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Journal of Biochemistry Advance Access published online on June 8, 2009
Journal of Biochemistry, doi:10.1093/jb/mvp088
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© The authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Identification and characterization of a selective radioligand for ELOVL6

Ken Shimanura1, Hidekazu Takahashi2, Hidefumi Kitazawa1, Yasuhisa Miyamoto1, Akira Nagumo1, Cheng Tang3, Dennis Dean3, Tsuyoshi Nagase2, Nagaaki Sato2 and Shigeru Tokita1

1Department of Metabolic Disorder, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan
2Department of Medicinal Chemistry, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan
3Merck Research Laboratories, Rahway, NJ 07065, USA

To whom correspondence should be addressed: Dr. Shigeru Tokita, PhD.,: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3,Tsukuba, Ibaraki, 300-2611, JAPAN Tel: +81-29-877-2000, Fax: +81-29-877-2027, E-mail: shigeru_tokita{at}merck.com

Received May 1, 2009; Accepted June 1, 2009


  Abstract

ELOVL6, a member of the elongation of very long chain fatty acids (ELOVL) family, has recently been identified as the rate-limiting enzyme for the elongation of palmitoyl-CoA. ELOVL6 deficient mice are protected from high-fat diet induced insulin resistance, suggesting that ELOVL6 might be a promising target for the treatment of metabolic disorders. Despite the increasing interest in Elovl6 as a therapeutic target, the lack of chemical tools for this enzyme has limited further elucidation of the biochemical and pharmacological properties of ELOVL6. We have identified Compound-A, a potent inhibitor for ELOVL6, by screening our company library and subsequently optimizing hit compounds. Compound-A potently inhibited human and mouse ELOVL6 and displayed more than 100-fold greater selectivity for ELOVL6 over other ELOVL family members. Consistent with its potent and selective inhibitory activity toward ELOVL6, [3H]Compound-A bound to ELOVL6 with high affinity while showing no specific binding to other ELOVL enzymes. The observation that [3H]Compound-A bound to ELOVL6 in a palmitoyl-CoA dependent manner in the absence of malonyl-CoA and NADPH suggests that Compound-A might recognize an enzyme-substrate complex e.g. an acyl-enzyme intermediate. Collectively, these observations demonstrate that Compound-A and its tritiated form are useful tools for biochemical and pharmacological characterization of ELOVL6.


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