广西师范大学学报（自然科学版） ›› 2012, Vol. 30 ›› Issue (3): 159-170.

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脂肪酸调控盐酸金刚烷结合在人血清白蛋白ⅡA亚域

梁宏1,2   

  1. 1.广西师范大学药用资源化学与药物分子工程国家重点实验室培育基地,广西桂林541004;
    2.广西师范大学化学化工学院,广西桂林541004
  • 收稿日期:2012-09-06 出版日期:2012-09-20 发布日期:2018-12-04
  • 作者简介:梁宏,男,1964年生,博士,广西师范大学教授,博士生导师。

Regulation of Amantadine Hydrochloride Binding with ⅡA Subdomain of Human Serum Albumin by Fatty Acid Chains

LIANG Hong1,2   

  1. 1.Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources,Guangxi Normal University, Guilin Guangxi 541004,China;
    2.College of Chemistry and Chemical Engineering,Guangxi Normal University, Guilin Guangxi 541004,China
  • Received:2012-09-06 Online:2012-09-20 Published:2018-12-04
  • Contact: LIANG Hong(1964—),male,born in Beiliu,Guangxi,Professor of Guangxi Normal University,PhD Supervisor.E-mail:hliang@gxnu.edu.cn
  • Supported by:
    Natural Science Foundation of China (31060121,21171043);Natural Science Foundation of Guangxi (2012GXNSFCB053001)

摘要： 人血清白蛋白是血液中最丰富的蛋白质,被利用来结合和运输许多不同类的内源和外源化合物。阴离子药物可以随意地结合在白蛋白的ⅡA亚域,而大多数阳离子药物却很难结合在该区域。本研究通过脂肪酸改变白蛋白进而调控阳离子药物结合在白蛋白ⅡA亚域。本文以具有抗病毒和抗帕金森病功效的盐酸金刚烷为例,体外研究结果表明过度的脂肪酸化白蛋白能够有助于稳定金刚烷与白蛋白相互作用。X-射线结晶学数据进一步阐明了该调控的结构机制。此外,本文的结构数据表明具有羧基的阴离子药物也许可以调控金刚烷与白蛋白相互结合。最终,本文从结构方面洞察了金刚烷与白蛋白相互结合的这种新颖方式,这将提供诱人的可能性去全方位开发独特的白蛋白ⅡA亚域的结合能力,致使白蛋白能够同时运输阴离子和阳离子药物。

关键词: 人血清白蛋白, 盐酸金刚烷, 脂肪酸, 荧光光谱, X-射线晶体学

Abstract: HSA is a major protein component of blood plasma that has been exploited to bind and transport a wide variety of endogenous and exogenous organic compounds.While anionic drugs readily associate with the ⅡA subdomain of HSA,most cationic drugs poorly associate to HSA at this subdomain.In this study,the association between cationic drugs and HSA by modifying HSA with fatty acid chains was improved.For our experiments,amantadine hydrochloride,a cationic drug with antiviral and antiparkinsonian effects were tested,the results suggest that extensive myristoylation of HSA can help stabilize the interaction between amantadine and HSA in vitro.The X-ray crystallography data further elucidates the structural basis of this regulation.Additionally,the crystallography data suggests that anionic drugs,with a functional carboxylate group,may enhance the association between amantadine and HSA by a mechanism similar to myristolation.Ultimately,the results provide critical structural insight into this novel association between cationic drugs and the HSA ⅡA subdomain,raising the tempting possibility to fully exploit the unique binding capacity of HSA's ⅡA subdomain to achieve simultaneous delivery of anionic and cationic drugs.

Key words: human serum albumin, amantadine hydrochloride, fatty acid chains, fluorescence spectrum, X-ray crystallography

中图分类号: 

  • Q512
[1] PETERS T.All about Albumin:Biochemistry,Genetics and Medical Applications[M].San Diego:Academic Press,1995.
[2] ELSADEK B,KRATZ F.Impact of albumin on drug delivery-new applications on the horizon[J].J Control Release,2012,157(1):4-28.
[3] TAHERI A,DINARVAND R,MANSOORI P,et al.Enhanced anti-tumoral activity ofmethotrexate-human serum albumin conjugated nanoparticles by targeting with luteinizing hormone-releasing hormone (LHRH) peptide[J].Int J Mol Sci,2011,12:4591-4608.
[4] NEUMANN E,FREI E,FIEHN C.Native albumin for targeted drug delivery[J].Expert Opin Drug Deliv,2010,7:915-925.
[5] CHUANG V T,KRAGH-HANSEN U,OTAGIRI M.Pharmaceutical strategies utilizing recombinant human serum albumin[J].Pharm Res,2002,19:569-577.
[6] SCHÖNFELD D L,RAVELLI R B,SKERRA A,et al.The 1.8-A crystal structure ofalpha1-acid glycoprotein (Orosomucoid) solved by UV RIP reveals the broad drug-binding activity of this human plasma lipocalin[J].J Mol Biol,2008,384:393-405.
[7] KRAGH-HANSEN U.Molecular aspects of ligand binding to serum albumin[J].Pharmacol Rev,1981,33:17-53.
[8] HE X M,CARTER D C.Atomic structure and chemistry of human serum albumin[J].Nature,1992,358:209-215.
[9] HEIN K L,KRAGH-HANSEN U,NISSEN P.Crystallographic analysis reveals a unique lidocaine binding site on human serum albumin[J].J Struct Biol,2010,171:353-360.
[10] EFTINK M R.Fluorescence quenching reactions:probing biologicalmacro-molecular structures[C]//DEWEY T G.Biophysical and Biochemical Aspects of Fluorescence Spectroscopy.New York:Plenum,1991:105-133.
[11] LAKOWICZ J R.Principle of fluorescence spectroscopy[M].3rd ed.New York:Springer,1999.
[12] LAKOWICZ J R,WEBER G.Quenching of fluorescence byoxygen.Probefor structural fluctuations in macromolec-ules[J].Biochemistry,1973,12:4161-4170.
[13] EFTINK M R.Fluorescence quenching:theory and applications[J].Topics in Fluorescence Spectroscopy,2002,2:53-126.
[14] WARE W R.Oxygen quenching of fluorescence in solution:ax experimentbl study of the diffusion process[J].J Phys Chem,1962,66:455-458.
[15] ABOU-ZIED O K,AL-SHIHI O I.Fluorescence quenching studies withproteins[J].J Am Chem Soc,2008,130:10793-10801.
[16] BHATTACHARYA A A,GRUNE T,CURRY S.Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to human serum albumin[J].J Mol Biol,2000,303:721-732.
[17] CURRY S,MANDELKOW H,BRICK P,et al.Crystal structure of humanserum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites[J].Nat Struct Biol,1998,5:827-835.
[18] DELANO W L.The Pymol Molecular Graphics System[M].San Carlos,CA:DeLano Scientific,2004.
[19] MINGHETTI P P,RUFFNER D E,DUGAICZYK A,et al.Molecular structure of thehuman albumin gene is revealed by nucleotide sequence within q11-22 of chromosome 4[J].J Biol Chem,1986,261:6747-6675.
[20] ABOU-ZIED O K,ALSHIHI O I.Characterization of subdomain ⅡA binding siteof human serum albumin in its native,unfolded,and refolded states using smallmolecular probes[J].J Am Chem Soc,2008,130:10793-10801.
[21] ZUNSZAIN P A,GHUMAN J,MCDONAGH A F,et al.Crystallographic analysis of human serum albumin complexed with 4Z,15E-bilirubin-IXalpha[J].J Mol Biol,2008,381:394-406.
[22] YAMAGUCHI S,ALDINI G,UCHIDA K,et al.Delta(12)-prostaglandin J(2) as aproduct and ligand of human ser-um albumin:formation of an unusual covalent adduct at His146[J].J Am Chem Soc,2010,132:824-832.
[23] GHUMAN J,ZUNSZAIN P A,CURRY S,et al.Structural basis of thedrug-binding specificity of human serum albumin[J].J Mol Biol,2005,353:38-52.
[24] CURRY S.Lessons from the crystallographic analysis of small molecule binding to human serum albumin[J].Drug Metab Pharmacokinet,2009,24:342-357.
[25] WAGNER S,KUFLEITNER J,AVON BRIESEN H.Nanoparticulate transportof oximes over an in vitro blood-brain barrier model[J].PloS One,2010,5:e14213.
[26] KRATZ F.Albumin as a drug carrier:design of prodrugs,drug conjugates and nanoparticles[J].Journal of Controlled Release,2008,132:171-183.
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