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91.
92.
93.
We report Hammett correlations, using 8-substituted flavins, to clarify the mechanism of hydroxylation by p-hydroxybenzoate hydroxylase (PHBH). The 8-position of the FAD isoalloxazine ring was chosen for modifications, because in PHBH it has minimal interactions with the protein, and it is accessible to solvent and away from the site of hydroxylation. Although two intermediates, a flavin-C4a-hydroperoxide and a flavin-C4a-hydroxide, are known to participate in hydroxylation, the mechanism of oxygen transfer remains controversial. Mechanisms as diverse as electrophilic aromatic substitution, diradical formation, and isoalloxazine ring opening have been proposed. In the studies reported here, it was possible to monitor spectrally each of the individual steps involved in hydroxylation, because the FAD cofactor acts as a reporter group. Thus, with PHBH, substituted separately with nine derivatives of FAD altered in the 8-position, quantitative structure-reactivity relationships (QSAR) have been applied to probe the mechanisms of formation of the flavin-C4a-hydroperoxide, the conversion to the flavin-C4a-hydroxide with concomitant oxygen transfer to the substrate, and the dehydration of the flavin-C4a-hydroxide to form oxidized FAD. The individual chemical steps in the mechanism of PHBH were not altered when using any of the modified flavins, and normal products were obtained; however, the rates of individual steps were affected, and depended on the electronic properties of the 8-substituent. Increased hydroxylation rates were observed when a more electrophilic flavin-C4a-hydroperoxide (i.e., with an electron-withdrawing substituent at the 8-position) is bound to PHBH. On the basis of QSAR analysis, we conclude that the mechanism of the hydroxylation step is best described by electrophilic aromatic substitution. 相似文献
94.
Acyl chain and headgroup specificity of human plasma lecithin:cholesterol acyltransferase. Separation of matrix and molecular specificities 总被引:2,自引:0,他引:2
To determine how substrate fluidity and molecular structure independently regulate cholesteryl ester formation, the substrate specificity of lecithin:cholesterol acyltransferase with respect to a number of model reassembled high density lipoproteins (R-HDLs) is reported. The R-HDLs are composed of 1 mol % apolipoprotein A-I, 89 mol % of sphingomyelin or a nonhydrolyzable diether analog of phosphatidylcholine (PC) plus 10 mol % of test lipids that are potential acyl donors; a trace of [3H]cholesterol, which permits quantification of cholesteryl ester formation is also included. With respect to the lipid class of the acyl donor, the rate of ester formation decreases in the order phosphatidylethanolamine greater than phosphatidylcholine greater than N,N,-dimethylphosphatidylethanolamine greater than phosphatidylglycerol - phosphatidic acid greater than phosphatidylserine greater than dipalmitin greater than tripalmitin. Within an R-HDL composed of 90% PC ether or sphingomyelin, the relative rates of ester formation are greatest for dipalmitoyl and dimyristoyl PC, with distearoyl PC being almost unreactive; in a solid lipid environment, the rate with respect to unsaturation of the PC is greatest for oleate. In a fluid lipid environment, all unsaturated PCs were utilized nearly equally. All lipids tested were most reactive within an R-HDL composed of an unsaturated PC ether and least reactive within an R-HDL composed mostly of sphingomyelin. These results suggest that the rates of ester formation by lecithin:cholesterol acyltransferase are separate functions of the identity and the microscopic environment of the acyl donor. This is the first example of the use of diether analogs for the separation of the effects of macromolecular and molecular structure on the specificity of lecithin:cholesterol acyltransferase. 相似文献
95.
96.
Several aspects of the interaction of xanthine oxidase with arsenite are investigated. Room temperature potentiometric titrations using EPR to monitor Molybdenum reduction reveal midpoint potentials of -225 mV for the Mo(VI)-arsenite/Mo(V)-arsenite couple and -440 mV for the Mo(V)-arsenite/Mo(IV)-arsenite couple at pH 8.3. Under the same conditions, the values for native enzyme are -395 mV and -420 mV, respectively. The predicted effects of the altered Mo(VI)/Mo(V) potential on the distributions of reducing equivalents in partially reduced enzyme are compared with the experimentally observed effects in optical experiments. The bleaching that occurs on reduction of the chromophore that is generated when arsenite binds to oxidized enzyme is characterized and found to be associated with reduction of Mo(V)-arsenite to Mo(V)-arsenite. This probe enables determination of the midpoint potential for this conversion using optical data. From such data at a series of pH values ranging from 6.15 to 9.9, a pH dependence of -60 mV/pH unit increase is determined for this couple above pH 7. The ability of arsenite to bind to reduced xanthine oxidase and to desulfo enzyme are also investigated. Reduced active enzyme binds arsenite much more tightly (Kd less than 0.1 microM) and more rapidly than does oxidized active enzyme (Kd = 8 microM); oxidized desulfo enzyme binds arsenite almost as tightly (Kd = 20 microM) as does the oxidized active enzyme. 相似文献
97.
Pro-cathepsin L is an inactive zymogen that has been shown previously to undergo autolysis at pH 3.0 to give mature forms of the enzyme. We have now been able to demonstrate that this enzyme can undergo activation at pH 5.5 in the presence of negatively charged surfaces. Activation could also be measured at pH 6.0, but no activation occurred at pH 6.5 or higher. The initiation of activation depends upon the presence of a small percentage of active pro-enzyme, and this is then followed by a more rapid activation to give mature forms of the enzyme. No significant intermediate molecular forms of the enzyme were seen. The time taken for processing of the pro-enzyme to single-chain mature enzyme is comparable to that seen in biosynthetic pulse-chase experiments. 相似文献
98.
The fluorescence substrate kynuramine was used as a probe of the catalytic site of plasma amine oxidase. Under anaerobic conditions, the binding of kynuramine causes several spectroscopic changes. The Stokes shift (deltav = 5326 cm-) associated with binding of the substrate to the enzyme can be attributed to nonpolar properties of the binding site, whereas the increase in emission anisotropy (A = 33) indicates rigid attachment of the substrate to the enzyme. The fluorescence enhancement that follows the binding of substrate was used to determine the association constant (Ka). The enzyme plasma amine oxidase binds only 1 molecule of substrate with a Ka = 1.8 X 10(5) M-1 under anaerobic conditions. The use of fluorescence substrates seems to offer the possibility of monitoring conformational changes occurring prior to the catalytic event. 相似文献
99.
Jonathan Massey Simon Rothwell Clare Rusbridge Anna Tauro Diane Addicott Hector Chinoy Robert G. Cooper William E. R. Ollier Lorna J. Kennedy 《PloS one》2013,8(2)
A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 “graded” controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA-DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR = 1.92, p = 0.032). When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR = 4.08, p = 0.00011). Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis. 相似文献
100.
Manohar Salla Mark S. Butler Nicholas L. Massey Janet C. Reid Matthew A. Cooper Avril A.B. Robertson 《Bioorganic & medicinal chemistry letters》2018,28(4):793-795
This study describes the syntheses of di, tetra and hexa deuterated analogues of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950. In di and tetra deuterated analogues, deuteriums were incorporated into the 1,2,3,5,6,7-hexahydro-s-indacene moiety, whereas in the hexa deuterated MCC950 deuteriums were incorporated into the 2-(furan-3-yl)propan-2-ol moiety. The di deuterated MCC950 analogue was synthesised from 4-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one 5. Tetra deuterated analogues were synthesised in 10 chemical steps starting with 5-bromo-2,3-dihydro-1H-inden-1-one 9, whereas the hexa deuterated analogue was synthesised in four chemical steps starting with ethyl-3-furoate 24. All of the compounds exhibited similar activity to MCC950 (IC50?=?8?nM). These deuterated analogues are useful as internal standards in LC-MS analyses of biological samples from in vivo studies. 相似文献