De novo fatty acid biosynthesis in humans is accomplished by a multidomain protein, the Type I fatty acid synthase (FAS). Although ubiquitously expressed in all tissues, fatty acid synthesis is not essential in normal healthy cells due to sufficient supply with fatty acids by the diet. However, FAS is overexpressed in cancer cells and correlates with tumor malignancy, which makes FAS an attractive selective therapeutic target in tumorigenesis. Herein, we present a crystal structure of the condensing part of murine FAS, highly homologous to human FAS, with octanoyl moieties covalently bound to the transferase (MAT-malonyl-/acetyltransferase) and the condensation (KS-β-ketoacyl synthase) domain. The MAT domain binds the octanoyl moiety in a novel (unique) conformation, which reflects the pronounced conformational dynamics of the substrate-binding site responsible for the MAT substrate promiscuity. In contrast, the KS binding pocket just subtly adapts to the octanoyl moiety upon substrate binding. Besides the rigid domain structure, we found a positive cooperative effect in the substrate binding of the KS domain by a comprehensive enzyme kinetic study. These structural and mechanistic findings contribute significantly to our understanding of the mode of action of FAS and may guide future rational inhibitor designs.

中文翻译：

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I型脂肪酸合酶陷于辛酰基结合状态。

人体内从头进行脂肪酸生物合成是通过多结构域蛋白I型脂肪酸合成酶（FAS）完成的。尽管在所有组织中普遍存在，但是由于饮食中脂肪酸的充足供应，脂肪酸合成在正常健康细胞中不是必需的。然而，FAS在癌细胞中过表达并与肿瘤恶性肿瘤相关，这使FAS成为肿瘤发生中有吸引力的选择性治疗靶标。在本文中，我们介绍了鼠FAS的缩合部分的晶体结构，该结构与人FAS高度同源，具有与转移酶（MAT-丙二酸-/乙酰基转移酶）和缩合（KS-β-酮酰基合酶）结构域共价结合的辛酰基部分。MAT域以新颖的（独特的）构象结合辛酰基部分，这反映了负责MAT底物混杂的底物结合位点的明显构象动力学。相反，KS结合口袋在底物结合后仅微妙地适应辛酰基部分。除了刚性结构域结构外，我们还通过全面的酶动力学研究在KS结构域的底物结合中发现了积极的协同作用。这些结构和机理上的发现大大有助于我们对FAS的作用方式的理解，并可能指导未来合理的抑制剂设计。通过全面的酶动力学研究，我们发现了KS域的底物结合具有积极的协同作用。这些结构和机理上的发现大大有助于我们对FAS的作用方式的理解，并可能指导未来合理的抑制剂设计。通过全面的酶动力学研究，我们发现了KS域的底物结合具有积极的协同作用。这些结构和机理上的发现大大有助于我们对FAS的作用方式的理解，并可能指导未来合理的抑制剂设计。