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Journal of Biochemistry Advance Access originally published online on June 8, 2009
Journal of Biochemistry 2009 146(3):429-437; 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 Shimamura1, Hidekazu Takahashi2, Hidefumi Kitazawa1, Yasuhisa Miyamoto1, Akira Nagumo1, Cheng Tang3, Dennis Dean3, Tsuyoshi Nagase2, Nagaaki Sato2 and Shigeru Tokita1,*

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

*To whom correspondence should be addressed. Tel: +81-29-877-2000, Fax: +81-29-877-2027, E-mail: shigeru.tokita{at}po.rd.taisho.co.jp

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 >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.

Key Words: elongases, ELOVL6, inhibitor, radioligand, ligand binding

Abbreviations: ELOVL, elongation of very long-chain fatty acids


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