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101.
The enzymatic reaction of triosephosphate isomerase (TIM) is controlled by the movement of a loop (loop6, residues 166-176). Crystal structures of TIMs from a variety of sources have revealed that the loop6, which is in an open conformation in the unliganded enzyme, adopts a closed conformation in inhibitor complexes. In contrast, structures with loop open conformation are obtained in most of the complexes of TIM from the malarial parasite Plasmodium falciparum (PfTIM). W168 is a conserved N-terminal hinge residue, involved in different sets of interactions in the "open" and "closed" forms of loop6. The role of W168 in determining the loop conformation was examined by structural studies on the mutant W168F and its complexes with ligands. The three-dimensional structures of unliganded mutant (1.8 A) and complexes with sulfate (2.8 A) and glycerol-2-phosphate (G2P) (2.8 A) have been determined. Loop6 was found disordered in these structures, reflecting the importance of W168 in stabilizing either the open or the closed states. Critical sequence differences between the Plasmodium enzyme and other TIMs may influence the equilibrium between the closed and open forms. Examination of the environment of the loop6 shows that its propensity for the open or the closed forms is influenced not only by Phe96 as suggested earlier, but also by Asn233, which occurs in the vicinity of the active site. This residue is Gly in the other TIM sequences and probably plays a crucial role in the mode of ligand binding, which in turn affects the loop opening/closing process in PfTIM. 相似文献
102.
The insertion of alpha-hydroxy acids into peptide chains provides a convenient means for investigating the effects of hydrogen bond deletion on polypeptide secondary structures. The crystal structures of three oligopeptides containing L-lactic acid (Lac) residue have been determined. Peptide 1, Boc-Val-Ala-Leu-Aib-Val-Lac-Leu-Aib-Val-Ala-Leu-OMe (Boc: tert-butyloxycarbonyl; Aib: alpha- aminoisobutyric acid; OMe: methyl ester), and peptide 2, Boc-Val-Ala-Leu-Aib-Val-Lac-Leu-Aib-Val-Leu-OMe, adopt completely helical conformations in the crystalline state with the Lac(6) residue comfortably accommodated in the center of a helix. The distance between the O atoms of Leu(3) CO group and the Lac(6) O (ester) in both the structures is 3.1-3.3 A. The NMR and CD studies of peptide 1 and its all-amide analogue 4, Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-OMe, provide firm evidence for a continuous helical conformation in solution in both the cases. In a 14-residue peptide 3, Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Val-Ala-Leu-Aib-Val-Lac-Leu-OMe, residues Val(1)-Leu(10) adopt a helical conformation. Aib(11) is the site of chiral reversal resulting in helix termination by formation of a Schellman motif. Residues 12-14 adopt nonhelical conformations. The loss of the hydrogen bond near the C-terminus appears to facilitate the chiral reversal at Aib(11). Published 2001 John Wiley & Sons, Inc. Biopolymers 59: 276-289, 2001 相似文献
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105.
Sirtuin (Sir2) proteins being key regulators of numerous cellular processes have been, over the recent past, the subject of intense study. Sirs have been implicated in diverse physiological processes ranging from aging and cancer to neurological dysfunctions. Studies on Sir2s using tools of genetics, molecular biology, biochemistry and structural biology have provided significant insight into the diverse functions of this class of deacetylases. This apart, medicinal chemistry approaches have enabled the discovery of modulators (both activators and inhibitors) of Sir2 activity of diverse chemical structures and properties. The availability of these small molecule modulators of Sir2 activity not only has pharmacological significance but also opens up the possibility of exploiting chemical genetic approaches in understanding the role of this multi-functional enzyme in cellular processes. 相似文献
106.
Enzymatic efficiency and structural discrimination of substrates from nonsubstrate analogues are attributed to the precise assembly of binding pockets. Many enzymes have the additional remarkable ability to recognize several substrates. These apparently paradoxical attributes are ascribed to the structural plasticity of proteins. A partially defined active site acquires complementarity upon encountering the substrate and completing the assembly. Human hypoxanthine guanine phosphoribosyltransferase (hHGPRT) catalyzes the phosphoribosylation of guanine and hypoxanthine, while the Plasmodium falciparum HGPRT (PfHGPRT) acts on xanthine as well. Reasons for the observed differences in substrate specificities of the two proteins are not clear. We used ultraviolet resonance Raman spectroscopy to study the complexes of HGPRT with products (IMP, GMP, and XMP), in both organisms, in resonance with the purine nucleobase electronic absorption. This led to selective enhancement of vibrations of the purine ring over those of the sugar-phosphate backbone and protein. Spectra of bound nucleotides show that HGPRT distorts the structure of the nucleotides. The distorted structure resembles that of the deprotonated nucleotide. We find that the two proteins assemble similar active sites for their common substrates. While hHGPRT does not bind XMP, PfHGPRT perturbs the pK(a) of bound XMP. The results were compared with the mutant form of hHGPRT that catalyzed xanthine but failed to perturb the pK(a) of XMP. 相似文献
107.
[Cp∗IrCl2]2 is used as an efficient promoter for the synthesis of sugar acetals and ketals with good to excellent yields. The catalyst is found to be general for a wide range of sugars. 相似文献
108.
In aerobic respiration, the tricarboxylic acid cycle is pivotal to the complete oxidation of carbohydrates, proteins, and lipids to carbon dioxide and water. Plasmodium falciparum, the causative agent of human malaria, lacks a conventional tricarboxylic acid cycle and depends exclusively on glycolysis for ATP production. However, all of the constituent enzymes of the tricarboxylic acid cycle are annotated in the genome of P. falciparum, which implies that the pathway might have important, yet unidentified biosynthetic functions. Here we show that fumarate, a side product of the purine salvage pathway and a metabolic intermediate of the tricarboxylic acid cycle, is not a metabolic waste but is converted to aspartate through malate and oxaloacetate. P. falciparum-infected erythrocytes and free parasites incorporated [2,3-(14)C]fumarate into the nucleic acid and protein fractions. (13)C NMR of parasites incubated with [2,3-(13)C]fumarate showed the formation of malate, pyruvate, lactate, and aspartate but not citrate or succinate. Further, treatment of free parasites with atovaquone inhibited the conversion of fumarate to aspartate, thereby indicating this pathway as an electron transport chain-dependent process. This study, therefore, provides a biosynthetic function for fumarate hydratase, malate quinone oxidoreductase, and aspartate aminotransferase of P. falciparum. 相似文献
109.
Gupta P Bhatia S Dhawan A Balwani S Sharma S Brahma R Singh R Ghosh B Parmar VS Prasad AK 《Bioorganic & medicinal chemistry》2011,19(7):2263-2268
Regio- and enantioselective synthesis of (S)-(+)-3-arylamino-1-chloropropan-2-ols has been achieved by the epoxide ring opening of (±)-epichlorohydrin with different aromatic amines in the presence of Candida rugosa lipase. Activities of seven model (S)-(+)-3-arylamino-1-chloropropan-2-ols, out of 10 compounds synthesized, have been evaluated for the inhibition of tumor necrosis factor-α TNF-α) induced expression of intercellular adhesion molecule-1 (ICAM-1), which is one of the factors responsible for the modulation of inflammation in biological systems; (S)-(+)-1-chloro-3-(2'-chlorophenylamino)-propan-2-ol has been found to exhibit highest activity, that is, 86% inhibition of TNF-α induced expression of ICAM-1 at a concentration of 40 μg/ml. 相似文献
110.
A chromone analog inhibits TNF-alpha induced expression of cell adhesion molecules on human endothelial cells via blocking NF-kappaB activation 总被引:3,自引:0,他引:3