Abstract：
The human fatty acid synthase (hFASN) produces fatty acids for cellar membrane construction, energy storage, biomolecule modifications and signal transduction. Abnormal expression and functions of hFASN highly associate with numerous human diseases such as obesity, diabetes, and cancers, and thereby it has been considered as a valuable potential drug target. So far, the structural and catalytic mechanisms of most of the hFASN enzymatic modules have been extensively studied, except the key dehydratase module (hDH). Here we presented the enzymatic characterization and the high-resolution crystal structure of hDH. We demonstrated that the hDH preferentially catalyzes the acyl substrates with short lengths between 4 to 8-carbons, and exhibits much lower enzymatic activity on longer substrates. Subsequent structural study showed that hDH displays a pseudo-dimeric organization with a single L-shaped composite hydrophobic catalytic tunnel as well as an atypical ACP binding site nearby, indicating that hDH achieves distinct substrate recognition and dehydration mechanisms compared to the conventional bacterial fatty acid dehydratases identified. Our findings laid the foundation for understanding the biological and pathogenic functions of hFASN, and may facilitate therapeutical drug development against diseases with abnormal functionality of hFASN.
摘要：
人脂肪酸合成酶（hFASN）产生用于细胞膜构建的脂肪酸，储能，生物分子修饰和信号转导。hFASN的异常表达和功能与许多人类疾病如肥胖高度相关,糖尿病,和癌症，因此，它被认为是一个有价值的潜在药物靶标。到目前为止,大多数hFASN酶模块的结构和催化机理已被广泛研究，除了关键脱水酶模块(hDH)。在这里，我们介绍了hDH的酶学表征和高分辨率晶体结构。我们证明了hDH优先催化长度在4到8个碳之间的酰基底物，并且在更长的底物上表现出低得多的酶活性。随后的结构研究表明，hDH表现出假二聚组织，具有单个L形复合疏水催化隧道以及附近的非典型ACP结合位点，表明与鉴定的常规细菌脂肪酸脱水酶相比,hDH实现了不同的底物识别和脱水机制。我们的发现为理解hFASN的生物学和致病功能奠定了基础。并且可以促进针对hFASN功能异常的疾病的治疗药物开发。
