed a novel compound having the formula ##STR1## which exhibits antifungal activity.

Antifungal agent obtained from hormonema

New antibiotic eicosenoic acids and a method of producing it are described. The acids have been found to have antifungal properties.

Wendy S. Horn

Papers

Sphingofungins E and F : novel serinepalmitoyl transferase inhibitors from Paecilomyces variotii

Inhibition of serine palmitoyl-transferase activity by lipoxamycin.

Isolation and Structural Determination of Enfumafungin, a Triterpene Glycoside Antifungal Agent That Is a Specific Inhibitor of Glucan Synthesis

Antifungal agent obtained from hormonema

Antibiotic eicosenoic acids