Research Progress of Structure and Function of Oligopeptide Transporter PepT2

Abstract

Abstract: The oligopeptide transporter PepT2 of mammal is a high-affinity and low capacity transporter, it can transport small peptides and peptide-like drugs to all kinds of tissue cells . PepT2 is mainly expressed in the renal medulla cells, but also found in brain, central nervous system, lung, mammary gland and pancreas. PepT2 functionally characterized in the kidney has been considered to play a key role in efficient reabsorb small peptides generated by luminal peptidases. The structure and function of PepT2 were summarized in this paper.

Key words: PepT2, Structure, Function

Zhao Dongxin, Zhao Shanshan, Lu Kui . Research Progress of Structure and Function of Oligopeptide Transporter PepT2[J]. Biotechnology Bulletin, 2013, 0(6): 25-31.

References

[1] Daniel H, Kottra G. The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology[J]. Pflugers Arch, 2004, 447(5):610-618.
[2] Romano A, Barca A, Kottra G, Daniel H. Functional expression of SLC15 Peptide transporters in rat thyroid follicular cells[J]. Mol Cell Endocrinol, 2010, 315(1):174-181.
[3] Newstead S. Towards a structural understanding of alternating access within the proton dependent oligopeptide transporter(POT)family[J]. Biophysical Journal, 2012, 102(3):605a.
[4] Rubio-Aliaga I, Boll M, Daniel H. Cloning and characterization of the gene encoding the mouse peptide transporter PEPT2[J]. Biochem Biophys Res Commun, 2000, 276(2):734-741.
[5] Terada T, Irie M, Okuda M, Inui K. Genetic variant Arg57His in human H^{+/peptide cotransporter2 causes a complete loss of transport function[J]. Biochem Biophys Res Commun, 2004, 316(2):416-420.
[6] Pedretti A, De Luca L, Marconi C, et al. Fragmental modeling of hPepT2 and analysis of its binding features by docking studies and pharmacophore mapping[J]. Bioorg Med Chem, 2011, 19(15):4544-4551.
[7] Ocheltree SM, Shen H, Hu YJ, Keep RF. Role and relevance of peptide transporter2(PEPT2)in the kidney and choroid plexus:in vivo studies with glycylsarcoine in wild-type and PEPT2 knockout mice[J]. J Pharmacol Exp Ther, 2005, 315(1):240-247.
[8] Biegel A, Knutter I, Hartrodt B, et al. The renal type H^{+/peptide symporter PEPT2:Structure-affinity relationships[J]. Amino Acids, 2006, 31(2):137-156.
[9] Inui K, Saito H, Terada T, et al. Molecular cloning and tissue distribution of rat peptide transporter PEPT2[J]. Biochim Biophys Acta, 1996, 1280:173-177.
[10] Wang MH, Zhang XZ, Wang QS. Comparative analysis of vertebrate PEPT1 and PEPT2 genes[J]. Genetica, 2010, 138(6):587-599.
[11] 陈西敬, 王广基. 药物转运蛋白在药物吸收、分布和排泄中的作用及对新药研发的意义[J]. 中国药科大学学报, 2003, 34(6):483-486.
[12] Ostaszewska T, Dabrowski K, Kamaszewski M, et al. The effect of plant protein-based diet supplemented with dipeptide or free amino acids on digestive tract morphology and PepT1 and PepT2 expressions in common carp(Cyprinus carpio L.)[J]. Comp Biochem Physiol A Mol Integr Physiol, 2010, 157(3):158-169.
[13] Groneberg DA, Doring F, Theis S, et al. Peptide transport in the mammary gland:expression and distribution of PEPT2 mRNA and protein[J]. Am J Physiol Endocrinol Metab, 2002, 282(5):E1172-E1176.
[14] Frey IM, Rubio-Aliaga I, Klempt M, et al. Phenotype analysis of mice deficient in the peptide transporter PEPT2 in response to alterations in dietary protein intake[J]. Pflugers Arch, 2006, 452:300-306.
[15] Sala-Rabanal M, Loo DD, Hirayama BA, Wright EM. Molecular mechanism of dipeptide and drug transport by the human renal H⁺/oligopeptide cotransporter hPEPT2[J]. Am J Physiol Renal Physiol, 2008, 294(6):F1442-F1432.
[16] 于辉, 李华, 关绣霞. 小肽转运载体的分子营养学的研究进展[J].佛山科学技术学院学报:自然科学版, 2005, 23(3):77-80.
[17] Daniel H. Function and molecular structure of brush border membrane peptide/H⁺ symporters[J]. J. Membrane Biol, 1996, 154(3):197-203.
[18] Pinsonneault J, Nielsen UC. Genetic variants of the human H⁺/dipe-ptide transporter PEPT2:analysis of haplotype functions[J]. Pharmacology and Experimental Therapeutics, 2004, 311(3):1088-1096.
[19] Inui K, Terada T, Saito H. N-terminal halves of rat H⁺/peptide transporters are responsible for their substrate recognition[J]. Pharm Res, 2000, 1(17):15-20.
[20] Rubio-Aliaga I, Daniel H. Mammalian peptide transporters as targets for drug delivery[J]. Trends Pharmacol Sci, 2002, 9(23):434-440.
[21] Doring F, Martini C, Walter J, et al. Importance of a small N-terminal region in mammalian peptide transporters for substrate affinity and function[J]. J Membr Boil, 2002, 186(2):55-62.
[22] Meredith D, Boyd CA. Structure and function of eukaryotic peptide transporters[J]. Cell Mol Life Sci, 2000, 57(5):754-778.
[23] 苍健, 刘克辛. 寡肽转运体PEPT2在药物肾脏转运中的作用和活性调节[J]. 药物与临床, 2010, 7(18):49-52.
[24] Guo XJ, Meng Q, Liu Q, et al. Construction, identification and application of HeLa cells stably transfected with human PEPT1 and PEPT2[J]. Peptides, 2012, 34(16):395-403.
[25] Daniel H, Spanier B, Weitz D. From bacteria to man:archaic proton dependent peptide transporters at work[J]. Physiology, 2006, 21(2):93-102.
[26] Bahadduri PM, Pinsonneault JK, Bao SY, Knoell DL. Functional characterization of the peptide transporter PEPT2 in primary cultures of human upper airway epithelium[J]. Am J Respir Cell Mol Biol, 2005, 32(4):319-325.
[27] Liu R, Tang AM, Tan YL, et al. Interethnic differences of PEPT2(SLC15A2)polymorphism distribution and associations with cephalexin pharmacokinetics in healthy Asian subjects[J]. Eur J Clin Pharmacol, 2009, 65(1):65-70.
[28] Brandsch M, Brandsch C, Ganapathy ME, et al. Influence of proton and essential histidyl residues on the transport kinetics of the H^{+/peptide cotransport systems in intestine(PEPT1)and kidney(PEPT2)[J]. Biophysica Acta, 1997, 1324(2):251-262.
[29] Daniel H, Adibi SA. Transport of beta-lactam antibiotics in kidney brush border membrane. Determinants of their affinity for the oligopeptide/H^{+ symporter[J]. J Clin Invest, 1993, 92:2215-2223.
[30] Ganapathy ME, Brandsch M, Prasad PD, et al. Differential recogn-ition of β-lactam antibiotics by intestinal and renal peptide trans-porters, PEPT 1 and PEPT 2[J]. J Biol Chem, 1995, 270(43):25672-25677.
[31] Luckner P, Brandsch M. Interaction of 31 β-lactam antibiotics with the H⁺/peptide symporter PEPT2:analysis of affinity constants and comparison with PEPT1[J]. Eur J Pharm Biopharm, 2005, 59(1):17-24.
[32] Terada T, Saito H, Inui K. Interaction of β-lactam antibiotics with histidine residue of rat H⁺/peptide cotransporters, PEPT1 and PEPT2[J]. J Biol Chem, 1988, 10(273):5582-5585.
[33] Keep RF, Smith DE. Chapter 231-Oligopeptide and Peptide-Like Drug Transport[M]//Kastin A. Handbook of Biologically Active Peptides. Academic Bess is an imprint of Elsevier, 2013, 2:1688-1695.
[34] Xiang JM, Chiang PP, Hu YJ, et al. Role of PEPT2 in glycylsarcosine transport in astrocyte and glioma cultures[J]. Neurosci Lett, 2006, 396(3):225-229.
[35] Biegel A, Gebauer S, Knutter I. Recognition of 2-aminothiazole-4-acetic acid derivatives by the peptide transporters PEPT1 and PEPT2[J]. Eur J Pharm Sci, 2007, 32(1):69-76.
[36] Zimmermann M, Kappert K, Stan AC. U373-MG cells express PepT2 and accumulate the fluorescently tagged dipeptide-derivative β-Ala-Lys-N-AMCA[J]. Neurosci Lett, 2010, 486(3):174-178.
[37] Kouodom MN, Boscutti G, Celegato M, et al. Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy[J]. J Inorg Biochem, 2012, 117:248-260.
[38] Knütter I, Hartrodt B, Tóth G, et al. Synthesis and characterization of a new and radiolabeled high-affinity substrate for H⁺/peptide cotransporters[J]. FEBS J, 2007, 274(22):5905-5914.
[39] Steffansen B, Nielsen CU, Frokjaer S. Delivery aspects of small peptides and substrates for peptide transporters[J]. Eur J Pharm Biopharm, 2005, 60(2):241-245.
[40] Daniel H, Rubio-Aliaga I. An update on renal peptide transporters[J]. Am J Physiol Renal Physiol, 2003, 284:F885-F892.
[41] 周苗苗, 吴跃明, 刘建新. 小肽转运载体2在奶牛乳腺小肽摄取中的作用研究[J]. 动物营养学报, 2011, 23(8):1303-1308.
[42] Jappar D, Hu YJ, Smith DE. Transport mechanisms of carnosine in SKPT cells:contribution of apical and basolateral membrane transporters[J]. Pharmaceutical Research, 2009, 26(1):172-181.
[43] Shu C, Shen H, Teuscher NS, et al. Role of PEPT2 in peptide/mimetic trafficking at the blood-cerebrospinal fluid barrier:studies in rat choroid plexus epithelial cells in primary culture[J]. Pharmacol Exp Ther, 2002, 301(3):820-829.
[44] Teuscher NS, Keep RF, Smith DE. PEPT2-mediated uptake of neuropeptides in rat choroid plexus[J]. Pharmaceutical Research, 2001, 6(18):807-813.
[45] Hu YJ, Ocheltree SM, Smith DE, et al. Glycyl-L-glutamine disposition in rat choroid plexus epithelial cells in primary culture:role of PEPT2[J]. Pharma Res, 2005, 22(8):1281-1286.
[46] Dringen R, Hamprecht B, Broer S. The peptide transporter PepT2 mediates the uptake of the glutathioneprecursor CysGly in astroglia-rich primary cultures[J]. J Neu-rochem, 1998, 71:388-393.
[47] Hussain I, Zanic-Grubisic T, Kudo Y. Functional and molecular cha-racterization of a peptide trans-porter in the rat PC12 neuroendoc-rine cell line[J]. FEBS Lett, 2001, 508:350-354.
[48] 张旋. PepT2 mRNA 在内毒素致急性肺损伤大鼠肺组织表达研究.[D]. 昆明:昆明医学院, 2006.
[49] 李莉, 宋鑫, 王殿华. 肽转运载体与药物转运[J]. 中国临床药学杂志, 2008, 17(1):61-64.
[50] 范淳, 陈代文, 余冰. 小肽转运载体(PEPT1和PEPT2)研究进展[J]. 饲料工业, 2007, 28(1):11-15.
[51] 赵东欣, 薛永亮, 卢奎.寡肽转运蛋白PepT2 及其药物转运[J]. 中国生物化学与分子生物学报, 2010, 26(1):1-8.
[52] Groneberg DA, Springer J, Doring F, et al. Localization of the peptide transporter PEPT2 in the lung:implications for pulmonary oligopeptide uptake[J]. Am J Pathol, 2001, 158(2):707-714.
[53] Wang ZY, Pal D, Patel A, et al. Influence of overexpression of efflux proteins on the function and gene expression of endogenous peptide transporters in MDR-transfected MDCKII cell lines[J]. Int J Pharm, 2013, 44(1-2):40-49.
[54] 黎航航. 草鱼PepTl与PepT2基因全长cDNA克隆和PepT2组织表达研究[D]. 长沙:湖南农业大学, 2012.
[55] 杨建香, 金晓露, 魏宁波, 刘红云. 小肽转运载体2的转运机制及功能研究[J]. 动物营养学报, 2013, 13(6):1-5}}}}