Abstract
The glyoxylate cycle is a sequence of anaplerotic reactions catalyzed by the key enzymes isocitrate lyase (ICL) and malate synthase, and plays an important role in the pathogenesis of microorganisms during infection. An icl-deletion mutant of Candida albicans exhibited reduced virulence in mice compared with the wild type. Five diketopiperazines, which are small and stable cyclic peptides, isolated from the marine-derived Streptomyces puniceus Act1085, were evaluated for their inhibitory effects on C. albicans ICL. The structures of these compounds were elucidated based on spectroscopic data and comparisons with previously reported data. Cyclo(L-Phe-L-Val) was identified as a potent ICL inhibitor, with a half maximal inhibitory concentration of 27 μg/mL. Based on the growth phenotype of the icl-deletion mutants and icl expression analyses, we demonstrated that cyclo(L-Phe-L-Val) inhibits the gene transcription of ICL in C. albicans under C2-carbon-utilizing conditions.
Highlights
The glyoxylate cycle exists in a wide range of organisms, such as archaea, bacteria, fungi, plants, and nematodes
This cycle plays roles in cell metabolic processes as an anaplerotic pathway of the tricarboxylic acid cycle catalyzed by isocitrate lyase (ICL) and malate synthase, which is a key component of the glyoxylate cycle [1]
The function of cycle this cycle hasconfirmed been confirmed by theofanalysis of mutant microorganisms deficient in and malate synthase, which are key components of the glyoxylate pathogenic microorganisms deficient in ICL and malate synthase, which are key components of the cycle
Summary
The glyoxylate cycle exists in a wide range of organisms, such as archaea, bacteria, fungi, plants, and nematodes This cycle plays roles in cell metabolic processes as an anaplerotic pathway of the tricarboxylic acid cycle catalyzed by isocitrate lyase (ICL) and malate synthase, which is a key component of the glyoxylate cycle [1]. An icl-deletion mutant of C. albicans was unable to utilize C2 carbon substrates and had diminished virulence compared with the wild-type strain [2,5,6,7,8] As this cycle does not exist in mammalian cells, ICL appears to be a prospective target for the development of antifungal drugs. As part of our ongoing search for inhibitors of C. albicans ICL, we encountered Streptomyces puniceus puniceus Act1085, isolated from marine sediment from Jeju Island, Republic of Korea [20].
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