Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholinesterases (acetylcholinesterase and butyrylcholinesterase) exhibit additional catalytic activities apart from their well-known action in hydrolyzing choline esters. An amine-sensitive aryl acylamidase activity is exhibited by both acetyl- and butyrylcholinesterases. A metallocarboxypeptidase-like activity is found associated with both acetyl- and butyrylcholinesterases. The peptidase activity exhibited by butyrylcholinesterase was located in a 50-kDa COOH-terminal fragment. Acetylcholinesterase is implicated in noncholinergic functions in the substantia nigra. A relationship between tumorigenesis, cell differentiation, and cholinesterases has been speculated. The sequence similarities between different esterases, lipases, thyroglobulin, cell adhesion proteins, and cholinesterases would make it appear that cholinesterases are capable of exhibiting more than one biological activity and their functions are wider than what is hitherto known.
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PMID:Noncholinergic functions of cholinesterases. 822 8

Unlike autoimmune thyroid disease (AITD) in which a number of autoantigens have been identified and characterized, the situation in thyroid associated ophthalmopathy (TAO) is far from clear. A number of candidate antigens have been identified by probing Western blots of orbital tissue (OT) with sera from TAO patients, the most frequently cited being proteins of molecular weight 23, 28, 55, 64, 78 and 120 kilodaltons. In an attempt to identify autoantigens in TAO we have produced a lambda gt11 human eye muscle expression library. This has been screened with sera from four patients with severe TAO whose antibodies bind to one or more of the aforementioned candidate antigens or to a thyroglobulin/acetylcholinesterase (Tg/Ache) shared epitope. Four clones were isolated and characterized; clone R14 encodes the carboxyl terminal 193 amino acids of an IgE binding protein, clones R10 and R13 encode unknown proteins having significant similarity with heat shock protein 27 and the U1 small nuclear ribonucleoprotein respectively. Clone R1 encodes an unknown peptide of 347 amino acids having no similarity with proteins in available data banks. R1 clone affinity purified autoantibodies bind to a protein of Mr 78 kD in a Western blot of porcine eye muscle tissue. Autoantibodies to the R1 recombinant lysogen were clearly demonstrated in 5 of 20 sera from Graves disease patients, its role merits further investigation. The possible relevance of these clones to the pathogenesis of TAO is discussed as well as the limitations of this type of approach in the identification of unknown autoantigens.
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PMID:Muscle autoantigens in thyroid associated ophthalmopathy: the limits of molecular genetics. 822 83

Newly synthesized thyroglobulin (Tg), the major secretory glycoprotein of the thyroid gland, folds and homodimerizes in the endoplasmic reticulum (ER) before its export to the site of iodination, where it serves as the precursor for thyroid hormone synthesis. In families with defective Tg export, affected individuals suffer from a thyroidal ER storage disease characterized by a distended thyrocyte ER containing misfolded Tg, along with induced ER molecular chaperones. Inherited as an autosomal recessive trait, deficient Tg causes congenital hypothyroidism in newborns that, if untreated, results in goiter along with serious cognitive and growth defects. Recently, a similar phenotype has been observed in inbred cog/cog mice, although the precise molecular defect has remained undefined. Here, we have isolated and cloned a full-length 8.5-kb Tg cDNA from cog/cog mice and unaffected isogenic AKR/J mice. Comparison of the complete sequences reveals that cog/cog mice express a Leu-2263 --> Pro missense mutation in the acetylcholinesterase-homology domain of Tg. Heterologous expression studies in COS cells indicate that cog Tg exhibits a severe defect in exit from the ER. Site-directed mutagenesis of cog Tg to convert the single amino acid back to Leu-2263 restores normal Tg secretion. We conclude that the cog mutation in Tg is responsible for this ER storage disease that causes thyroid dyshormonogenesis.
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PMID:A single amino acid change in the acetylcholinesterase-like domain of thyroglobulin causes congenital goiter with hypothyroidism in the cog/cog mouse: a model of human endoplasmic reticulum storage diseases. 970 74

The comparative analysis of the products of the limited proteolysis of bovine thyroglobulin with trypsin by SDS-polyacrylamide gel electrophoresis in non-reducing and reducing conditions revealed the presence of disulfide linkages between some of the fragments. In order to define the disulfide bond pattern between the proteolytic fragments of thyroglobulin, these were isolated by SDS-polyacrylamide gel electrophoresis in non-reducing conditions and electrophoretic transfer onto polyvinylidene difluoride membranes. Individual bands were desorbed from the membranes and re-analyzed by SDS-polyacrylamide gel electrophoresis in reducing conditions. The resulting peptides were identified by comparison with the peptides directly obtained by SDS-electrophoresis in reducing conditions, and characterized by amino-terminal peptide sequencing either in this study or in a previous investigation (Gentile F., Salvatore G., Eur. J. Biochem. 218 (1993) 603-621). The analysis revealed that several fragments, produced by cleavages within the context of various cysteine-rich repeats of type 1 and within cysteine-rich repeat 3b.1, did not separate in the absence of reduction. On the other hand, the products of the cleavages at the carboxy-terminal extremity of the linker between type 2 and type 3 cysteine-rich repeats, and in the middle of the acetylcholinesterase-similar domain of thyroglobulin separated freely, with no need for reduction. On the base of these data, a model is presented in which distinct subsets of cysteine-rich repeats and the carboxy-terminal, acetylcholinesterase-similar domain of thyroglobulin form sequentially aligned subdomains with internal disulfide linkages.
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PMID:The disulfide bond pattern between fragments obtained by the limited proteolysis of bovine thyroglobulin. 1040 84

Here, we studied the fragmentation of the prothyroid hormone, thyroglobulin (Tg), which occurs during thyroid hormone synthesis, a process which involves iodide, thyroperoxidase, and the H2O2-generating system, consisting of glucose and glucose oxidase. Various peptides were found to be immunoreactive to autoantibodies to Tg from patients and monoclonal antibodies directed against the immunodominant region of Tg. The smallest peptide (40 kDa) bore thyroid hormones and was identified at the C-terminal end of the Tg molecule, which shows homologies with acetylcholinesterase. Similar peptides were obtained by performing metal-mediated oxidation of Tg via a Fenton reaction. It was concluded that the oxidative stress induced during hormone synthesis generates free radicals, which, in turn, cleave Tg into immunoreactive peptides.
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PMID:Production of immunoreactive thyroglobulin C-terminal fragments during thyroid hormone synthesis. 1087 53

The rdw rat is a hereditary hypothyroid variant initially derived from the Wistar-Imamichi strain. Proteome analysis by two-dimensional gelelectrophoresis showed that molecular chaperones accumulated in the thyroid glands, suggesting retention of abnormal proteins in the endoplasmic reticulum (ER). Anatomical studies indicated that thyroglobulin (Tg) was not secreted into the follicular lumina, but retained in the dilated ER. Sequencing of the entire Tg complementary DNA from the rdw rat revealed a missense mutation (G2320R) in the acetylcholinesterase-like domain at the 2320th amino acid residue. Carbohydrate residues of the G2320R Tg mutant were of the high-mannose ER type, as shown by sensitivity to the treatment with endoglycosidase H. Molecular chaperones, GRP94, GRP78, and calreticulin, were all accumulated in the rdw rat thyroid glands. Computer analysis of protein secondary structure predicted that the mutation would cause extension of the helix where beta-sheet and turns were formed in the normal Tg. Altered folding of Tg might account for the impaired intracellular transport of Tg and activated premature degradation by the same mechanism as in ER storage diseases.
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PMID:A novel missense mutation (G2320R) in thyroglobulin causes hypothyroidism in rdw rats. 1108 35

Various proteins/enzymes obtained commercially were tested for the presence of endogenously nitrated tyrosine by Western blot analysis omitting reducing agent in the step of SDS-PAGE. Histones II-S and VIII-S, IgG, cAMP-dependent protein kinase (PKA), phosphorylase b, and phosphorylase kinase exhibited strong immunoreactive bands. Histone VI-S, glycogen synthase, lactate dehydrogenase, actin, thyroglobulin, and macroglobulin exhibited moderate immunoreactivity. Histone III-S, casein, acetyl cholinesterase, DNase I, and lipase had only traceable immunoreactivity. Whereas histone VII-S, pyruvate kinase, trypsin, pepsin, chymotrypsin, protease IV, and protease XIII, and glutathione S-transferase lacked immunoreactivity. A variation of immunoreactivity between hypertensive and normaltensive rat hearts was found in the histone-agarose fractions of crude extracts. Additionally, nitrotyrosine immunoreactivity was observed in non-mammalian organisms including Eschericia coli, Saccharomyces cerevisiae and Triticum vulgaris. Upon the treatment of 15 microM peroxynitrite (PN), strong oxidant derived from nitric oxide (NO), the apparent Km of PKA for cAMP increased from approximately 10(-8) to 10(-6) M. The results imply that the varied nitration of tyrosine residues in proteins/enzymes may occur as a post-translational modification in vivo, and such discriminative nitration may be vital in PN/NO-regulated signal transduction cascade.
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PMID:Protein nitration. 1119 83

In a 22-yr-old healthy woman, a fetal goiter was diagnosed coincidentally by ultrasound during the sixth month of gestation, and hypothyroidism was affirmed by a high TSH (336 mU/liter) concentration after cordocentesis. A second ultrasound examination at 27 wk gestation showed further enlargement of the goiter (34/21 mm). Two intraamniotic injections of 200 microg levothyroxine were performed during the seventh month of pregnancy. Ultrasound studies revealed a fetal goiter size of 30/18 mm during the eighth month of gestation. The woman delivered at term a female infant with an Apgar score of 10 at 1 and 5 min. Cord blood analysis indicated elevated TSH (284 mU/liter) and low free T(4) (5.5 pmol/liter) levels. The serum thyroglobulin (Tg) concentration was low (0.8 ng/ml), whereas ultrasound of the neonate indicated an enlarged thyroid gland (32/15/14 mm). During the second pregnancy, ultrasound examination revealed a goiter, and fetal hypothyroidism was also confirmed after umbilical vein blood sampling (TSH, 472 mU/liter). After two intraamniotic injections of 500 microg levothyroxine, the woman delivered a male infant at 37 wk of pregnancy. In cord blood the serum TSH concentration was 39 mU/liter, and the serum Tg level was low (0.7 ng/ml). The parents were nonconsanguineous. After birth of the two affected siblings, genomic DNA sequencing identified the presence of compound heterozygous mutations of the Tg gene: the paternal mutation consists of a cytosine deletion at nucleotide 1143 in exon 9 (1143delC), resulting in a frameshift that generates a stop codon at position 382, and the maternal mutation is a guanine to adenine substitution at position 6725 in exon 38, creating the R2223H missense mutation in the acetylcholinesterase homology domain of Tg. In conclusion, we report two siblings with congenital goiter and hypothyroidism caused by compound heterozygous mutations of the Tg gene.
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PMID:Compound heterozygous mutations in the thyroglobulin gene (1143delC and 6725G-->A [R2223H]) resulting in fetal goitrous hypothyroidism. 1291 34

Secretion of thyroglobulin (Tg, a large homodimeric glycoprotein) is essential to deliver Tg to its site of iodination for thyroxine biosynthesis. An L2263P missense mutation in Tg has been proposed as the molecular defect causing congenital goitrous hypothyroidism in cog/cog mice due to perturbed Tg homodimerization, resulting in its retention within the endoplasmic reticulum. The mutation falls within a carboxyl-terminal region of Tg with high structural similarity to the entirety of acetylcholinesterase (AChE), a secretory protein that also forms homodimers. We provide new evidence that authentic AChE and the cholinesterase-like domain of Tg share a common tertiary structure. Moreover, we find that a Tg truncation, deleted of the cholinesterase-like region (but not a comparably sized deletion of internal Tg regions), blocks Tg export. Appending to this truncation a cDNA encoding authentic AChE results in translation of a chimeric protein in which AChE is present in a native, enzymatically active (albeit latent) conformation, and this fully rescues Tg secretion. Introduction of the cog mutation inhibits AChE enzyme activity, and established denaturing mutations of AChE block secretion of the Tg. Additional studies show that the native structure of the AChE region functions as a "dimerization domain," facilitating intracellular transport of Tg to the site of thyroid hormonogenesis.
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PMID:The acetylcholinesterase homology region is essential for normal conformational maturation and secretion of thyroglobulin. 1476 82

Autoantibodies against human thyroglobulin are a hallmark of autoimmune thyroid disease in humans, and are often found in normal subjects. Their pathogenic significance is debated. Several B-cell epitope-bearing peptides have been identified in thyroglobulin. They are generally located away from the cysteine-rich regions of tandem sequence repetition. It is possible that our current epitopic map is incomplete because of the difficulty that proteolytic and recombinant approaches have in restituting conformational epitopes based upon proper pairing between numerous cysteinyl residues. Furthermore, the homology of cysteine-rich repeats with a motif occurring in several proteins, endowed with antiprotease activity, suggests that these regions may normally escape processing and presentation to the immune system, and brings attention to the mechanisms, such as oxidative cleavage, by which such cryptic epitopes may be exposed. A number of T-cell epitope-bearing peptides, endowed with thyroiditogenic power in susceptible mice, were also identified. None of them was dominant, as none was able to prime in vivo lymph node cells that would proliferate or transfer autoimmune thyroiditis to syngeneic hosts, upon stimulation with intact thyroglobulin in vitro. More than half of them are located within the acetylcholinesterase-homologous domain of thyroglobulin, and overlap B-cell epitopes associated with autoimmune thyroid disease, while the others are located within cysteine-rich repeats. The immunopathogenic, non-dominant character of these epitopes also favours the view that the development of autoimmune thyroid disease may involve the unmasking of cryptic epitopes, whose exposure may cause the breaking of peripheral tolerance to thyroglobulin. Further research in this direction seems warranted.
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PMID:Thyroglobulin as an autoantigen: what can we learn about immunopathogenicity from the correlation of antigenic properties with protein structure? 1509 79


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