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1.
Diglyceride analogs were studied with respect to their abilities to activate protein kinase C (Ca2+- and phospholipid-dependent protein kinase) in the presence of low calcium and phospholipid. Analogs which lacked either a free hydroxyl group at the 3 position or an ester moiety at the 1 position were without activity. It was concluded that the hydrophilic moieties of the active diglycerides are crucial for activity. However, diglyceride analogs containing additional hydrophilic moieties in one of the acyl side chains did not exhibit enhanced activity when compared to diglycerides containing two fatty acyl groups. Diglyceride analogs with a modified glycerol backbone were also studied. Homologous diglycerides with either one or two methylene groups between the 3-methylene group of the diglyceride and the hydroxyl group possessed markedly reduced activities when compared to the appropriate unmodified diglyceride. Isomers of these homologues which contained either a methyl group at the 1 position, or dimethyl groups incorporated at the 1 and 3 positions, were virtually without activity. Where studied, none of the diglyceride analogs prepared possessed antagonist activity. The results of these experiments are discussed with respect to the extreme specificity observed. 相似文献
2.
In vivo isomerization of all-trans- to 11-cis-retinoids in the eye occurs at the alcohol oxidation state 总被引:2,自引:0,他引:2
The vertebrate biochemical pathway for regeneration of visual pigments in the living eye after bleaching is largely uncharacterized. Since isomerization of an all-trans-retinoid to an 11-cis-retinoid could conceivably occur via the aldehyde, alcohol, or ester forms of vitamin A, it is important to determine the oxidation state of the retinoid that is isomerized in vivo. To address this problem, light-adapted rats and frogs were injected intraperitoneally with a mixture of [15-3H]-all-trans-retinol and [15-14C]-all-trans-retinol. After 4 or 24 h of dark adaptation, labeled retinoids in the animal's eyes were analyzed. All rats had the expected 50% loss of 3H label (relative to 14C) in 11-cis-retinal, a loss of 3H that must occur when [15-3H]retinol is oxidized to retinal. 11-cis-Retinyl esters in the rats' eyes at 4 h retained 67% of the 3H label, and this could be increased to 81% when the rats were pretreated with 4-methylpyrazole, an alcohol dehydrogenase inhibitor known to inhibit dark adaptation. This result demonstrates that retinoid isomerization occurs at the alcohol oxidation state in the rat eye. Had it occurred at the aldehyde oxidation state, at least 50% of the 3H in the 11-cis-retinyl esters would have been lost. The importance of this isomerization pathway is emphasized by the observation that dark-adapting rats whose alcohol dehydrogenase(s) had been inhibited by 4-methylpyrazole had increased amounts of 11-cis-retinyl ester in their eyes relative to control rat eyes, a result that is understandable only if retinoids are isomerized in vivo at the alcohol oxidation state.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
3.
all-trans-retinoids and dihydroretinoids as probes of the role of chromophore structure in rhodopsin activation 总被引:1,自引:0,他引:1
The absorption of a photon of light by rhodopsin results in the cis to trans isomerization of the 11-cis-retinal Schiff base chromophore. In the studies reported here, an attempt is made to determine the mechanism of the energization of rhodopsin as it relates to the chemistry of the isomerization process and the geometrical state of the chromophore. Studies were performed with vitamin A analogues to probe this mechanism. Both 11-cis-7,8-dihydroretinal and 9-cis-7,8-dihydroretinal form bleachable pigments when combined with opsin. Photolysis of these pigments in the presence of G-protein results in the activation of the latter as revealed by its GTPase activity. Phosphodiesterase is also activated when it is included in the incubation. Therefore, the possibility that rhodopsin is energized by mechanisms involving photochemically induced charge transfer from the protonated Schiff base to the beta-ionone ring can be discarded. Further studies were conducted with all-trans-vitamin A derivatives to determine if these compounds can form the GTPase-activating state R*, a situation that is possible, in principle, by microscopic reversibility. Neither all-trans-retinal nor its oxime, when incubated with bovine opsin in the dark, caused activation of the GTPase, requiring at least a 5 kcal/mol energy gap between them. Furthermore, stoichiometric adducts of all-trans-retinoids and opsin were also unable to mediate activation of the GTPase. Since both all-trans-15,16-dihydroretinylopsin and all-trans-retinoylopsin possess an all-trans-retinoid permanently adducted to opsin, it can be concluded that the all-trans-retinoid chromophore-opsin linkage may be necessary but not sufficient to achieve activation of the visual pigment. 相似文献
4.
Effects of Light on Dopamine Metabolism in the Chick Retina 总被引:5,自引:4,他引:1
The effect of prolonged exposure to light on the activity of dopaminergic neurons and dopamine (DA) metabolism of chick retinae was investigated. alpha-Fluoromethyldopa, a potent and specific irreversible inactivator of aromatic amino acid decarboxylase, was used to assess DA turnover after inhibition of synthesis, and also to assess in vivo tyrosine hydroxylase activity by dihydroxyphenylalanine accumulation. After 48 h of light exposure, retinal DNA in 12-day-old chicks was about 30% higher (p less than 0.005) whereas dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were elevated two to three times (p less than 0.005) the level of controls kept in the dark for the same period. DA turnover was about twofold faster in the light (t 1/2 = 31 min) than in the dark (t 1/2 = 65 min). Tyrosine hydroxylase, assayed in vitro with saturating levels of cofactor and substrate, increased by about 50% after light exposure. The apparent tyrosine hydroxylase activity in vivo was approximately sixfold higher in the light than the dark. These results are interpreted and discussed in terms of the regulation of DA synthesis, and the use of DOPAC and HVA as indices of DA function in the retina. 相似文献
5.
6.
Lecithin retinol acyltransferase (LRAT) is an essential enzyme in vitamin A metabolism and mobilization. The membrane-bound enzyme catalyzes the transfer of an acyl group from the sn-1 position of lecithin to vitamin A to generate retinyl esters. The sequence of LRAT is novel and hence does not suggest a mechanistic class to which the enzyme belongs. However, the activity of the enzyme is exceedingly sensitive to affinity labeling and group-specific reagents directed toward thiol groups. LRAT from human retinal pigment epithelium has cysteine residues at positions 161, 168, 182, and 208. Site-specific mutagenic studies show that C182 and C208 can be converted to alanines with little affect on activity. The activities of the C161A and C168A mutants are virtually nil. Moreover, while C168S is substantially active, C161S possesses only a few percent of the activity of wild-type (WT) LRAT. Also, pH-rate profiles show that C168S has virtually the same profile as WT LRAT, while C161S shows an aberrant profile quite unlike that of WT LRAT. Therefore, LRAT is a thiol acyltransferase and C161 may be the essential nucleophilic residue critical for catalysis. 相似文献
7.
Characterization of two new alleles at the goat CSN1S2 locus 总被引:5,自引:0,他引:5
L. Ramunno G. Cosenza M. Pappalardo E. Longobardi D. Gallo N. Pastore P. Di Gregorio & A. Rando 《Animal genetics》2001,32(5):264-268
Two novel alleles at the goat CSN1S2 locus have been identified: CSN1S2(F) and CSN1S2(D). Sequence analyses revealed that the CSN1S2(F) allele is characterized by a G --> A transition at the 13th nucleotide in exon 3 changing the seventh amino acid of the mature protein from Val to Ile. The CSN1S2(D) allele, apparently associated with a decreased synthesis of alpha s2-casein, is characterized by a 106-bp deletion, involving the last 11 bp of the exon 11 and the first 95 bp of the following intron. Methods (PCR-RFLP and PCR) for identification of carriers of these alleles have been developed. 相似文献
8.
Hui Li Shuyi Wang Fang-Hua Lee Ryan S. Roark Alex I. Murphy Jessica Smith Chengyan Zhao Juliette Rando Neha Chohan Yu Ding Eunlim Kim Emily Lindemuth Katharine J. Bar Ivona Pandrea Cristian Apetrei Brandon F. Keele Jeffrey D. Lifson Mark G. Lewis Thomas N. Denny Barton F. Haynes Beatrice H. Hahn George M. Shaw 《Journal of virology》2021,95(11)
9.
Fernanda R. Andre Paloma Freire dos Santos Daniela G. Rando 《Journal of molecular modeling》2016,22(1):23
Src tyrosine kinases are a family of non-receptor proteins that are responsible for the growth process, cellular proliferation, differentiation and survival. Lack of Src kinase control has been associated with the development of certain human cancers. This family of proteins is constituted of four domains, with SH1 being the kinase or catalytic domain. SH1 also presents three important regulatory sites. Two residues, Tyr416 and Tyr527, are responsible for important phosphorylation processes that lead to, respectively, activation and deactivation of these kinases. More recently, however, a set of four cysteine residues located near the C-terminus-Cys483, Cys487, Cys496 and Cys498-has been associated with the activation of the Src kinases through S-nitrosylation reactions. Particularly, the Cys498 has been specified as a fundamental residue when considering this regulatory mechanism. Aiming to understand the role of these four cysteines in S-nitrosylation, theoretical studies of electrostatic, steric and hydrophobic properties were performed with a sequence of 20 amino acids, enclosing the four cysteine residues under study, extracted from the PDB coordinates of the crystal obtained from the inactive state of Src kinase. Results indicate that Cys498 is buried deeply in the protein, in hydrophobic surroundings in which NO is more likely to suffer decomposition into the electrophilic intermediates known to be responsible for S-nitrosylation reactions. Electronic calculated properties, such as punctual atomic charges, electrostatic potentials and molecular orbital energy, also demonstrated the good nucleophilic potential of Cys498. 相似文献
10.
Regulation of protein kinase C activity by lipids 总被引:9,自引:0,他引:9
R R Rando 《FASEB journal》1988,2(8):2348-2355
Protein kinase C is activated by the simultaneous presence of phospholipid, a diglyceride, and Ca2+. Under physiological conditions the activity of the enzyme is regulated by the availability of diglycerides, which are the products of phosphoinositide hydrolysis. The phospholipid-kinase interactions appear not to be of a highly specific nature. Phosphatidylserine (PS) is presumed to be the endogenous lipid that interacts with the kinase, but other acidic lipids can substitute. On the other hand, the kinase-diglyceride interactions are highly specific in nature, as would be expected of a physiological regulator. These interactions are stereo-specific and stoichiometric with respect to diglyceride. The specificity is directed toward the glycerol backbone and hydrophilic oxygen moieties of the diglyceride. The removal of one or more of the oxygen atoms or the addition of a single methyl group to the glycerol backbone virtually abolishes the activity of a putative diglyceride activator. The extreme specificity of the kinase toward the diglycerides, however, must be contrasted with the abilities of structurally diverse tumor promotors and irritants to activate the kinase. Specific small-molecule antagonists of protein kinase C have yet to be developed. The small-molecule antagonists that have been developed so far have been relatively nonspecific cationic lipids that appear to function by interfering with the interaction between the acidic phospholipids and Ca2+. 相似文献