Metabolomic identification of the target of the filopodia protrusion inhibitor glucopiericidin A.
Identifying the targets of bioactive compounds is a major challenge in chemical biological research. Here, we identified the functional target of the natural bioactive compound glucopiericidin A (GPA) through metabolomic analysis. We isolated GPA while screening microbial samples for a filopodia protrusion inhibitor. Interestingly, GPA alone did not inhibit filopodia protrusion, but synergistically inhibit protrusion with the mitochondrial respiration inhibitor, piericidin A (PA). These results suggested that GPA might inhibit glycolysis. Capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) provided strong evidence that GPA suppresses glycolysis by functionally targeting the glucose transporter. GPA may therefore serve as a glucose transporter chemical probe. Simultaneous inhibition of both glycolysis and mitochondrial respiration dramatically decreased intracellular ATP levels, indicating that GPA inhibits ATP-dependent filopodia protrusion with PA. Our results represent a challenge of molecular target identification using metabolomic analysis.
Kitagawa
Mitsuhiro
M
Department of Biosciences and Informatics, Keio University, Kohokuku, Yokohama, Kanagawa, Japan.
Ikeda
Satsuki
S
Tashiro
Etsu
E
Soga
Tomoyoshi
T
Imoto
Masaya
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D019075:Electrophoresis, Capillary / Q000379:methods; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D055442:Metabolome; D011554:Pseudopodia / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D051246:Glucose Transport Proteins, Facilitative; D011725:Pyridines; C052314:glucopiericidin A; D000255:Adenosine Triphosphate; C100213:piericidin A