Borrelidin B: isolation, biological activity, and implications for nitrile biosynthesis.
Borrelidin (1) is a nitrile-containing bacterially derived polyketide that is a potent inhibitor of bacterial and eukaryotic threonyl-tRNA synthetases. We now report the discovery of borrelidin B (2), a tetrahydro-borrelidin derivative containing an aminomethyl group in place of the nitrile functionality in borrelidin. The discovery of this new metabolite has implications for both the biosynthesis of the nitrile group and the bioactivity of the borrelidin compound class. Screening in the SToPS assay for tRNA synthetase inhibition revealed that the nitrile moiety is essential for activity, while profiling using our in-house image-based cytological profiling assay demonstrated that 2 retains biological activity by causing a mitotic stall, even in the absence of the nitrile motif.
Department of Chemistry and Biochemistry, University of California, Santa Cruz , 1156 High Street, Santa Cruz, California 95064, United States.
Christopher J
CJ
Schulze
Walter M
WM
Bray
Frank
F
Loganzo
My-Hanh
MH
Lam
Teresa
T
Szal
Anabella
A
Villalobos
Frank E
FE
Koehn
Roger G
RG
Linington
D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism; D005233:Fatty Alcohols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000378:metabolism; D013914:Threonine-tRNA Ligase / Q000037:antagonists & inhibitors*
D005233:Fatty Alcohols; D009570:Nitriles; C005066:borrelidin; D000604:Amino Acyl-tRNA Synthetases; D013914:Threonine-tRNA Ligase