STRUCTURAL STUDIES ASSOCIATED WITH THE CATALYSIS OF FATTY ACID SYNTHASE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 脂肪酸合成酶（FAS）催化脂肪酸的从头合成，在胚胎发生和能量平衡中起着重要作用。 FAS抑制剂有可能作为肥胖症的治疗剂，从而降低相关心血管疾病和癌症的风险。 动物胞质FAS是一种272 kDa的多酶多肽，需要二聚化才能发挥活性。 生化证据表明FAS亚基呈现卷曲的头对头结构。 这个模型已经证实了我们随后的结构表征的单个FAS颗粒的电子显微镜（EM），是与最近发表的晶体结构。 然而，在这两种结构的羧基末端结构域未被确定，其已知的构象迁移率一致。 我们建议继续我们的调查FAS的EM明确地确定这些移动的羧基末端结构域的位置，并调查FAS二聚体在脂肪酸合成的每一步假定的构象。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fatty acid synthase (FAS) catalyzes the de novo synthesis of fatty acids and plays an essential role in embryogenesis and energy homeostasis. Inhibitors of FAS have the potential as treamtents for obesity, thereby reducing the risk for related cardiovascular diseases, and for cancer. The animal cytosolic FAS is a 272 kDa multienzyme polypeptide that requires dimerization for activity. Biochemical evidence suggests that FAS subunits assume a coiled, head-to-head architecture. This model has been substantiated by our subsequent structural characterization of single FAS particles by electron microscopy (EM) and is consistent with a recently published crystal structure. However in both structures the carboxyl-terminal domains were not identified, consistent with their known conformational mobility. We propose to continue our investigations of FAS by EM to unequivocally determine locations of these mobile carboxyl terminal domains and to investigate the conformations assumed by the FAS dimer at each step in fatty acid synthesis.