Dr.Vladimir Denic （University of California San Francisco）

2007年10月03日(水) 15:30 より 17:00 まで

生理学研究所１階会議室

分子細胞生物学研究部門 大隅良典 内線7515

While the majority of fatty acids in the cell are 16 and 18 carbons long, a fraction of these are further elongated into essential very long-chain fatty acids (VLCFAs) of diverse lengths. The enzymatic machinery responsible for VLCFA synthesis has been difficult to characterize because it comprises a series of detergent-labile protein complexes embedded in the endoplasmic reticulum (ER) membrane. As a result, the molecular mechanism responsible for generating VLCFA structural diversity has remained elusive. We have recently identified a key missing enzyme in this process and this allowed us to reconstitute VLCFA synthesis in proteoliposomes containing purified ER membrane components. Through homolog domain swapping and engineering experiments involving a another enzyme in this multiprotein machine, we found that the position of a lysine on one face of a helical transmembrane domain directly controls the final chain length of VLCFA products. This mutational flexibility of VLCFA synthase has enabled the structural diversification of VLCFAs during evolution and should facilitate rational design of "unnatural" VLCFAs with novel bioactivities as well as small-molecule therapeutics that selectively target this process.