Inhibitory activity to protein prenylation and antifungal activity of zaragozic acid D3, a potent inhibitor of squalene synthase produced by the fungus, Mollisia sp. SANK 10294.
Recently we found novel zaragozic acids (ZAs), F-10863A (zaragozic acid D3, ZAD3), B, C and D in the culture broth of the fungus Mollisia sp. SANK 10294 as potent inhibitors of squalene synthase. There are several other enzymes that use farnesylpyrophosphate as their substrate. Among them we chose farnesyl-protein transferase and examined whether ZAD3 and F-10863B inhibit this enzyme's activity. ZAD3 and F-10863B inhibited farnesyl-protein transferase with IC50 values of 0.60 and 3.7 microM, respectively. They also inhibited geranylgeranyl-protein transferase at similar concentrations. In addition, they exhibited potent antifungal activity.
Tanimoto
T
T
Pharmacology Laboratory, Sankyo Co., Ltd., Tokyo, Japan.
Ohya
S
S
Tsujita
Y
Y
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001203:Ascomycota / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D005658:Fungi / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D017368:Protein Prenylation / Q000187:drug effects*; D014233:Tricarboxylic Acids / Q000737:chemistry / Q000494:pharmacology*
D000935:Antifungal Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; C112876:F 10863B; D014233:Tricarboxylic Acids; C112877:zaragozic acid D3; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D013186:Farnesyl-Diphosphate Farnesyltransferase