細(xì)胞內(nèi)一種稱為脂肪酸合成酶的分子復(fù)合體合成脂肪,。美國兒童醫(yī)院奧克蘭研究所Stuart Smith博士與來自加州Scripps研究所的研究人員合作,，詳細(xì)報(bào)道該酶復(fù)合體如何相互協(xié)作合成脂肪,。該復(fù)合體很有可能成為開發(fā)新一代抗肥胖和抗癌癥藥物的靶標(biāo)。這項(xiàng)研究發(fā)表在2 月Nature Structural and Molecular Biology雜志上,。
Smith 博士表示，脂肪酸合成酶擁有一種相當(dāng)復(fù)雜的結(jié)構(gòu)。此前預(yù)期該酶復(fù)合體結(jié)構(gòu)相當(dāng)柔性,，因而很難利用X 光晶體衍射分析這種復(fù)合體結(jié)構(gòu)。2008 年,，瑞士一組研究人員解析了該復(fù)合體的X 光衍射結(jié)構(gòu),，但僅提供了眾多構(gòu)型中的一個(gè)。近期的研究利用最前沿的電子顯微鏡捕獲脂肪酸合成酶眾多不同構(gòu)型的圖片,，將這些圖片以適當(dāng)方式動(dòng)態(tài)排列,，從而可以全程顯示該酶復(fù)合體不同構(gòu)型的運(yùn)動(dòng)。結(jié)果顯示,，位于該酶復(fù)合體X 光結(jié)構(gòu)中邊遠(yuǎn)位置的多種酶可以始終與參與催化的酶保持接觸,。
部分制藥公司聚焦于脂肪酸合成酶抑制劑的開發(fā)，后者阻斷碳水化合物向脂肪轉(zhuǎn)化,，抑制胃口,，并延緩癌癥細(xì)胞的生長。來自X 光和電子顯微鏡圖像的結(jié)構(gòu)信息,，將有助于具有治療價(jià)值的高效抑制劑設(shè)計(jì),。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature Structural & Molecular Biology 18 January 2009 | doi:10.1038/nsmb.1532
Conformational flexibility of metazoan fatty acid synthase enables catalysis
Edward J Brignole1, Stuart Smith2 & Francisco J Asturias1
Abstract
The metazoan cytosolic fatty acid synthase (FAS) contains all of the enzymes required for de novo fatty acid biosynthesis covalently linked around two reaction chambers. Although the three-dimensional architecture of FAS has been mostly defined, it is unclear how reaction intermediates can transfer between distant catalytic domains. Using single-particle EM, we have identified a near continuum of conformations consistent with a remarkable flexibility of FAS. The distribution of conformations was influenced by the presence of substrates and altered by different catalytic mutations, suggesting a direct correlation between conformation and specific enzymatic activities. We interpreted three-dimensional reconstructions by docking high-resolution structures of individual domains, and they show that the substrate-loading and condensation domains dramatically swing and swivel to access substrates within either reaction chamber. Concomitant rearrangement of the -carbon–processing domains synchronizes acyl chain reduction in one chamber with acyl chain elongation in the other.
1 Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
2 Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, California 94609, USA.
