Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anti-angiotensin II (Ang) antibodies could become important receptor mimicking tools if an antibody with binding properties identical to a particular Ang receptor could be generated. For this purpose, anti-Ang sera from mice were screened for antibodies with structure-affinity relationships similar or identical to a particular Ang receptor. Mice were immunized with BSA-coupled [Sar1]Ang and the sera were screened in ELISA for crossreactivity with the Ang analogues saralasin, L158,809, EXP 3147, DuP 753, DuP 532, PD 123177, PD 123319 and the non-related compounds ACTH, naloxone, and CP 96,345. All sera had at least some cross-reactivity with saralasin and some also with L158,809, a potent non-peptide Ang antagonist, selective for the AT1 site. One serum out of eight recognized most Ang analogues except the AT2 selective PD 123177 and PD 123319. ELISA detection antigens were prepared by two different BSA conjugations: [Sar1]Ang was N-terminally attached and [Sar1,Lys8]Ang was C-terminally attached. Against both detection antigens, the peptide antagonists saralasin and [Sar1,Phe(Br5)8]Ang displaced in a sigmoidal manner the antibodies with an IC50-value of 0.4 mM. L158,809 and EXP 3147 displaced also in a parallel manner, suggesting an apparently homogenous population of binding sites. The selectivity profile of the serum has some resemblance to the AT1 selectivity profile but the observed affinities are too low to suggest AT1 receptor mimicry.
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PMID:Anti-angiotensin antibodies cross-reactive with nonpeptide angiotensin antagonists as angiotensin receptor model. 838 92

Losartan is the first recently approved drug against hypertension disease that competes with the biological action of angiotensin II (AII) at the AT1 receptor. Its design was based on the mimicry of the C-terminal segment of AII. Due to the biological significance of Losartan, its structure elucidation and conformational properties are reported as determined by NMR spectroscopy and computational analysis. In addition, molecular modeling of the peptide Sarmesin [Sar1Tyr(OMe)4AII], a competitive antagonist of AII, was also developed based on NMR and computational analysis data. Sarmesin's C-terminal was used as a template for superimposition with specific molecular features of interest in the structure of Losartan such as the conformation of biphenyltetrazole, the n-butyl chain, and the orientation of hydroxymethylimidazole relative to the biphenyl template. The major conclusions derived from this study are the following: (a) Sarmesin, like the AII superagonist [Sar1]AII, adopts a conformation which keeps in close proximity the key amino acids Sar1 (or Arg2)-Tyr(OMe)4-His6-Phe8. (b) Losartan favors a low-energy conformation in which imidazole and tetrazole rings are placed in the opposite site relative to the spacer phenyl ring plane; the hydroxymethyl group is placed away from the spacer phenyl ring, the alkyl chain is oriented above the spacer phenyl ring, and the two phenyl rings deviate approximately 60 degrees from being coplanar. (c) Overlay of the C-terminal region of Sarmesin with Losartan using equivalent groups revealed an excellent match. (d) Interestingly, the matching between enantiomeric structures of Losartan was not equivalent, proposing that the chirality of this molecule is significant in order to exert its biological activity. These findings open a new avenue for synthetic chemists to design and synthesize peptidomimetic drugs based on the C-terminal segment of the proposed model of Sarmesin. The new candidate drug molecules are not restricted to structurally resemble Losartan as the design is hitherto focused.
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PMID:An effort to understand the molecular basis of hypertension through the study of conformational analysis of losartan and sarmesin using a combination of nuclear magnetic resonance spectroscopy and theoretical calculations. 1034 24

Initial studies have demonstrated the significance of the agonistic angiotensin II receptor AT1 autoantibody (AT1-AA) in preeclampsia, although it is unclear what factors induce its generation. Since the epitope recognized by AT1-AA shares high homology with parvovirus B19 (PVB19) capsid proteins, we have investigated the relationship between the presence of AT1-AA in maternal circulation and PVB19 sero-prevalence in normal and abnormal pregnancy. We determined the parvovirus IgG sero-prevalence in normal pregnancies in the second trimester and those with abnormal uterine perfusion that are at risk for preeclampsia. Secondly, pregnancies at delivery with preeclampsia or intrauterine growth restriction were included. All women with normal perfusion were AT1-AA-negative and 80% were parvovirus-IgG-positive. Sixty-three percent of pregnancies with abnormal uterine perfusion were AT1-AA-positive and 71% IgG-positive. Fifty-two percent of the IgG-positive pregnancies in this subgroup were also AT1-AA-positive, and 9 of the 10 parvovirus IgG-negative women were AT1-AA-positive. In the third trimester, 87% of pregnancies with manifest disease were AT1-AA-positive and 58% IgG-positive. While 79% of the PVB19 IgG-positive pregnancies were also AT1-AA-positive, all parvovirus IgG-negative women were AT1-AA-positive. In all groups, AT1-AA activity did not differ between parvovirus IgG-negative and positive women. We find parvovirus IgG-positive pregnant women in all subgroups without relation to AT1-AA presence. This favors AT1-AA generation to be independent of epitope mimicry between parvovirus B19 capsid proteins and the AT1 receptor.
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PMID:Is parvovirus B19 the cause for autoimmunity against the angiotensin II type receptor? 1715 Feb 55

Mutations in ATRX constitute the most prevalent genetic abnormalities in gliomas. The presence of ATRX mutations in glioma serves as a marker of better prognosis with longer patient survival although the underlying mechanisms are poorly understood. In the present study, we found that ATRX biological function was significantly involved in DNA replication and repair. CRISPR/Cas9-mediated genetic inactivation of ATRX induced inhibition of cell proliferation, invasion and vasculogenic mimicry. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in ATRX knockout glioma cells. Moreover, we confirmed that ATRX knockout resulted in a failure to trigger ATM phosphorylation and finally restrained the activation of downstream proteins of the ATM pathway. The ATM-associated DNA repair pathway was extensively compromised in ATRX knockout cells owing to decreased histone H3K9me3 availability. Public databases also showed that patients with low ATRX expression exhibited preferable overall survival and profited more from TMZ treatment. These data suggest that ATRX is involved in DNA damage repair by regulating the ATM pathway and might serve as a prognostic maker in predicting TMZ chemosensitivity.
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PMID:Loss of ATRX suppresses ATM dependent DNA damage repair by modulating H3K9me3 to enhance temozolomide sensitivity in glioma. 2937 38