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Membrane type 1 matrix metalloproteinase-associated degradation of tissue inhibitor of metalloproteinase 2 in human tumor cell lines

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第15期275卷 11368-11378页

作者： Maquoi, E Frankenne, F Baramova, E Munaut, C Sounni, NE Remacle, A Noël, A Murphy, G Foidar, JM Univ Liege Lab Tumor & Dev Biol B-4000 Liege Belgium Univ E Anglia Sch Biol Sci Norwich NR4 7TJ Norfolk England

Tissue inhibitor of metalloproteinase 2 (TIMP-2) is required for the membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent activation of pro-MMP-2 on the cell surface. MT1-MMP-bound TIMP-2 has been shown to function as a receptor for secreted pro-MMP-2, resulting in the formation of a trimolecular complex. In the presence of uncomplexed active MT1-MMP, the prodomain of cell surface-associated MMP-2 is cleaved, and activated MMP-2 is released. However, the behavior of MT1-MMP-bound TIMP-2 during MMP-2 activation is currently unknown. In this study, I-125-labeled recombinant TIMP-2 (I-125-rTIMP-2) was used to investigate the fate of TIMP-2 during pro-MMP-2 activation by HT1080 and transfected A2058 cells. HT1080 and A2058 cells transfected with MT1-MMP cDNA (but not vector-transfected A2058 cells) were able to bind I-125-rTIMP-2, to activate pro-MMP-2, and to process MT1-MMP into an inactive 43-kDa form, Under these conditions, I-125-rTIMP-2 bound to the cell surface was rapidly internalized and degraded in intracellular organelles through a bafilomycin A(1)-sensitive mechanism, and I-125-bearing low molecular mass fragment(s) were released in the culture medium. These different processes were inhibited by hydroxamic acid-based synthetic MMP inhibitors and rTIMP-2, but not by rTIMP-1 or cysteine, serine, or aspartic proteinase inhibitors. These results support the concept that the MT1-MMP-dependent internalization and degradation of TIMP-2 by some tumor cells might be involved in the regulation of pericellular proteolysis.

关键词：酶激活氢离子浓度基质金属蛋白酶2/代谢基质金属蛋白酶类膜相关膜蛋白质类/代谢金属内肽酶类/生理学肿瘤/代谢苯丙氨酸/类似物和衍生物苯丙氨酸/药理学蛋白酶抑制药/药理学重组蛋白质类/代谢金属蛋白酶2组织抑制剂/代谢肿瘤细胞培养的人类

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A new data analysis method to determine binding constants of small molecules to proteins using equilibrium analytical ultracentrifugation with absorption optics

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ANALYTICAL BIOCHEMISTRY 2001年第1期299卷 98-107页

作者： Arkin, M Lear, JD Sunesis Pharmaceut Inc S San Francisco CA 94080 USA Univ Penn Dept Biochem & Biophys Philadelphia PA 19104 USA

In principle, equilibrium analytical ultracentrifugation (AU) can be used to quantify the binding stoichiometry and affinity between small-molecule ligands and proteins in aqueous solution. We show here that heteromeric binding constants can be determined using a data-fitting procedure which utilizes a postfitting computation of the total amount of each component in the centrifuge cell. The method avoids overconstraining the fitting of the radial concentration profiles, but still permits unique binding constants to be determined using measurements at a single wavelength. The computational program is demonstrated by applying it to data obtained with mixtures of a 500-Da molecule and interleukin-2, a 16-kDa protein. The 1:1 binding stoichiometry and heteromeric dissociation constants (K-ab) determined from centrifuge data at two different wavelengths are within the 4-9 muM range independently determined from a functional assay. Values for K-ab have been obtained for ligands with affinities as weak as 500 muM. This AU method is applicable to compounds with significant UV absorbance (similar to0.2) at concentrations within similar to5- to 10-fold of their K-ab. The method, which has been incorporated into a user procedure for IgorPro (Wavemetrics, Oswego, OR), is included as supplementary material. (C) 2001 Elsevier Science.

关键词：半数抑制浓度白细胞介素2/代谢动力学配体光学/仪器和设备苯丙氨酸/类似物和衍生物蛋白质结合/生理学蛋白质类/代谢可重复性结果溶液分光光度法/仪器和设备统计数据/方法超速离心法/仪器和设备

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Synthesis and biological evaluation of substituted 4-(OBz)phenylalanine derivatives as novel N-type calcium channel blockers

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 1999年第8期9卷 1121-1126页

作者： Hu, LY Ryder, TR Nikam, SS Millerman, E Szoke, BG Rafferty, MF Parke Davis Pharmaceut Res Ann Arbor MI 48105 USA Elan Pharmaceut Inc Menlo Park CA 94025 USA

Selective N-type Voltage Activated Calcium Channel (VACC) blockers have shown utility in several models of stroke and pain. In the process of searching for small molecules as N-type calcium channel blockers, we have identified a series of N,N-dialkylpeptidylamines (e.g., PD 175069) with potent functional activity at N-type VACC. Further modification of the leucine moiety of PD 175069 with a cyclized ring structure provides a series of novel molecules. Syntheses and pharmacological evaluation of the series are presented. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.

关键词：钙通道阻滞药/化学合成钙通道阻滞药/药代动力学半数抑制浓度模型化学苯丙氨酸/类似物和衍生物苯丙氨酸/化学合成苯丙氨酸/药代动力学肿瘤细胞培养的人类

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N-carboxy-L-phenylalanine anhydride

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ACTA CRYSTALLOGRAPHICA SECTION C-CRYSTAL STRUCTURE COMMUNICATIONS 2000年第4期56卷 469-470页

作者： Kanazawa, H Fukushima Univ Dept Educ Matsukawa Fukushima 9601296 Japan

The molecules of the title compound, 4-benzyl-1,3-oxazolidene-2,5-dione, C10H9NO3, are linked by intermolecular hydrogen bonds between the imino group of the five-membered ring and an adjacent carbonyl O-atom, along the c axis. The benzyl groups are stacked in a layer and the five-membered rings are arranged in another layer sandwiched by the benzyl group layer. This sandwich structure should explain the high polymerizability of the title compound in the solid state.

关键词：酐类/化学结晶学 X线氢键合模型分子分子构象苯丙氨酸/类似物和衍生物苯丙氨酸/化学

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Identification of two pairs of spatially approximated residues within the carboxyl terminus of secretin and its receptor

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第34期275卷 26032-26039页

作者： Dong, MQ Asmann, YW Zang, MW Pinon, DI Miller, LJ Mayo Clin & Mayo Fdn Dept Internal Med Ctr Basic Res Digest Dis Rochester MN 55905 USA Mayo Clin & Mayo Fdn Dept Biochem Mol Biol Ctr Basic Res Digest Dis Rochester MN 55905 USA

The carboxyl-terminal domains of secretin family peptides have been shown to contain key determinants for high affinity binding to their receptors. In this work, we have examined the interaction between carboxyl-terminal residues within secretin and the prototypic secretin receptor. We previously utilized photoaffinity labeling to demonstrate spatial approximation between secretin residue 22 and the receptor domain that includes the first 30 residues of the amino terminus (Dong, M., Wang, Y., Pinon, D. I., Hadac, E. M., and Miller, L. J. (1999) J. Biol. Chem. 274, 903-909), Here, we further refined the site of labeling with the p-benzoyl-phenylalanine (Bpa(22)) probe to receptor residue Leu(17) using progressive cleavage of wild type and mutant secretin receptors (V13M and V16M) and sequence analysis, We also developed a new probe incorporating a photolabile Bpa at position 26 of secretin, closer to its carboxyl terminus. This analogue was also a potent agonist (EC50 = 72 +/- 6 pM) and bound to the secretin receptor specifically and with high affinity (K-i = 10.3 +/- 2.4 nM). It covalently labeled the secretin receptor at a single site saturably and specifically. This was localized to the segment between residues Gly(34) and Ala(41) using chemical and enzymatic cleavage of labeled wild type and A41M mutant receptor constructs and immunoprecipitation of epitope-tagged receptor fragments. Radiochemical sequencing identified the site of covalent attachment as residue Leu(36), These new insights, along with our recent report of contact between residue 6 within the aminoterminal half of secretin and this same amino-terminal region of this receptor (Dong, M,, Wang, Y,, Hadac, E, M., Pinon, D, I., Holicky, E. L., and Miller, L. J. (1999) J. Biol. Chem. 274, 19161-19167), support a key role for this region, making the molecular details of this interaction of major interest.

关键词：丙氨酸/代谢氨基酸序列 CHO细胞仓鼠亚科甘氨酸/代谢动力学配体分子序列数据分子量苯丙氨酸/类似物和衍生物苯丙氨酸/代谢光亲和标记/代谢蛋白质结构二级受体 G-蛋白偶联受体胃肠激素/化学受体胃肠激素/代谢分泌素/化学分泌素/代谢构效关系动物

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Tissue selectivity of antidiabetic agent nateglinide:: Study on cardiovascular and β-cell K_ATP channels

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期291卷 1372-1379页

作者： Hu, SL Wang, SY Dunning, BE Novartis Inst Biomed Res Summit NJ 07901 USA

Nateglinide (NAT) stimulates insulin secretion from pancreatic beta-cells by closing K-ATP channels. Because K-ATP channels are widely distributed in cardiovascular (CV) tissues, we assessed the tissue specificity of NAT by examining its effect on K-ATP channels in enzymatically isolated rat beta-cells, rat cardiac myocytes, and smooth muscle cells from porcine coronary artery and rat aorta with the patch-clamp method. The selectivity of known antidiabetic agents glyburide (GLY) and repaglinide (REP) was also studied for comparison. NAT was found to inhibit K-ATP channels in the cells from porcine coronary artery and rat aorta with IC(50)s of 2.3 and 0.3 mM, respectively, compared with 7.4 mu M in rat beta-cells, indicating a respective 311- and 45-fold selectivity (p < .01) for beta-cells. With an IC50 of 5.0 nM in beta-cells, REP displayed an similar to 16-fold (p < .05) selectivity for beta-cells over both types of vascular cells. GLY was nonselective between vascular and beta-cells. At equipotent concentrations (2X respective IC(50)s in beta-cells), NAT, GLY, and REP all caused 62% reduction of pancreatic K-ATP current but a respective 39, 55, and 66% inhibition of cardiac K-ATP current. These data collectively indicate that NAT, when compared with GLY and REP, at concentrations effective in stimulating insulin secretion is least likely to cause detrimental CV effects via blockade of CV K-ATP channels.

关键词：主动脉胸/药物作用氨甲酸酯类/药理学心血管系统/药物作用冠状血管/药物作用环己烷类/药理学格列本脲/药理学心脏/药物作用降血糖药/药理学胰岛/药物作用胰岛/代谢肌平滑血管/细胞学肌平滑血管/药物作用苯丙氨酸/类似物和衍生物苯丙氨酸/药理学哌啶类/药理学钾通道/药物作用钾通道内向整流大鼠 Sprague-Dawley 猪动物男(雄)性大鼠

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Regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) by bone resorptive factors in osteoblastic cells

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JOURNAL OF CELLULAR PHYSIOLOGY 2000年第2期185卷 207-214页

作者： Uchida, M Shima, M Shimoaka, T Fujieda, A Obara, K Suzuki, H Nagai, Y Ikeda, T Yamato, H Kawaguchi, H Kureha Chem Ind Co Ltd Biomed Res Labs Shinjuku Ku Tokyo 1690073 Japan Osaka Univ Fac Med Dept Pediat Osaka 530 Japan Univ Tokyo Grad Sch Med Dept Orthopaed Surg Tokyo Japan

In addition to their stimulating function on osteoclastic bone resorption, bone resorptive factors may regulate proteinases and related factors in osteoblastic cells to degrade bone matrix proteins. This study investigated the regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalioproteinases (TIMPs) by bone resorptive factors in the cultures of mouse osteoblastic MC3T3-E1 cells, mouse primary osteoblastic (POB) cells, and neonatal mouse calvariae. Expression of either MMP-2, -3, -9, -11, -13, and -14 or TIMP-1, -2, and -3 was detected in MC3T3-E1 cells and POB cells. When the bone resorptive factors parathyroid hormone, 1,25-dihydroxyvitamin D-3, prostaglandin E-2, interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) were added to the cell cultures, MMP-13 mRNA levels were found predominantly to increase by all resorptive factors in the three cultures. mRNA levels of either MMP-3 and -9 or TIMP-1 and -3 were found to increase mainly by the cytokines IL-1 beta and TNF-alpha. BB94, a nonselective MMP inhibitor, neutralized the Ca-45 release stimulated by these resorptive factors to an extent similar to that of calcitonin, strongly suggesting that bone resorptive factors function at least partly through MMP formation. We propose that MMP-13 mRNA expression in osteoblastic cells may play an important role in stimulating matrix degradation by both systemic and local resorptive factors, whereas either MMP-3 and -9 or TIMP-1 and -3 might modulate matrix degradation by local cytokines only. (C) 2000 Wiley-Liss, Inc.

关键词：动物新生/代谢骨质吸收/病理生理学载体蛋白质类/药理学细胞系细胞因子类/生理学明胶酶类/代谢激素类/药理学基质金属蛋白酶类/拮抗剂和抑制剂基质金属蛋白酶类/代谢膜糖蛋白类/药理学小鼠近交系成骨细胞/代谢成骨细胞/生理学苯丙氨酸/类似物和衍生物苯丙氨酸/药理学 RANK配体核因子κB受体活化因子颅骨/药物作用颅骨/代谢噻吩类/药理学金属蛋白酶类组织抑制剂/代谢动物小鼠

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ACTIVE-SITE-DIRECTED ALKYLATION OF CHYMOTRYPSIN BY REAGENTS UTILIZING VARIOUS DEPARTING GROUPS

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JOURNAL OF MEDICINAL CHEMISTRY 1976年第11期19卷 1284-1286页

作者： LARSEN, D SHAW, E BROOKHAVEN NATL LAB DEPT BIOL UPTON NY 11973 USA

Affinity-labeling reagents are useful for the inactivation of proteases in vivo but are apparently limited in application by the possibility of side reactions. In addition, increased specificity would be desirable. Substrate-derived chloromethyl ketones, 1 class of protease inhibitors, were examined with the hope that replacement of the departing group halogen by other substituents might lead to improved inhibitor characteristics. Analogs of Z-Phe-Ch2X were synthesized in which X is a sulfonate or carboxylate substituent and examined as inactivators of chymotrypsin. The sulfonate esters were more reactive than the previously studied halogen derivatives.

关键词：烷化剂/化学合成烷化剂/药理学糜蛋白酶/拮抗剂和抑制剂苯丙氨酸/类似物和衍生物苯丙氨酸/化学合成苯丙氨酸/药理学构效关系

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Pancreatic β-cell K_ATP channel activity and membrane-binding studies with nateglinide:: A comparison with sulfonylureas and repaglinide

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期293卷 444-452页

作者： Hu, SL Wang, SY Fanelli, B Bell, PA Dunning, BE Geisse, S Schmitz, R Boettcher, BR Novartis Inst Biomed Res Metab & Cardiovasc Dis Dept Summit NJ 07901 USA Novartis Pharma Res Core Technol Area Basel Switzerland

Nateglinide (A-4166) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes. The aim of this study was to determine whether nateglinide's interaction at the K-ATP channel/sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models. Binding studies were carried out with membranes prepared from RIN-m5F cells and HEK-293 cells expressing recombinant human sulfonylurea receptor 1 (SUR1). The relative order for displacement of [H-3]glibenclamide in competitive binding experiments with RIN-m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide > L-nateglinide > tolbutamide. The results with HEK-293/recombinant human SUR1 cells were similar with the exception that glipizide was more potent than repaglinide. Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [H-3]glibenclamide, consistent with both compounds competitively binding to the glibenclamide-binding site on SUR1. Finally, the inability to measure [H-3]nateglinide binding suggests that nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with K-ATP channels in rat pancreatic beta-cells was investigated with the patch-clamp method. The relative potency for inhibition of the K-ATP channel was repaglinide. glibenclamide. nateglinide. Kinetics of the inhibitory effect on K-ATP current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide. The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide. These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at the K-ATP channel.

关键词： ATP结合匣式转运子结合竞争性/药物作用氨甲酸酯类/药代动力学氨甲酸酯类/药理学细胞膜/药物作用细胞膜/代谢细胞分离细胞培养的环己烷类/药理学葡萄糖/代谢格列本脲/药理学糖基转移酶类低血糖症/血液低血糖症/化学诱导降血糖药/药理学胰岛素/代谢胰岛/代谢 KATP通道动力学膜蛋白质类膜片钳术苯丙氨酸/类似物和衍生物苯丙氨酸/药理学哌啶类/药代动力学哌啶类/药理学钾通道阻滞剂钾通道/药物作用钾通道内向整流大鼠 Sprague-Dawley 阻遏蛋白质类/生物合成阻遏蛋白质类/遗传学酿酒酵母蛋白质类磺酰脲化合物/药代动力学磺酰脲化合物/药理学动物人类男(雄)性大鼠

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Simultaneous enantiomeric determination of dansyl-D,L-phenylalanine by fluorescence spectroscopy in the presence of α-acid glycoprotein

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ANALYTICAL CHEMISTRY 1999年第10期71卷 1958-1962页

作者： Yan, Y Myrick, ML Univ S Carolina Dept Chem & Biochem Columbia SC 29208 USA

Few techniques are amenable to real-time analysis of enantiomers. In this paper, total complexation by a-acid glycoprotein (AGP) is shown to discriminate between enantiomers of dansyl-D,L-phenylalanine (DPs) by changing the local environment of the D and L enantiomers (DDP and DLP, respectively) from hydrophilic to hydrophobic. DDP and DLP show the same native fluorescence at lambda(ex)/lambda(em), = 200/544 nm in the absence of AGP, but show shifted emissions with a component at lambda(ex)/lambda(em) = 220/497 nm in the presence of AGP and in lipophilic solutions. The conditions for an analytical determination have been optimized, and the method has been used to measure the enantiomeric composition of DDP/DLP mixtures with concentration ratios varying over 2 orders of magnitude. The mechanism of chiral recognition for DDP and DLP by AGP is discussed and should be equally applicable to other dansyl-derivative amino acid enantiomers. The association constants for AGP with DDP and with DLP have been determined to be 1.33 x 10(2) L g(-1) and 2.29 x 10(2) L g(-1), respectively.

关键词：丹磺酰化合物/分析指示剂和试剂血清类黏蛋白/分析苯丙氨酸/类似物和衍生物苯丙氨酸/分析光谱法荧光立体异构现象动物牛

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