Functional characterization of ttmM unveils new tautomycin analogs and insight into tautomycin biosynthesis and activity.
The biosynthetic gene cluster for tautomycin (TTM), a potent protein phosphatase (PP) inhibitor has recently been characterized. Inactivation of ttmM, which encodes a putative C3' hydroxylase, afforded mutant SB6005 which accumulated three new 3'-deshydroxy TTM analogs, supporting the function of TtmM and the previously proposed linear pathway for TTM biosynthesis. Bioassays reveal the importance of the C3' OH moiety in PP inhibition and that PP inhibition is not the exclusive mechanism driving TTM-induced cell death.
Ju
Jianhua
J
Division of Pharmaceutical Sciences, UW Paul P. Carbone Comprehensive Cancer Center Small Molecule Screening Facility, University of Wisconsin National Cooperative Drug Discovery Group, University of Wisconsin, Madison, Wisconsin 53705-2222, USA.
Li
Wenli
W
Yuan
Qiuping
Q
Peters
Noel R
NR
Hoffmann
F Michael
FM
Rajski
Scott R
SR
Osada
Hiroyuki
H
Shen
Ben
B
D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D008055:Lipids / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D005810:Multigene Family / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
D005663:Furans; D008055:Lipids; D011714:Pyrans; D013141:Spiro Compounds; C053079:tautomycin; C058744:tautomycetin; D010749:Phosphoprotein Phosphatases