Clorobiocin biosynthesis in Streptomyces: identification of the halogenase and generation of structural analogs.
Clorobiocin (clo) and novobiocin (nov) are potent inhibitors of bacterial DNA gyrase. The two substances differ in the substitution pattern at C-8' of the aminocoumarin ring, carrying a chlorine atom or a methyl group, respectively. By gene inactivation, clo-hal was identified as the gene of the halogenase responsible for the introduction of the chlorine atom of clorobiocin. Inactivation of cloZ did not affect clorobiocin formation, showing that this ORF is not essential for clorobiocin biosynthesis. Expression of the methyltransferase gene novO in the clo-hal(-) mutant led to the very efficient formation of a hybrid antibiotic containing a methyl group instead of a chlorine atom at C-8'. Comparison of the antibacterial activity of clorobiocin analogs with -Cl, -H, or -CH(3) at C-8' showed that chlorine leads to 8-fold higher activity than hydrogen and to 2-fold higher activity than a methyl group.
Eustáquio
Alessandra S
AS
Pharmazeutische Biologie, Pharmazeutisches Institut, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Gust
Bertolt
B
Luft
Thomas
T
Li
Shu Ming
SM
Chater
Keith F
KF
Heide
Lutz
L
D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D008780:Methyltransferases / Q000096:biosynthesis; D009154:Mutation; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000737:chemistry; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D013302:Streptomyces / Q000201:enzymology / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; C492924:novclobiocin 101; C492925:novclobiocin 102; D009675:Novobiocin; C006260:clorobiocin; D010088:Oxidoreductases; D008780:Methyltransferases