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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of new compounds, 6-amino-1-naphthalenesulfonamides (ANSN), were used as fluorescent detecting groups for substrates of amidases. These compounds have a high quantum fluorescent yield, and the sulfonyl moiety permits a large range of chemical modification. Fifteen ANSN substrates with the structure (N alpha-Z)Arg-ANSNR1R2 were synthesized and evaluated for their reactivity with 8 proteases involved in blood coagulation and fibrinolysis. Thrombin, activated protein C, and urokinase rapidly hydrolyzed substrates with monosubstituted sulfonamide moieties (R1 = H). The maximum rate of substrate homologue). The hydrolysis rates for substrates with branched substituents were slower than their linear analogues. Monosubstituted (N alpha-Z)Arg-ANSNR1R2 possessing cyclohexyl or benzyl groups in the sulfonamide moiety were hydrolyzed by these three enzymes at rates similar to that of the n-butyl homologue (except the cyclohexyl compound for u-PA). Factor Xa rapidly hydrolyzed substrates with short alkyl chains, especially when R1 = R2 = CH3 or C2H5. Lys-plasmin and rt-PA demonstrated low activity with these compounds, and the best results were accomplished for monosubstituted compounds when R2 = benzyl (for both enzymes). Factor VIIa and factor IXa beta exhibited no activity with these substrates. A series of 14 peptidyl ANSN substrates were synthesized, and their reactivity for the same 8 enzymes was evaluated. Thrombin, factor Xa, APC, and Lys-plasmin hydrolyzed all of the substrates investigated. Urokinase, rt-PA, and factor IXa beta exhibited reactivity with a more limited group of substrates, and factor VIIa hydrolyzed only one compound (MesD-LGR-ANSN(C2H5)2). The substrate ZGGRR-ANSNH (cyclo-C6H11) showed considerable specificity for APC in comparison with other enzymes (kcat/KM = 19,300 M-1 s-1 for APC, 1560 for factor IIa, and 180 for factor Xa). This kinetic advantage in substrate hydrolysis was utilized to evaluate the activation of protein C by thrombin in a continuous assay format. Substrate (D-LPR-ANSNHC3H7) was used to evaluate factor IX activation by the factor VIIa/tissue factor enzymatic complex in a discontinuous assay. A comparison between the commercially available substrate chromozyme TH (p-nitroanilide) and the ANSN substrate with the same peptide sequence (TosGPR) demonstrated that aminonaphthalenesulfonamide increased the specificity (kcat/KM) of substrate hydrolysis by thrombin more than 30 times, with respect to factor Xa substrate hydrolysis.
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PMID:Aminonaphthalenesulfonamides, a new class of modifiable fluorescent detecting groups and their use in substrates for serine protease enzymes. 160 66

We report on a computer algorithm capable of predicting the location of T-helper-cell epitopes in protein antigen (Ag) by analysing the Ag amino acid sequence. The algorithm was constructed with the aim of identifying segments in Ag which are resistant to proteolytic degradation by the enzymes cathepsin B, L, and D. These are prominent enzymes in the endocytic pathway through which soluble protein Ag enter APC, and resistant segments in Ag may, therefore, be expected to contain more T-cell determinants than susceptible segments. From information available in the literature on the substrate specificity of the three enzymes, it is clear that a cysteine is not accepted in any of the S2, S1, S1', and S2' subsites of cathepsin B and L, and not in the S1 and S1' subsites of cathepsin D. Moreover, we have noticed that cysteine-containing T-cell determinants in a number of protein Ag are particularly rich in the amino acids alanine, glycine, lysine, leucine, serine, threonine, and valine. By searching protein Ag for clusters of amino acids containing cysteine and two of the other amino acids we were able to predict 17 out of 23 empirically known T-cell determinants in the Ag with a relatively low number of false (positive) predictions. Furthermore, we present a new principle for searching Ag for potential amphipatic alpha-helical protein segments. Such segments accord well with empirically known T-cell determinants and our algorithm produces a lower number of false positive predictions than the principle based on discrete Fourier transformations previously described.
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PMID:T-helper-cell determinants in protein antigens are preferentially located in cysteine-rich antigen segments resistant to proteolytic cleavage by cathepsin B, L, and D. 171 25

Human T cells spontaneously bind sheep E and this reflects physiologic interactions between specific adhesion molecules, principally T cell CD2, and the sheep equivalent of LFA-3. This interaction is important in T cell adhesion and in transmission of accessory activational signals. In this respect, E rosettes provide a partial analogue for T cell:accessory cell interaction and rosetting induces functional alterations in T cells. In studies of Ag-dependent T cell activation, we have obtained evidence that the formation of covalent Schiff bases between ligands on APC and T cell is an essential element. In our study, the specific chemical criteria defining Schiff base formation were applied to T cell E rosettes formed at room temperature, as follows: 1) Prior formation of Schiff bases on T cell epsilon-amino groups by glutaraldehyde inhibited E rosette formation. 2) Rosette formation was inhibited in the presence of exogenous lysine. 3) Reduction of constitutive T cell aldehydes by NaBH4 inhibited subsequent E rosette formation. In response to these chemical modifications of cellular ligands, T cell E rosette formation and T cell inductive interaction with APC were affected in the same way. 4) Oxidation of NaBH4-treated T cells by NaIO4 or galactose oxidase to regenerate cell-surface aldehydes on N-acetylneuraminic acid or galactose residues respectively, consistently restored E rosette formation. 5) Conversion of reversible Schiff bases to irreversible secondary amines by NaCNBH3 stabilized E rosettes against mechanical disruption. Together, these data demonstrate that E rosettes provide an analogue for the Schiff base-forming reactions that are essential in specific T cell activation.
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PMID:Erythrocyte rosettes provide an analogue for Schiff base formation in specific T cell activation. 236 92

The effect of human T cell leukemia/lymphoma virus type I (HTLV-I) infection on the function and the phenotype of a human proliferating/cytotoxic T cell clone, specific for tetanus toxin, was investigated. During the period after infection, two distinct phases were observed, based on growth properties, phenotype, and functional activity of the infected cells. Phase I HTLV-I infected cells (0 to about 150 days after infection) proliferated in an IL-2-dependent way, but without the requirement for repetitive antigenic stimulation. No differences in expression of the CD2, CD3, CD4, Tp103, and CD28 Ag between these cells and the parental cells could be demonstrated, with the exception of the expression of IL-R p55 and HLA-DR Ag, which were constitutively expressed on the phase I cells. The phase I HTLV-I-infected cells, as well as the parental 827 cells reacted with a mAb specific for an epitope on the variable part of the TCR beta-chain, indicating that the TCR was not altered after HTLV-I infection. Like the parental clone, the phase I cells proliferated in response to tetanus toxin, but the tetanus toxin-specific response of the phase I cells did not require the presence of APC. Results of experiments, in which the levels of intracellular Ca2+ were measured, indicated that HTLV-I cells can acquire the capability to process Ag and present that to themselves. Phase I HTLV-I-infected T cells had lost their cytotoxic activity which was likely to be due to an effect on the lytic machinery rather than on Ag recognition by the TCR, inasmuch as it was found that phase I HTLV-I-infected T cells did no longer contain N-alpha-benzyloxy-L-lysine thiobenzylester-serine esterase activity. Furthermore, it was found that phase I HTLV-I-infected T cells had a diminished capacity to form conjugates with target cells. From a period of about 200 days after HTLV-I infection, phase II cells emerged that proliferated strongly in the absence of IL-2 and that had lost all functional activity. These cells did not express the CD3/T cell receptor complex on their surface. Phase I as well as phase II HTLV-I-infected cells were targets for CTL raised in the autologous donor.
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PMID:Human T cell leukemia/lymphoma virus type I infection of a CD4+ proliferative/cytotoxic T cell clone progresses in at least two distinct phases based on changes in function and phenotype of the infected cells. 246 94

The inductive interaction between class II+ APC and Th cell was investigated in a human system at the chemical level. The study set out to test the predictions of a model of Ag presentation in which epsilon-amino groups and carbonyl groups at the surface of APC and T cell react covalently to form reversible intercellular Schiff bases. In the experimental system of oxidative mitogenesis this process results in T cell activation. If oxidative mitogenesis is an experimental amplification of a physiologic process, and intercellular Schiff base formation is essential in Ag presentation, then it should be possible to inhibit Ag presentation by prior formation of Schiff bases on the surface of participating cells. In this situation Ag-induced T cell activation and T cell activation induced by periodate oxidation should invariably behave in the same way. It should also be possible to demonstrate Schiff base formation occurring between accessory cells and lymphocytes directly and definitively by means of specific reduction with sodium cyanoborohydride. Aldehyde treatment of accessory cells should prevent this intercellular Schiff base formation. In this study the following observations were made. 1) Both Ag-specific and periodate-induced T cell activation were inhibited by aldehyde treatment of class II+ accessory cells. 2) Noncross-linking donors of carbonyl groups other than aldehydes inhibited Ag-specific T cell activation. 3) Brief, low-dose treatment of T cells with aldehydes inhibited Ag-dependent T-cell activation. 4) Exogenous amino groups in the form of lysine and other amino acids inhibited both Ag-specific and periodate-induced T-cell activation. 5) The weak reducing agent sodium cyanoborohydride which is specific for Schiff bases at neutral pH inhibited both Ag-induced and periodate-induced T cell activation. Responses to PHA were markedly prolonged by this reagent. 6) Schiff base formation occurring between accessory cells and lymphocytes was detected directly and definitively by means of radiolabeling with NaCNB(3H)3 at neutral pH. These data are consistent with the view that the formation of reversible covalent Schiff bases between ligands on APC and T cell is an essential process in Ag-induced T cell activation.
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PMID:Evidence for an intercellular covalent reaction essential in antigen-specific T cell activation. 247

Rabbit polyclonal antibodies to a synthetic peptide, NH2-Asp-Thr-Asn-Gln-Val-Asp-Gln-Lys-Asp-Gln-Leu-Asp-Phe-Arg-CONH2 (A Pep), have been produced. This sequence is identical to that contained in the tetradecapeptide released from bovine protein C (PC) as a result of its conversion to its activated form (APC), except that Phe13 replaced the normal Pro13, in order to discourage cross-reactivity of antibodies to the carboxylterminal portion of APep with PC. The antibody pool obtained reacted with PC and showed virtually no cross-reactivity toward either APC or several typical plasma proteins. This general approach should serve well as a means of production of antibodies with a designed specificity capable of distinguishing between forms of the same protein that arise by release of peptide material.
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PMID:Generation of an antibody with a designed specificity difference for protein C and activated protein C. 280 12

Lisinopril (MK521), a lysine analogue of enalaprilic acid, the bioactive metabolite of enalapril, has a longer half-life than enalaprilic acid, and is excreted unchanged in the urine. Its kinetic profile and antihypertensive and hormonal effects have been investigated in an open study in 3 groups each of 6 hypertensive patients, with normal, moderate and severe impairment of renal function. Serum drug level, blood pressure, converting enzyme activity (CEA), plasma renin activity (PRA), aldosterone concentration (PAC), and serum potassium and creatinine were measured during 1 week following a single oral dose and subsequently following 8 daily doses of 5 mg lisinopril. Accumulation of lisinopril was found in the severe renal failure group. CEA was suppressed to less than 10% of its initial value from 4 to 24 h after the initial dose in all three groups, and the suppression was more marked and lasted longer in patients with severe renal failure. An inverse correlation was found in all patients between log serum lisinopril concentration and log CEA. Lisinopril lowered blood pressure in all three groups over 24 h. PRA rose and PAC fell similarly in the groups. Serum potassium increased in the renal failure groups and creatinine remained unchanged in all groups. Thus, when lisinopril 5 mg is given daily to patients with severe renal failure it may accumulate. The high serum lisinopril concentration does not cause an excessive antihypertensive effect. In patients with severe renal failure, adjustment of the dose or the dosing frequency to the degree of renal failure is recommended to avoid administration of doses in excess of those required to achieve adequate inhibition of converting enzyme.
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PMID:Lisinopril in hypertensive patients with and without renal failure. 303 22

Previous study has shown that reduced T cell response to peptide alpha 146-162 of Torpedo californica acetylcholine receptor (tAChR) in B6.C-H-2bm12 (bm12) mice, a mutant of C57BL/6 (B6) mice, correlated with its nonsusceptiblity to experimental autoimmune myasthenia gravis. There are three amino acid differences between the I-A beta b of the two strains (positions 67, 70, and 71). We synthesized peptides I-A beta b62-76 (peptide b6), I-A beta bm1262-76 (peptide bm), and three additional peptides, b6(67F), b6(70Q), and b6(71K), and determined their ability to bind peptide alpha 146-162 and the dissociation constants (Kd) of the binding. Peptide alpha 146-162 bound with a significantly higher affinity to peptide b6 than to peptides bm or b6(71K), suggesting that the lower affinity of peptide alpha 146-162 to I-Abm12 is a factor in the reduced response to this peptide by bm12 T cells. This was confirmed by measurement of the Kd values of the binding of peptide alpha 146-162 to the I-A molecules of B6 and bm12. Furthermore, APC of bm12 presented the peptide, or tAChR, poorly to peptide-specific or to tAChR-specific B6 T cells. The major effect is caused by the change of Thr-71 in I-A beta b to lysine in I-A beta bm12. However, APC of B6 also presented peptide alpha 146-162 much less efficiently to peptide-specific T cells of bm12. This demonstrated that these three amino acid changes also influence the T cell receptor recognition of peptide-MHC complex and that both B6 and bm12 T cells recognizing peptide alpha 146-162 or tAChR are under a high H-2 restriction.
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PMID:Effect of amino acid substitutions within the region 62-76 of I-A beta b on binding with and antigen presentation of Torpedo acetylcholine receptor alpha-chain peptide 146-162. 753 3

To identify a site within the insulin receptor ectodomain which forms a binding pocket for B25 Phe and is responsible for initiating conformational changes required for high affinity binding of insulin we have used a novel photoreactive insulin, despentapeptide-(B26-B30) [B25 p-azidophenylalanine-alpha-carboxamide] insulin (APC insulin). This derivative has a highly photoreactive azido group incorporated into the aromatic ring of the B25 phenylalanine amide. APC insulin bound to human insulin receptors overexpressed on a transfected Chinese hamster ovary cell line (P3-A) with an apparent potency of 9-fold relative to that of native insulin and stimulated lipogenesis in rat adipocytes with an average potency equal to porcine insulin. Addition of biotin to the B1 Phe amino group to form despentapeptide-(B26-B30) [B1 (6-biotinylamidocaproyl)phenylalanine B25 p-azidophenylalanine-alpha-carboxamide] insulin derivative (Bio-APC insulin) did not adversely affect receptor-binding affinity and provided a convenient ligand for purification of cross-linked complexes. The efficiency of receptor cross-linking with these reagents was high (70%). To identify the site(s) of cross-linking, the insulin receptor in P3-A cells was first metabolically labeled with various individual 3H-labeled amino acids and then photoaffinity labeled with 125I-Bio-APC insulin, isolated, and digested with Lys-C endoproteinase. The resulting cross-linked peptide fragments were separated by streptavidin-affinity chromatography and sequenced. The smallest identified fragment comprised residues 704-718 of the COOH terminus of the alpha-subunit of the insulin receptor. This B25 Phe cross-linked region of the alpha-subunit lies just upstream of the Exon 11-encoded 12-amino acid COOH-terminal region. Aromatic residues in this predicted alpha-helical region may form a binding pocket for B25 Phe to initiate conformational changes required for stabilizing the high affinity binding state.
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PMID:Cross-linking of a B25 azidophenylalanine insulin derivative to the carboxyl-terminal region of the alpha-subunit of the insulin receptor. Identification of a new insulin-binding domain in the insulin receptor. 796 85

When examining the effects of analogue peptides on changes in response patterns of a human Th0 clone DT13.2 that recognizes a peptide fragment (18RSLRTVTPIRMQGG31) derived from a group I allergen in Dermatophagoides farinae in the context of HLA-DQ6 (DQA1*0102/DQB1*0602), we found that replacement of the 21st residue Arg to Lys resulted in a significant increase in IFN-gamma production, with no remarkable changes either in proliferative response or IL-4 production, at high doses of the peptide. Selective enhancement of IFN-gamma production by the analogue peptide was accompanied by an increased production of IL-12, which was suppressed by an anti-IL-12 Ab down to the level of IFN-gamma production induced by the wild-type peptide. On the contrary, co-incubation with neutralizing Abs to IFN-gamma and IFN-gamma receptor did not affect IL-12 production, indicating that increased production of IL-12 stimulated by the analogue peptide was not due to an effect of IFN-gamma from T cells. Peptide-induced up-regulation of CD40 ligand expression at high peptide concentrations showed no difference between the wild-type and analogue peptides. These data collectively indicate that certain T cell/APC interactions mediated through TCR and altered TCR ligands affect APC responses and that signals transmitted to APC are as indispensable as those to T cells in determining T cell response patterns.
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PMID:Altered TCR ligands affect antigen-presenting cell responses: up-regulation of IL-12 by an analogue peptide. 894 86


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