The mechanism of antifungal action of (S)-2-amino-4-oxo-5-hydroxypentanoic acid, RI-331: the inhibition of homoserine dehydrogenase in Saccharomyces cerevisiae.
We have explored the mechanism by which an antifungal antibiotic, (S)-2-amino-4-oxo-5-hydroxypentanoic acid, RI-331, preferentially inhibits protein biosynthesis in Saccharomyces cerevisiae, by inhibiting the biosynthesis of the aspartate family of amino acids, methionine, isoleucine and threonine. This inhibition was effected by inhibiting the biosynthesis of their common intermediate precursor homoserine. The target enzyme of RI-331 was homoserine dehydrogenase (EC.1.1.1.3) which is involved in converting aspartate semialdehyde to homoserine in the pathway from aspartate to homoserine. The enzyme is lacking in animals. So the antibiotic is selectively toxic to prototrophic fungi.
Yamaki
H
H
Institute of Applied Microbiology, University of Tokyo, Japan.
Yamaguchi
M
M
Imamura
H
H
Suzuki
H
H
Nishimura
T
T
Saito
H
H
Yamaguchi
H
H
D000429:Alcohol Oxidoreductases / Q000096:biosynthesis*; D000622:Aminolevulinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D001223:Aspartate-Semialdehyde Dehydrogenase / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism; D006714:Homoserine / Q000378:metabolism; D006715:Homoserine Dehydrogenase / Q000096:biosynthesis*; D007700:Kinetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology*
D000935:Antifungal Agents; D001224:Aspartic Acid; D006714:Homoserine; C058222:2-amino-5-hydroxy-4-oxopentanoic acid; D000622:Aminolevulinic Acid; D000429:Alcohol Oxidoreductases; D006715:Homoserine Dehydrogenase; D001223:Aspartate-Semialdehyde Dehydrogenase