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J. Biol. Chem., Vol. 277, Issue 44, 41744-41749, November 1, 2002

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Differential Sensitivity between Fks1p and Fks2p against a Novel -1,3-Glucan Synthase Inhibitor, Aerothricin1^*

Osamu Kondoh, Tsuyoshi Takasuka, Mikio Arisawa, Yuko Aoki, and Takahide Watanabe

From the Department of Mycology, Nippon Roche Research Center, Kamakura, Kanagawa 247-8530, Japan

Fks1p and Fks2p are catalytic subunits of -1,3-glucan synthase, which synthesize -1,3-glucan, a main component of the cell wall in Saccharomyces cerevisiae. Although Fks1p and Fks2p are highly homologous, sharing 88.1% identity, it has been shown that Fks2p is more sensitive than Fks1p to one of echinocandin derivatives, which inhibits -1,3-glucan synthase activity. Here we show a similar differential sensitivity between Fks1p and Fks2p to a novel -1,3-glucan synthase inhibitor, aerothricin1. To investigate the molecular mechanism of this differential sensitivity, we constructed a series of chimeric genes of FKSs and examined their sensitivity to aerothricin1. As a result, it was shown that a region around the fourth extracellular domain of Fks2p, containing 10 different amino acid residues from those of Fks1p, provided Fks1p aerothricin1 sensitivity when the region was replaced with a corresponding region of Fks1p. In order to identify essential amino acid residues responsible for the sensitivity, each of the 10 non-conserved amino acids of Fks1p was substituted into the corresponding amino acid of Fks2p by site-directed mutagenesis. Surprisingly, only one amino acid substitution of Fks1p (K1336I) conferred Fks1p hypersensitivity to aerothricin1. On the other hand, reverse substitution of the corresponding amino acid of Fks2p (I1355K) resulted in loss of hypersensitivity to aerothricin1. These results suggest that the 1355th isoleucine of Fks2p plays a key role in aerothricin1 sensitivity.

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