脂肪酸合酶
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脂肪酸合酶（英語：Fatty acid synthase）是一個具有多種功能的酶系統，在哺乳動物中，其分子量高達272kDa。在脂肪酸合酶中，底物和中間產物分子在各個功能結構域（可以位于同一酶分子，也可以位于不同酶分子）中傳遞直到完成脂肪酸的整個合成過程。[1][2][3][4][5]
目錄 |
代謝功能
脂肪酸是脂肪族類酸，在能量運輸和儲存、細胞結構、提供激素合成的中間物等多個方面發揮著關鍵作用。脂肪酸的合成需要將乙酰輔酶A和丙二酸單酰輔酶A通過一系列的克萊森縮合反應然后脫羧（生物素作輔酶）來完成。在脂肪鏈的延伸過程中，通過連續的酮還原酶、脫水酶以及烯脂酰ACP還原酶的作用，加入的酮基（酰基）被還原為完全飽和的脂肪鏈。延伸中的脂肪鏈在這些酶活性位點之間循環傳遞時，共價連接在酰基載體蛋白的磷酸泛酰巰基乙胺（phophopantetheine）輔基上，并通過硫酯酶的作用而被釋放。
分類
脂肪酸合酶被分為兩大類：
結構
哺乳動物中的脂肪酸合酶含有兩個等同的多功能單鏈（形成同源二聚體），每一條氨基酸鏈的N端區域含有三個催化結構域（酮脂酰合成酶、脫水酶和單酰/乙酰轉移酶），而C端區域則含有四個結構域（醇還原酶、酮脂酰還原酶、?；d體蛋白和硫酯酶），這兩個區域被中間600個氨基酸殘基組成的核心區域所分隔。[6][7]
脂肪酸合酶組構的傳統模型（“頭對尾”模型）大部分是基于雙功能試劑1,3-dibromopropanone（DBP）能夠將一個脂肪酸合酶單體上的酮脂酰合成酶結構域活性位點上的半胱氨酸（Cys161）的巰基和另一個單體上的載體蛋白結構域中的磷酸泛酰巰基乙胺輔基聯接在一起的現象。[8][9]
但對脂肪酸合酶二聚體所進行的突變研究發現酮脂酰合成酶和單酰/乙酰轉移酶結構域可以與二聚體中任何一個單體上的載體蛋白共同作用；[10][11] 而對于DBP聯接實驗結果的再分析顯示酮脂酰合成酶的活性位點Cys161的巰基可以被聯接到任一單體中載體蛋白4'-磷酸泛酰巰基乙胺的巰基上。[12]。而且，近來發現只含有一個完整單體的異源二聚化的脂肪酸合酶能夠進行棕櫚酸酯的合成。[13] 以上的這些實驗結果與之前的“頭對尾”模型并不相符，于是另一個模型被提出：兩個單體上的酮脂酰合成酶和單酰/乙酰轉移酶結構域位于接近脂肪酸合酶二聚體中心的位置，在這一位置上，它們能夠與任一單體中的載體蛋白接觸。[14]
調控
脂肪酸合酶的代謝與體內平衡是由上游刺激因子（Upstream Stimulatory Factor）和固醇調節元件結合蛋白（sterol regulatory element binding protein-1c，SREBP-1c）進行轉錄調控，以對進食行為和胰島素做出反應。[15][16]
疾病相關
脂肪酸合酶的基因可能是一個癌基因。[17] 在癌癥研究中發現，脂肪酸合酶的水平在乳腺癌中發生上調，它可以作為不準確癌癥診斷的指標，也是化療中的潛在靶標。[18][19]
參見
參考文獻
- ↑ Alberts, A.W., Strauss, A.W., Hennessy, S. & Vagelos, P.R. Regulation of synthesis of hepatic fatty acid synthetase: binding of fatty acid synthetase antibodies to polysomes. Proc. Natl. Acad. Sci. USA 72, 3956?3960
- ↑ Stoops, J.K. et al. Presence of two polypeptide chains comprising fatty acid synthetase. Proc. Natl. Acad. Sci. USA 72, 1940?1944 (1975)
- ↑ Smith, S., Agradi, E., Libertini, L. & Dileepan, K.N. Specific release of the thioesterase component of the fatty acid synthetase multienzyme complex by limited trypsinization. Proc. Natl. Acad. Sci. USA 73, 1184?1188 (1976)
- ↑ Wakil, S.J. Fatty acid synthase, a proficient multifunctional enzyme. Biochemistry 28, 4523?4530 (1989)
- ↑ Smith, S., Witkowski, A. & Joshi, A.K. Structural and functional organization of the animal fatty acid synthase. Prog. Lipid Res. 42, 289?317
- ↑ Chirala, S.S., Jayakumar, A., Gu, Z.W. & Wakil, S.J. Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer. Proc. Natl. Acad. Sci. USA 98, 3104?3108 (2001)
- ↑ Smith, S. The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. FASEB J. 8, 1248?1259 (1994)
- ↑ Stoops, J.K. & Wakil, S.J. Animal fatty acid synthetase. A novel arrangement of the -ketoacyl synthetase sites comprising domains of the two subunits. J. Biol. Chem. 256, 5128?5133 (1981)
- ↑ Stoops, J.K. & Wakil, S.J. Animal fatty acid synthetase. Identification of the residues comprising the novel arrangement of the -ketoacyl synthetase site and their role in its cold inactivation. J. Biol. Chem. 257, 3230?3235
- ↑ Joshi, A.K., Rangan, V.S. & Smith, S. Differential affinity labeling of the two subunits of the homodimeric animal fatty acid synthase allows isolation of heterodimers consisting of subunits that have been independently modified. J. Biol. Chem. 273, 4937?4943 (1998)
- ↑ Rangan, V.S., Joshi, A.K. & Smith, S. Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry 40, 10792?10799 (2001)
- ↑ Witkowski, A. et al. Dibromopropanone cross-linking of the phosphopantetheine and active-site cysteine thiols of the animal fatty acid synthase can occur both inter- and intrasubunit. Reevaluation of the side-by-side, antiparallel subunit model. J. Biol. Chem. 274, 11557?11563 (1999)
- ↑ Joshi, A.K., Rangan, V.S., Witkowski, A. & Smith, S. Engineering of an active animal fatty acid synthase dimer with only one competent subunit. Chem. Biol. 10, 169?173 (2003)
- ↑ Asturias FJ et al., Structure and molecular organization of mammalian fatty acid synthase. Nature Structural & Molecular Biology 12, 225 - 232 (2005) PMID 15711565
- ↑ Paulauskis JD, Sul HS.Hormonal regulation of mouse fatty acid synthase gene transcription in liver.J Biol Chem. 1989 Jan 5;264(1):574-7.
- ↑ Latasa MJ, Griffin MJ, Moon YS, Kang C, Sul HS. Occupancy and function of the -150 sterol regulatory element and -65 E-box in nutritional regulation of the fatty acid synthase gene in living animals.Mol Cell Biol. 2003 Aug;23(16):5896-907.
- ↑ Baron A, Migita T, Tang D, Loda M. Fatty acid synthase: a metabolic oncogene in prostate cancer?. J Cell Biochem. 2004, 91 (1): 47–53. doi:10.1002/jcb.10708. PMID 14689581.
- ↑ Hunt DA. Lane HM. Zygmont ME. Dervan PA. Hennigar RA. MRNA stability and overexpression of fatty acid synthase in human breast cancer cell lines. [Journal Article] Anticancer Research. 27(1A):27-34, 2007 Jan-Feb. UI: 17352212
- ↑ Gansler TS. Hardman W 3rd. Hunt DA. Schaffel S. Hennigar RA. Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. [Journal Article] Human Pathology. 28(6):686-92, 1997 Jun. UI: 9191002
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