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Structure type: monomer
Trivial name: khafrefungin
Compound class: glycoside

• Article ID: 7794
  Mandala SM, Thornton RA, Rosenbach M, Milligan J, Garcia-Calvo M, Bull HG, Kurtz MB "Khafrefungin, a novel inhibitor of sphingolipid synthesis" - Journal of Biological Chemistry 272(51) (1997) 32709-32714
  

  In the course of screening for antifungal agents we have discovered a novel compound isolated from an endophytic fungus that inhibits fungal sphingolipid synthesis. Khafrefungin, which is composed of aldonic acid linked via an ester to a C22 modified alkyl chain, has fungicidal activity against Candida albicans, Cryptococcus neoformans, and Saccharomyces cerevisiae. Sphingolipid synthesis is inhibited in these organisms at the step in which phosphoinositol is transferred to ceramide, resulting in accumulation of ceramide and loss of all of the complex sphingolipids. In vitro, khafrefungin inhibits the inositol phosphoceramide synthase of C. albicans with an IC50 of 0.6 nM. Khafrefungin does not inhibit the synthesis of mammalian sphingolipids thus making this the first reported compound that is specific for the fungal pathway.

  antifungal activity, khafrefungin, sphingolipid synthesis inhibition

  NCBI PubMed ID: 9405490
  Publication DOI: 10.1074/jbc.272.51.32709
  Journal NLM ID: 2985121R
  Publisher: Baltimore, MD: American Society for Biochemistry and Molecular Biology
  Correspondence: suzanne_mandala@merck.com
  Institutions: Department of Biochemistry, Merck Research Laboratories, Rahway, USA
  Methods: deacetylation, TLC, biological assays, radiolabeling, HPLC, alkaline hydrolysis, extraction, cell growth, derivatization, evaporation
  
   
  
  (fungi)
  CSDB ID 45648 (all data & tools)
• Article ID: 7795
  Mandala SM, Harris GH "Isolation and characterization of novel inhibitors of sphingolipid synthesis: australifungin, viridiofungins, rustmicin, and khafrefungin" - Methods in Enzymology 311 (2000) 335-348
  

  Sphingolipid synthesis is an essential process in yeast and the pathogenic fungi that cause life-threatening human infections such as candidiasis, aspergillosis, and cryptococcosis. Although many steps in the human and fungal sphingolipid biosynthetic pathway are similar, there are several enzymes found uniquely in fungi that are potential targets for the development of nontoxic therapeutic antifungals. In the screening program, it has been found that natural products are a rich source of structurally diverse inhibitors of sphingolipid synthesis. Natural product inhibitors to four different enzymes that affect sphingolipid synthesis have been discovered: sphingofungins, lipoxamycin, myriocin/ISP1, and viridiofungins inhibit serine palmitoyltransferase; fumonisin B1 and australifungin, inhibit ceramide synthase; aureobasidins, khafrefungin, and rustmicin inhibit inositol phosphoceramide synthase; and minimoidin inhibits the fatty acid elongation pathway. Most of these compounds have fungicidal activity against a broad spectrum of pathogenic fungi, but only the inhibitors of inositol phosphoceramide are fungal selective; compounds that inhibit early biosynthetic steps show comparable activity against orthologous mammalian enzymes. This chapter describes a method to identify sphingolipid inhibitors and detailed protocol for the isolation of australifungin. More abbreviated descriptions of the isolation of viridiofungins, khafrefungin, and rustmicin are also included.

  antifungal activity, khafrefungin, sphingolipid synthesis inhibition

  NCBI PubMed ID: 10563338
  Publication DOI: 10.1016/s0076-6879(00)11094-8
  Journal NLM ID: 0212271
  Correspondence: suzanne_mandala@merck.com
  Institutions: Department of Infectious Disease, Merck Research Laboratories, Rahway, USA
  Methods: biological assays, HPLC, extraction, CC, cell growth
  
   
  
  (fungi)
  CSDB ID 45649 (all data & tools)