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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Human fatty acid synthase: Structure and substrate selectivity of the thioesterase domain.
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Human fatty acid synthase: Structure and substrate selectivity of the thioesterase domain.

机译：人脂肪酸合酶：硫酯酶结构域的结构和底物选择性。

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摘要

Human fatty acid synthase is a large homodimeric multifunctional enzyme that synthesizes palmitic acid. The unique carboxyl terminal thioesterase domain of fatty acid synthase hydrolyzes the growing fatty acid chain and plays a critical role in regulating the chain length of fatty acid released. Also, the up-regulation of human fatty acid synthase in a variety of cancer makes the thioesterase a candidate target for therapeutic treatment. The 2.6-A resolution structure of human fatty acid synthase thioesterase domain reported here is comprised of two dissimilar subdomains, A and B. The smaller subdomain B is composed entirely of alpha-helices arranged in an atypical fold, whereas the A subdomain is a variation of the alpha/beta hydrolase fold. The structure revealed the presence of a hydrophobic groove with a distal pocket at the interface of the two subdomains, which constitutes the candidate substrate binding site. The length and largely hydrophobic nature of the groove and pocket are consistent with the high selectivity of the thioesterase for palmitoyl acyl substrate. The structure also set the identity of the Asp residue of the catalytic triad of Ser, His, and Asp located in subdomain A at the proximal end of the groove.
机译：人脂肪酸合酶是合成棕榈酸的大同型二聚体多功能酶。脂肪酸合酶的独特的羧基末端硫酯酶结构域水解增长的脂肪酸链，并在调节释放的脂肪酸的链长中起关键作用。同样，在多种癌症中人脂肪酸合酶的上调使得硫酯酶成为治疗的候选靶标。此处报道的人脂肪酸合酶硫酯酶结构域的2.6-A分辨率结构由两个不同的亚结构域A和B组成。较小的亚结构域B完全由非典型折叠的α螺旋组成，而A子结构域是一个变体α/β水解酶折叠的数目。该结构揭示了在两个亚结构域的界面处存在带有远端袋的疏水凹槽，该凹槽构成候选底物结合位点。凹槽和凹穴的长度和大部分疏水性与硫酯酶对棕榈酰基酰基底物的高选择性相一致。该结构还设置了位于沟槽近端子域A中的Ser，His和Asp催化三联体的Asp残基的身份。

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