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1.
The mean dimensions of thecis N-methyl peptide unit have been arrived at by analysing the crystal structure data on compounds containing such units. These
dimensions can be used as standard in conformational studies on cyclic peptides. While the bonds meeting at C are almost coplanar,
those meeting at N show a slight pyramidal disposition. A comparison of the dimensions of the normal and N-methylatedcis peptide units show that there are perceptible differences in the parameters connected with N. In addition, the flexibility
of thecis peptide unit has been analysed by studying the distribution of the parameters in different classes of compounds such as cyclic
di, tri and higher peptides. The salient features are: (i) The angle CαCN in cyclic dipeptide and the angle CδNCα in higher peptides tend to be lower, when the peptide unit is associated with a prolyl residue; (ii) in cyclic tripeptides
the internal anglesviz., CαCN and CNCα are significantly larger thereby increasing the intra-annular space; (iii) the bond Cα-C is distinctly shorter when it occurs in cyclic dipeptides. The results lead to the conclusion that thecis peptide unit takes up aneed-based flexibility in its dimension. 相似文献
2.
The activity of -carboline-2-N-methyltransferase results in the formation of neurotoxic N-methylated -carbolinium compounds. We have hypothesized that these N-methylated -carbolinium cations may contribute to the development of idiopathic Parkinson's disease. This report describes experiments undertaken to optimize assay conditions for bovine brain -carboline-2-N-methyltransferase activity. The activity of -carboline-2-N-methyltransferase is primarily localized in the cytosol, has a pH optimum of 8.5–9, and obeys Michaelis-Menten kinetics with respect to its substrates, 9-methylnorharman (9-MeNH) and S-adenosyl-L-methionine (SAM). Kinetic constants, KM and Vmax, with respect to 9-MeNH, are 75 M and 48 pmol/h/mg protein, respectively. The KM for SAM is 81 M and the Vmax is 53 pmol/h/mg protein. In addition, enzyme activity is inhibited by S-adenosyl-L-homocysteine (SAH) or zinc, and is increased 2-fold in the presence of iron or manganese. Enzyme characterization is a prerequisite to the purification of this N-methyltransferase from bovine brain as well as comparison of its activity in human brain from control and Parkinson's disease individuals. 相似文献
3.
《Bioorganic & medicinal chemistry》2014,22(21):6156-6162
There are many natural peptides with multiple N-methylamino acids that exhibit potent attractive biological activities. N-methylation of a peptide bond(s) is also one of the standard approaches in medicinal chemistry of bioactive peptides, to improve the potency and physicochemical properties, especially membrane permeability. In this study, we investigated a facile synthesis process of N-methylated peptides via simultaneous N-methylation of several peptide bonds in the presence of peptide bonds that were not to be methylated. As a model study, we investigated the synthesis of the antiproliferative depsipeptide, IB-01212. We used a pseudoproline to protect the non-methylated peptide bond during a simultaneous N-methylation with MeI–Ag2O. Using further manipulations including a dimerization/cyclization process, IB-01212 and its derivatives were successfully synthesized. A preliminary structure–activity relationship study demonstrated that the symmetric structure contributed to the potent cytotoxic activity of IB-01212. 相似文献
4.
5.
《Bioorganic & medicinal chemistry letters》2014,24(23):5512-5515
Oxidative stress has been implicated in a variety of conditions, including cancer, heart failure, diabetes, neurodegeneration and other diseases. A potential biomarker for oxidative stress is the cystine/glutamate transporter, system xC−. l-Aminosuberic acid (l-ASu) has been identified as a system xC− substrate. Here we report a facile method for [11C]N-Me labeling of l-ASu, automation of the radiochemical process, and preliminary PET imaging with EL4 tumor bearing mice. The results demonstrate uptake in the tumor above background, warranting further studies on the use of radiolabeled analogs of l-ASu as a PET imaging agent for system xC−. 相似文献
6.
《Bioorganic & medicinal chemistry》2016,24(6):1163-1170
Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic hormone with wonderful glucose-lowering activity. However, its clinical use in type II diabetes is limited due to its rapid degradation at the N-terminus by dipeptidyl peptidase IV (DPP-IV). Among the N-terminal modifications of GLP-1, backbone-based modification was rarely reported. Herein, we employed two backbone-based strategies to modify the N-terminus of tGLP-1. Firstly, the amide N-methylated analogues 2–6 were designed and synthesized to make a full screening of the N-terminal amide bonds, and the loss of GLP-1 receptor (GLP-1R) activation indicated the importance of amide H-bonds. Secondly, with retaining the N-terminal amide H-bonds, the β-peptide replacement strategy was used and analogues 7–13 were synthesized. By two rounds of screening, analogue 10 was identified. Analogue 10 greatly improved the DPP-IV resistance with maintaining good GLP-1R activation in vitro, and showed approximately a 4-fold prolonged blood glucose-lowering activity in vivo in comparison with tGLP-1. This modification strategy will benefit the development of GLP-1-based anti-diabetic drugs. 相似文献
7.
Abstract The solution conformations of two potent antagonists of bradykinin (Arg1-Pro2-Pro3-Gly4- Phe5-Ser6-Pro7-Phe8-Arg9), [Aca-1, DArg0, Hyp3, Thi5, DPhe7,(N-Bzl)Gly8]BK (1) and [Aaa- 1, DArg0, Hyp3, Thi5,(2-DNal)7, Thi8]BK (2), were studied by using 2D NMR spectroscopy in DMSO-dg and molecular dynamics simulations. The NMR spectra of peptide 1 reveals the existence of at least two isomers arising from isomerization across the DPhe7-(N-Bzl)Gly8peptide bond. The more populated isomer possesses the cis peptide bond at this position. The ratio of cis/trans isomers amounted to 7:3. With both antagonists, the NMR data indicate a β-turn structure for the Hyp3-Gly4 residues. In addition, for peptide 2, position 2,3 is likely to be occupied by turn-like structures. The cis peptide bond between DPhe7 and (N- Bzl)Gly8 in analogue 1 suggests type VI β-turn at position 7,8. The molecular dynamics runs were performed on both peptides in DMSO solution. The results indicate that the structure of peptide 1 is characterized by type VIb β-turn comprising residues Ser-Arg9 and the βI or βII-turn involving the Pro2-Thi5 fragment, whereas peptide 2 shows the tendency towards the formation of type I β-turn at position 2,3. The structures of both antagonists are stabilized by a salt bridge between the guanidine moiety of Arg1 and the carboxyl group of Arg9. Moreover, the side chain of DArg0 is apart of the rest of molecule and is not involved in structural elements except for a few calculated structures. 相似文献
8.
Masao Kawai Tatsuo Yamamoto Keiichi Yamada Masashi Yamaguchi Shigehiro Kurobe Hatsuo Yamamura Shuki Araki Yasuo Butsugan Kyoko Kobayashi Ryoichi Katakai Kazuki Saito Terumi Nakajima 《Letters in Peptide Science》1998,5(1):5-12
Derivatives of gramicidin S (GS) and its mono- and di-d-cyclohexylalanine (d-Cha) analogs possessing various protecting groups on Orn side chains were prepared. 1H NMR spectra of the unsymmetrically protected analogs [Orn(X)2,Orn(X)2,d-Cha4]GS were similar to the composites of the spectra of the symmetrical derivatives [Orn(X)2,2,d-Cha4,4]GS and [Orn(X)2,2]GS, revealing the proximity of the protecting groups of NH of Orn residues at the 2 and 2 positions to the side chains of d-Phe (or d-Cha) residues at the 4 and 4 positions, respectively. The results indicated the presence of H-bonds between the NH of Orn and the carbonyl of d-Phe residues in the i i + 2 sense and not in i i – 3, which was also supported by the ROESY analysis. The substantially strong H-bonds can explain the observed resistance of the urethane NH of the Orn side chains in the GS derivatives to the N-methylation with CH3I–Ag2O in DMF. 相似文献
9.
Roland Vetter Jian Dai Nasrin Mesaeli Vincenzo Panagia Naranjan S. Dhalla 《Molecular and cellular biochemistry》1991,103(1):85-96
The effect of reagents that modify sulfur-containing amino acid residues in the phosphatidylethanolamine N-methyltransferase was studied in the isolated rat cardiac sarcolemma by employing S-adenosyl-L-[methyl-3H]methionine as a methyl donor. Dithiothreitol protected the sulfhydryl groups in the membrane and caused a concentration- and time-dependent increase of phospholipid N-methylation at three different catalytic sites. This stimulation was highest (9-fold) in the presence of 1 MM MgCl2 and 0.1 µM S-adenosyl-L-[methyl-3H]methionine at pH 8.0 (catalytic site 1), and was associated with an enhancement of Vmax without changes in Km for the methyl donor. Thiol glutathione was less stimulatory than dithiothreitol; glutathione disulfide inhibited the phosphatidylethanolamine N-methylation by 50%. The alkylating reagents, N-ethylmaleimide and methylmethanethiosulfonate, inhibited the N-methylation with IC5O of 6.9 and 14.1 µM, respectively; this inhibition was prevented by 1 mM dithiothreitol. These results indicate a critical role of sulfhydryl groups for the activity of the cardiac sarcolemmal phosphatidylethanolamine N-methyltransferase and suggest that this enzyme system in cardiac sarcolemma may be controlled by the glutathione/glutathione disulfide redox state in the cell.Abbreviations AdoMet
S-Adenosyl-L-methionine
- AdoHey
S-adenosyl-L-homocysteine
- DTNB
5,5dithiobis (2-nitrobenzoate)
- NEM
N-ethylmaleimide
- MMTS
methylmethanethiosulfonate
- DTT
dithiothreitol
- EDTA
Ethylenediaminetetraacetic acid
- GSH
glutathione
- GSSG
glutathione disulfide
- PE
phosphatidylethanolamine
- PMME
phosphatidyl-N-monomethylethamolamine
- PDME
phosphatidyl-N-dimethylethanolamine
- PC
phosphatidylcholine
- NPL
nonpolar lipids
- SL
sarcolemma 相似文献
10.
Roland Vetter Jian Daii Vincenzo Panagia Naranjan S. Dhalla 《Molecular and cellular biochemistry》1989,91(1-2):51-61
Premethylation of purified porcine cardiac sarcolemma (SL) in the presence of 0.15, 10 and 150 µM S-adenosyl-L-methionine (AdoMet) did not change the phosphorylation of SL proteins catalyzed either by intrinsic cyclic AMP-dependent protein kinase (cAK) or by added catalytic (C) subunit of this enzyme. On the other hand, membrane exhibited increased lipid methyltransferase activity after preincubation with MgATP and C subunit. Prephosphorylation of membranes stimulated the total [3H]-methyl incorporation into SL lipids assayed at 0.15 µM [3H]AdoMet due to an enhancement of Vmax and without changes in the Km value for AdoMet. Analysis of the methylated lipid products revealed an increased methyl group incorporation into a nonpolar lipid fraction whereas phosphatidylethanolamine-N-methylation was not affected by phosphorylation. The results suggest that the cyclic AMP-mediated signal transduction at the level of cardiac SL is not affected by methylation-induced modifications of the membrane lipid microdomains. On the other hand, an intrinsic SL lipid methyltransferase activity is apparently not related to the N-methylation of phospholipids, is modulated by cyclic AMP-dependent protein phosphorylation.Abbreviations AdoMet
S-adenosyl-L-methionine
- PE
phosphatidylethanolamine
- PMME
phosphatidyl-N-monomethylethanolamine
- PDME
phosphatidyl-N,N-dimethylethanolamine
- PC
phosphatidylcholine
- lyso-PC
lyso-phosphatidylcholine
- cAK
cyclic AMP-dependent protein kinase
- C subunit
catalytic subunit of cAK
- EGTA
ethylene glycol bis(-aminoethylether)N,N-tetraacetic acid
- Hepes
4-(2-hydroxylethyl)-1-piperazine-ethane-sulfonic acid
- pNPPase
p-nitrophenylphosphatase
- DTT
dithiothreitol
- Mr
relative molecular mass
- SL
sarcolemma 相似文献