上海藥物研究所藥物發(fā)現(xiàn)與設(shè)計(jì)中心(DDDC)羅成副研究員參與美國弗吉尼亞聯(lián)邦大學(xué)醫(yī)學(xué)院Sarah Spiegel教授“鞘氨醇磷酸酯（sphingosine-1-phosphate, S1P）調(diào)控機(jī)制的研究”，取得重大突破,，研究論文于2009年9月4日發(fā)表在《科學(xué)》（Science）雜志上（Science 2009, 325: 1254-1257）,。
該研究首次發(fā)現(xiàn)了S1P是一種組蛋白去乙酰化酶(HDAC)生理調(diào)節(jié)因子,，HDAC是S1P在細(xì)胞內(nèi)的直接靶標(biāo),，S1P通過HDAC調(diào)控基因的表達(dá)，具有調(diào)控基因表達(dá)的新功能,。該研究還闡明了S1P調(diào)控基因表達(dá)的機(jī)制,。S1P最初發(fā)現(xiàn)與細(xì)胞生長的調(diào)節(jié)有關(guān)，它是一種存在于細(xì)胞核中具有生物活性的脂質(zhì)信使，由2型鞘氨醇激酶（SphK2）產(chǎn)生,。SphK2選擇性聚集在編碼細(xì)胞周期蛋白依賴性激酶抑制劑p21或轉(zhuǎn)錄調(diào)節(jié)因子c-fos的基因啟動(dòng)子上,。S1P通過特異性結(jié)合HDAC1和HDAC2，抑制其活性,，進(jìn)而保護(hù)組氨酸末端賴氨酸不被去乙?；瑥亩岣呓M蛋白H3乙?；某潭?，促進(jìn)轉(zhuǎn)錄。因此,， S1P在調(diào)控基因表達(dá)中的新機(jī)制將為發(fā)展新型HDAC抑制劑,，開發(fā)抗腫瘤及免疫疾病的新型藥物奠定了基礎(chǔ)。
在該研究中,，上海藥物研究所研究人員利用分子模擬方法預(yù)測組蛋白去乙?；?HDAC)可能是S1P的作用靶標(biāo)，并預(yù)測了兩者間的結(jié)合模式和關(guān)鍵作用殘基,，進(jìn)而精確預(yù)測出S1P與HDAC的親合能力與HDAC現(xiàn)有抑制劑SAHA相當(dāng),。這些理論預(yù)測結(jié)果為該研究提供了關(guān)鍵的線索，并在實(shí)驗(yàn)上被Sarah Spiegel等證實(shí),。
該研究綜合運(yùn)用分子模擬和實(shí)驗(yàn)的手段研究S1P調(diào)控機(jī)制的生物學(xué)問題,，表明計(jì)算與實(shí)驗(yàn)的有機(jī)結(jié)合，可作為一種重要的研究策略,，為研究生命科學(xué)其它相關(guān)復(fù)雜問題提供了一種可靠的思路,。（生物谷Bioon.com）
生物谷推薦原始出處：
Science 4 September 2009:DOI: 10.1126/science.1176709
Regulation of Histone Acetylation in the Nucleus by Sphingosine-1-Phosphate
Nitai C. Hait,1 Jeremy Allegood,1 Michael Maceyka,1 Graham M. Strub,1 Kuzhuvelil B. Harikumar,1 Sandeep K. Singh,1 Cheng Luo,2,3 Ronen Marmorstein,2 Tomasz Kordula,1 Sheldon Milstien,4 Sarah Spiegel1,*
The pleiotropic lipid mediator sphingosine-1-phosphate (S1P) can act intracellularly independently of its cell surface receptors through unknown mechanisms. Sphingosine kinase 2 (SphK2), one of the isoenzymes that generates S1P, was associated with histone H3 and produced S1P that regulated histone acetylation. S1P specifically bound to the histone deacetylases HDAC1 and HDAC2 and inhibited their enzymatic activity, preventing the removal of acetyl groups from lysine residues within histone tails. SphK2 associated with HDAC1 and HDAC2 in repressor complexes and was selectively enriched at the promoters of the genes encoding the cyclin-dependent kinase inhibitor p21 or the transcriptional regulator c-fos, where it enhanced local histone H3 acetylation and transcription. Thus, HDACs are direct intracellular targets of S1P and link nuclear S1P to epigenetic regulation of gene expression.
1 Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
2 The Wistar Institute and Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
4 National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
