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Chemical Compound Review

AC1L18UV     6-[[4-[2-[2-[3-acetamido-2- [[[5-(2,4...

Synonyms: 63-EP2269990A1, 63-EP2269993A1, 63-EP2270001A1, 63-EP2270014A1, 63-EP2270018A1, ...
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Disease relevance of C1

  • C1 inhibitor and hereditary angioneurotic edema [1].
  • Similar observations were made in studies of the E. coli LexA repressor and phage P22 C1 transcription activator proteins [2].
  • As compared with placebo, prophylactic infusions of C1 inhibitor resulted in significantly lower daily symptom scores for the severity of edema of the extremities (P<0.01), larynx (P<0.05), abdomen (P<0.05), and genitourinary tract (P<0.05) [3].
  • The first was a crossover study consisting of two 17-day trials in which prophylactic infusions of either C1 inhibitor (25 plasma units per kilogram of body weight) or placebo were given intravenously every third day to six patients with hereditary angioedema [3].
  • Mean levels of the classical components C1, C4, and C2 in bacteremic patients in whom shock subsequently developed did not differ significantly (p greater than 0.05) from those of patients with uncomplicated bacteremia [4].

Psychiatry related information on C1

  • The pathologic conditions in which bradykinin generation appears important include hereditary and acquired C1 inhibitor deficiency, cough and angioedema due to ACE inhibitors, endotoxin shock, with contributions to conditions as diverse as Alzheimer's disease, stroke, control of blood pressure, and allergic diseases [5].
  • Complexing of tissue plasminogen activator with PAI-1, alpha 2-macroglobulin, and C1-inhibitor: studies in patients with defibrination and a fibrinolytic state after electroshock or complicated labor [6].
  • Fourth, protease-resistant PrPSc cores in sporadic Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker F198S disease brains all have an intact C1 cleavage site (Met111-His112), which precludes disruption of a domain associated with toxicity and fibrillogenesis [7].
  • In human monoclonal B cell disorders, however, the co-existence of paraprotein Id and its auto-anti-Id has been described in essential mixed cryoglobulinemia and in association with acquired C1 inhibitor deficiency [8].
  • A dissociative reaction coordinate path is implicated in which the primary reaction coordinate motion is the ribosyl C1' in motion between relatively immobile purine base and (Mg)(2)-pyrophosphate [9].

High impact information on C1

  • Phospholipid binding to the C1 domain triggers the cooperative dissociation of these interactions, allowing the N terminus to move out of the active site and thereby activating the enzyme [10].
  • The lipid second messenger diacylglycerol acts by binding to the C1 domains of target proteins, which translocate to cell membranes and are allosterically activated [10].
  • The core secondary structures are similar to a rabphilin-3A Zn2+-binding domain and to the C1 and LIM domains [11].
  • BACKGROUND: Hereditary angioedema results from a congenital deficiency of functional C1 inhibitor and is characterized by episodic bouts of edema, which may be life-threatening when they involve the larynx [3].
  • The maize C1 gene, which also encodes a Myb homolog, activates both the A1 and Bz1 genes, but only in the presence of a basic-helix-loop-helix coactivator encoded by the maize genes R or B [12].

Chemical compound and disease context of C1


Biological context of C1

  • However, an alternative pathway may involve members of the CalDAG-GEF/RasGRP protein family, which have structural features (calcium-binding EF hands and DAG-binding C1 domains) that suggest they can function in calcium and DAG signal integration [18].
  • Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis [19].
  • The biological role of the C1 inhibitor in regulation of vascular permeability and modulation of inflammation [20].
  • Fusion constructs between the wild-type C1 cDNA and the dominant inhibitor allele C1-I cDNA were used to identify the amino acid changes in C1 responsible for the C1-I inhibitory phenotype [21].
  • However, an amino-terminal domain of B was found to recruit a transcriptional activation domain by an interaction with C1 [22].

Anatomical context of C1

  • The syndrome of acquired angioedema and C1-inhibitor deficiency is associated with B-cell lymphoproliferative disease [23].
  • The continuously proliferating clones L/B AgA2, CB/Bm 7, Ba/C1, and Bc/Bm 11 were established from bone marrow of MRL/LPR, CBA/J, and BALB/c mice [24].
  • Clones L/B AgA2, CB/Bm 7, and Bc/Bm 11, but not Ba/C1, could develop into antibody-secreting cells after in vivo transfer [24].
  • We now report that the durations of adjacent open and shut intervals for both a C1 channel and a large conductance Ca-activated K channel in skeletal muscle are inversely related; shorter open intervals are adjacent to longer shut intervals [25].
  • In addition, I hypothesize that ATPases associated with various cellular activities regulate the recycling of soluble lipid carriers and that the Niemann Pick C1 protein facilitates the delivery of sterols from endosomal membranes to ORPs and/or the ensuing membrane dissociation of ORPs [26].

Associations of C1 with other chemical compounds

  • New structural and biochemical analyses of C1, C2, PH, FYVE, FERM and other domains have led to an unprecedented amount of information on the molecular interactions of these signaling proteins with regulatory lipids [27].
  • Mutation of a conserved sequence in the C1 promoter abolishes both ABA regulation and VP1 trans-activation [28].
  • These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity [29].
  • These results have been interpreted as indicating that the presence of serine at position 79 in GP C1 results in the stimulation of greater numbers of T cells involved in (a) the induction of EAE, (b) the in vitro proliferative response and (c) helper function in antibody production [30].
  • The amino terminus of the purified streptococcal superantigen was more homologous to the amino termini of staphylococcal enterotoxins B, C1, and C3 (SEB, SEC1, and SEC3), than to those of pyrogenic exotoxins A, B, C or other streptococcal toxins [31].

Gene context of C1

  • In vivo, C1-inhibitor bound to TPA at a rate of 553 mol-1.s-1 [32].
  • To obtain more information of the functional domains of the NPC1 protein, the mutational spectrum and the level of immunoreactive protein were investigated in skin fibroblasts from 30 unrelated patients with Niemann-Pick C1 disease [33].
  • C4A binds to a greater extent when C1 is on IgG immune aggregates [34].
  • Furthermore, the interaction of ch-uPA(RRHR) with PAI-2 was also substantially enhanced, while the interaction with other members of the serine proteinase inhibitor superfamily, protein nexin 1, alpha1-PI, and C1-inhibitor, was unaffected indicating that the RRHR motif is not a general serine proteinase inhibitor binding site [35].
  • Moreover, DGK-zeta directly interacts with Rac1 through a binding site located within its C1 domains [36].

Analytical, diagnostic and therapeutic context of C1

  • Radial double immunodiffusion experiments using antiserum to C1q, C1r, and C1s on HFf-treated serum demonstrated the dissociation of the C1 trimolecular complex, with concomitant reduction of C1r antigenicity that is indicative of C1 activation [37].
  • By means of monospecific antibody to C1- inhibitor, a competitive enzyme-linked immunosorbent assay (CELISA) was developed to measure directly platelet C1- inhibitor [38].
  • To test the effect of this substitution, a mutant C1 inhibitor containing Ala443-->Val was constructed by site-directed mutagenesis and expressed in COS-1 cells [39].
  • RF mixed with aggregated, reduced, and alkylated human IgG (Agg-R/A-IgG) in the fluid phase failed to significantly reduce the level of total hemolytic complement, CH50, or of individual complement components, C1, C2, C3, and C5 [40].
  • Northern blots showed that the N1 splice is expressed primarily in liver, while the C1 splice is predominant in testis [41].


  1. C1 inhibitor and hereditary angioneurotic edema. Davis, A.E. Annu. Rev. Immunol. (1988) [Pubmed]
  2. A role for a small stable RNA in modulating the activity of DNA-binding proteins. Retallack, D.M., Friedman, D.I. Cell (1995) [Pubmed]
  3. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. Waytes, A.T., Rosen, F.S., Frank, M.M. N. Engl. J. Med. (1996) [Pubmed]
  4. Activation of the properdin pathway of complement in patients with gram-negative of bacteremia. Fearon, D.T., Ruddy, S., Schur, P.H., McCabe, W.R. N. Engl. J. Med. (1975) [Pubmed]
  5. Formation of bradykinin: a major contributor to the innate inflammatory response. Joseph, K., Kaplan, A.P. Adv. Immunol. (2005) [Pubmed]
  6. Complexing of tissue plasminogen activator with PAI-1, alpha 2-macroglobulin, and C1-inhibitor: studies in patients with defibrination and a fibrinolytic state after electroshock or complicated labor. Bennett, B., Croll, A., Ferguson, K., Booth, N.A. Blood (1990) [Pubmed]
  7. Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues. Jiménez-Huete, A., Lievens, P.M., Vidal, R., Piccardo, P., Ghetti, B., Tagliavini, F., Frangione, B., Prelli, F. Am. J. Pathol. (1998) [Pubmed]
  8. Absence of auto-antiidiotypic activity between the IgM and IgG fractions of human mixed cryoglobulins. Stone, G.C., Nardella, F.A., Oppliger, I.R., Mannik, M. J. Immunol. (1988) [Pubmed]
  9. The 2.0 A structure of malarial purine phosphoribosyltransferase in complex with a transition-state analogue inhibitor. Shi, W., Li, C.M., Tyler, P.C., Furneaux, R.H., Cahill, S.M., Girvin, M.E., Grubmeyer, C., Schramm, V.L., Almo, S.C. Biochemistry (1999) [Pubmed]
  10. Structural mechanism for lipid activation of the Rac-specific GAP, beta2-chimaerin. Canagarajah, B., Leskow, F.C., Ho, J.Y., Mischak, H., Saidi, L.F., Kazanietz, M.G., Hurley, J.H. Cell (2004) [Pubmed]
  11. Crystal structure of a phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p. Misra, S., Hurley, J.H. Cell (1999) [Pubmed]
  12. The myb-homologous P gene controls phlobaphene pigmentation in maize floral organs by directly activating a flavonoid biosynthetic gene subset. Grotewold, E., Drummond, B.J., Bowen, B., Peterson, T. Cell (1994) [Pubmed]
  13. Human immunodeficiency virus type 1 activates the classical pathway of complement by direct C1 binding through specific sites in the transmembrane glycoprotein gp41. Ebenbichler, C.F., Thielens, N.M., Vornhagen, R., Marschang, P., Arlaud, G.J., Dierich, M.P. J. Exp. Med. (1991) [Pubmed]
  14. NaHCO3 and NaC1 tolerance in chronic renal failure. Husted, F.C., Nolph, K.D., Maher, J.F. J. Clin. Invest. (1975) [Pubmed]
  15. Characterization of the Mr difference between secreted murine fourth component of complement and the major plasma form: evidence for carboxyl-terminal cleavage of the alpha chain. Karp, D.R., Shreffler, D.C., Atkinson, J.P. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  16. Dual modulation of K channels by thyrotropin-releasing hormone in clonal pituitary cells. Dubinsky, J.M., Oxford, G.S. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  17. The tripartite immunity system of phages P1 and P7. Heinrich, J., Velleman, M., Schuster, H. FEMS Microbiol. Rev. (1995) [Pubmed]
  18. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Crittenden, J.R., Bergmeier, W., Zhang, Y., Piffath, C.L., Liang, Y., Wagner, D.D., Housman, D.E., Graybiel, A.M. Nat. Med. (2004) [Pubmed]
  19. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Carstea, E.D., Morris, J.A., Coleman, K.G., Loftus, S.K., Zhang, D., Cummings, C., Gu, J., Rosenfeld, M.A., Pavan, W.J., Krizman, D.B., Nagle, J., Polymeropoulos, M.H., Sturley, S.L., Ioannou, Y.A., Higgins, M.E., Comly, M., Cooney, A., Brown, A., Kaneski, C.R., Blanchette-Mackie, E.J., Dwyer, N.K., Neufeld, E.B., Chang, T.Y., Liscum, L., Strauss, J.F., Ohno, K., Zeigler, M., Carmi, R., Sokol, J., Markie, D., O'Neill, R.R., van Diggelen, O.P., Elleder, M., Patterson, M.C., Brady, R.O., Vanier, M.T., Pentchev, P.G., Tagle, D.A. Science (1997) [Pubmed]
  20. The biological role of the C1 inhibitor in regulation of vascular permeability and modulation of inflammation. Davis, A.E., Cai, S., Liu, D. Adv. Immunol. (2004) [Pubmed]
  21. Identification of functional domains in the maize transcriptional activator C1: comparison of wild-type and dominant inhibitor proteins. Goff, S.A., Cone, K.C., Fromm, M.E. Genes Dev. (1991) [Pubmed]
  22. Functional analysis of the transcriptional activator encoded by the maize B gene: evidence for a direct functional interaction between two classes of regulatory proteins. Goff, S.A., Cone, K.C., Chandler, V.L. Genes Dev. (1992) [Pubmed]
  23. Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins. Geha, R.S., Quinti, I., Austen, K.F., Cicardi, M., Sheffer, A., Rosen, F.S. N. Engl. J. Med. (1985) [Pubmed]
  24. Il-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Palacios, R., Steinmetz, M. Cell (1985) [Pubmed]
  25. Inverse relationship of the durations of adjacent open and shut intervals for C1 and K channels. McManus, O.B., Blatz, A.L., Magleby, K.L. Nature (1985) [Pubmed]
  26. Nonvesicular sterol transport: two protein families and a sterol sensor? Yang, H. Trends Cell Biol. (2006) [Pubmed]
  27. Subcellular targeting by membrane lipids. Hurley, J.H., Meyer, T. Curr. Opin. Cell Biol. (2001) [Pubmed]
  28. The Viviparous-1 gene and abscisic acid activate the C1 regulatory gene for anthocyanin biosynthesis during seed maturation in maize. Hattori, T., Vasil, V., Rosenkrans, L., Hannah, L.C., McCarty, D.R., Vasil, I.K. Genes Dev. (1992) [Pubmed]
  29. Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. Chen, Z., Koralov, S.B., Kelsoe, G. J. Exp. Med. (2000) [Pubmed]
  30. Immune response of Lewis rats to peptide C1 (residues 68-88) of guinea pig and rat myelin basic proteins. Kibler, R.F., Fritz, R.B., Chou, F., Jen Chou C-H, n.u.l.l., Peacocke, N.Y., Brown, N.M., McFarlin, D.E. J. Exp. Med. (1977) [Pubmed]
  31. A novel superantigen isolated from pathogenic strains of Streptococcus pyogenes with aminoterminal homology to staphylococcal enterotoxins B and C. Mollick, J.A., Miller, G.G., Musser, J.M., Cook, R.G., Grossman, D., Rich, R.R. J. Clin. Invest. (1993) [Pubmed]
  32. The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine. Chandler, W.L., Levy, W.C., Stratton, J.R. Circulation (1995) [Pubmed]
  33. Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Millat, G., Marçais, C., Tomasetto, C., Chikh, K., Fensom, A.H., Harzer, K., Wenger, D.A., Ohno, K., Vanier, M.T. Am. J. Hum. Genet. (2001) [Pubmed]
  34. Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A. Carroll, M.C., Fathallah, D.M., Bergamaschini, L., Alicot, E.M., Isenman, D.E. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  35. Introduction of an RRHR motif into chicken urokinase-type plasminogen activator (ch-uPA) confers sensitivity to plasminogen activator inhibitor (PAI)-1 and PAI-2 and allows ch-uPA-mediated extracellular matrix degradation to be controlled by PAI-1. Sipley, J.D., Alexander, D.S., Testa, J.E., Quigley, J.P. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  36. Regulation of neurite outgrowth in N1E-115 cells through PDZ-mediated recruitment of diacylglycerol kinase zeta. Yakubchyk, Y., Abramovici, H., Maillet, J.C., Daher, E., Obagi, C., Parks, R.J., Topham, M.K., Gee, S.H. Mol. Cell. Biol. (2005) [Pubmed]
  37. Activation of the classical pathway of complement by Hageman factor fragment. Ghebrehiwet, B., Silverberg, M., Kaplan, A.P. J. Exp. Med. (1981) [Pubmed]
  38. Platelet C1- inhibitor. A secreted alpha-granule protein. Schmaier, A.H., Smith, P.M., Colman, R.W. J. Clin. Invest. (1985) [Pubmed]
  39. Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein. Zahedi, R., Bissler, J.J., Davis, A.E., Andreadis, C., Wisnieski, J.J. J. Clin. Invest. (1995) [Pubmed]
  40. Complement fixation by rheumatoid factor. Tanimoto, K., Cooper, N.R., Johnson, J.S., Vaughan, J.H. J. Clin. Invest. (1975) [Pubmed]
  41. NH2-Terminal targeting motifs direct dual specificity A-kinase-anchoring protein 1 (D-AKAP1) to either mitochondria or endoplasmic reticulum. Huang, L.J., Wang, L., Ma, Y., Durick, K., Perkins, G., Deerinck, T.J., Ellisman, M.H., Taylor, S.S. J. Cell Biol. (1999) [Pubmed]
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