Terpendole E and its Derivative Inhibit STLC‐ and GSK‐1‐Resistant Eg5. Issue 7 (19th March 2014)

• Record Type: Journal Article
• Authors: Tarui, Yuka; Chinen, Takumi; Nagumo, Yoko; Motoyama, Takayuki; Hayashi, Toshiaki; Hirota, Hiroshi; Muroi, Makoto; Ishii, Yasuyuki; Kondo, Hisae; Osada, Hiroyuki; Usui, Takeo
• Is Part Of: Chembiochem. Volume 15:Issue 7(2014)
• Page Start: 934
• Page End: 938
• Publication Date: 2014-03-19
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201300808
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Terpendole E is first natural product found to inhibit mitotic kinesin Eg5, but its inhibitory mechanism remains to be revealed. Here, we report the effects of terpendole E and 11ketopaspaline (a new natural terpendole E analogue) on the Eg5–microtubule interaction and in several Eg5 mutants. 11‐Ketopaspaline is a shunt product from terpendole E, and it shows potent inhibitory activity against the microtubule‐stimulated ATPase activity of Eg5. Unlike other Eg5 inhibitors, such as <italic>S</italic>‐trityl‐<sc>L</sc>‐cysteine (STLC) and GSK‐1, both terpendole E and 11‐ketopaspaline only partially inhibited Eg5–microtubule interaction. Furthermore, terpendole E and 11‐ketopaspaline inhibited several Eg5 mutants that are resistant to STLC (Eg5^D130A, Eg5^L214A) or GSK‐1 (Eg5^I299F, Eg5^A356T), but with the same extent of inhibition against wild‐type Eg5. Because Eg5^D130A and Eg5^L214A show cross‐resistance to most known Eg5 inhibitors, which bind the L5 loop, these results suggest that terpendole E and its analogues have a different binding site and/or inhibitory mechanism to those for L5 loop‐binding type Eg5 inhibitors.</p> </abstract>