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Mutation for Nonsyndromic Mental Retardation in the trans-2-Enoyl-CoA Reductase TER Gene Involved in Fatty Acid Elongation Impairs the Enzyme Activity and Stability, Leading to Change in Sphingolipid Profile
| Title: | Mutation for Nonsyndromic Mental Retardation in the trans-2-Enoyl-CoA Reductase TER Gene Involved in Fatty Acid Elongation Impairs the Enzyme Activity and Stability, Leading to Change in Sphingolipid Profile |
| Authors: | Abe, Kensuke Browse this author | | Ohno, Yusuke Browse this author | | Sassa, Takayuki Browse this author →KAKEN DB | | Taguchi, Ryo Browse this author →KAKEN DB | | Caliskan, Minal Browse this author | | Ober, Carole Browse this author | | Kihara, Akio Browse this author →KAKEN DB |
| Keywords: | Fatty Acid | | Fatty Acid Metabolism | | Lipids | | Membrane | | Sphingolipid |
| Issue Date: | 20-Dec-2013 |
| Publisher: | Amer soc biochemistry molecular biology inc |
| Journal Title: | Journal of biological chemistry |
| Volume: | 288 |
| Issue: | 51 |
| Start Page: | 36741 |
| End Page: | 36749 |
| Publisher DOI: | 10.1074/jbc.M113.493221 |
| PMID: | 24220030 |
| Abstract: | Background: The P182L mutation in the trans-2-enoyl-CoA reductase (TER) gene required for very long-chain fatty acid (VLCFA) synthesis causes nonsyndromic mental retardation. Results: This mutation reduces the activity and stability of the TER enzyme. Conclusion: The impaired TER function affects VLCFA synthesis and thereby alters the cellular sphingolipid profile. Significance: Maintenance of a proper VLCFA level may be important for neural function. Very long-chain fatty acids (VLCFAs, chain length >C20) exist in tissues throughout the body and are synthesized by repetition of the fatty acid (FA) elongation cycle composed of four successive enzymatic reactions. In mammals, the TER gene is the only gene encoding trans-2-enoyl-CoA reductase, which catalyzes the fourth reaction in the FA elongation cycle. The TER P182L mutation is the pathogenic mutation for nonsyndromic mental retardation. This mutation substitutes a leucine for a proline residue at amino acid 182 in the TER enzyme. Currently, the mechanism by which the TER P182L mutation causes nonsyndromic mental retardation is unknown. To understand the effect of this mutation on the TER enzyme and VLCFA synthesis, we have biochemically characterized the TER P182L mutant enzyme using yeast and mammalian cells transfected with the TER P182L mutant gene and analyzed the FA elongation cycle in the B-lymphoblastoid cell line with the homozygous TER P182L mutation (TERP182L/P182L B-lymphoblastoid cell line). We have found that TER P182L mutant enzyme exhibits reduced trans-2-enoyl-CoA reductase activity and protein stability, thereby impairing VLCFA synthesis and, in turn, altering the sphingolipid profile (i.e. decreased level of C24 sphingomyelin and C24 ceramide) in the TERP182L/P182L B-lymphoblastoid cell line. We have also found that in addition to the TER enzyme-catalyzed fourth reaction, the third reaction in the FA elongation cycle is affected by the TER P182L mutation. These findings provide new insight into the biochemical defects associated with this genetic mutation. |
| Rights: | This research was originally published in the Journal of biological chemistry. Abe K, et al. Mutation for nonsyndromic mental retardation in the trans-2-enoyl-CoA reductase TER gene involved in fatty acid elongation impairs the enzyme activity and stability, leading to change in sphingolipid profile. The Journal of biological chemistry. 2013; 288(51):36741-9. (c)2013 the American Society for Biochemistry and Molecular Biology. |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/54774 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 木原 章雄
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