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:3.2.1.17 (lysozyme)
21,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levels of retinol-binding protein (RBP) and transthyretin (TTR) were determined in rat maternal livers, placenta, yolk sac, whole fetuses and fetal livers at different stages of gestation. Yolk sac concentrations of RBP and TTR expressed as micrograms per mg protein were three- to fivefold higher than liver values. TTR (moles) in the whole fetus was higher than RBP at all stages of gestation. Fetal hepatic RBP concentration was relatively constant throughout gestation, where fetal hepatic TTR concentration was low until close to parturition. RBP was observed in fetal microsomes at 12 d gestation. Incorporation of labeled amino acids into both RBP and TTR in vitro was observed in the yolk sac. In the 20-d fetal liver, incorporation to RBP and TTR was observed, whereas at 14 d gestation, incorporation only to RBP was observed. A small amount of synthesis of both proteins was also observed in the placenta. In the fetal circulation at 20-21 d gestation, no TTR-RBP complex was observed; instead a broad peak of RBP was found eluting at 20,000-40,000 daltons on gel chromatography. Incubation of fetal serum with maternal TTR resulted in an RBP peak eluting with an Mr of approximately 40,000. Treatment of the fetal serum with either lysozyme, neuraminidase or endoglycosidase H resulted in a 20,000 dalton RBP peak and following incubation with maternal TTR, a 70,000 dalton RBP-TTR complex was formed. Yolk sac, fetal liver and amniotic fluid on gel filtration exhibited a 40,000-20,000 dalton RBP peak. It is suggested that retinol transport in the fetus may involve RBP and TTR synthesized in the yolk sac as well as in fetal tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synthesis of retinol-binding protein and transthyretin in yolk sac and fetus in the rat. 357 57

Significant advances were made this year in the understanding of serum amyloid A isotypes and in the definition of different amyloid light-chain proteins. Increasing numbers of hereditary amyloid-related transthyretin mutations have been reported (more than 30 to date). Two new hereditary amyloid proteins in several different kinships have appeared, ie, fibrinogen A alpha and lysozyme, each with a single point mutation. Both were found in patients with non-neurogenic hereditary amyloidosis with severe nephropathy. In islet amyloid polypeptide, the amyloid of adult-onset diabetes, the amino-acid sequence Ala-Ile-Leu-Ser at positions 25 to 28 appears to be critical for fibrillogenesis.
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PMID:Proteins of the systemic amyloidoses. 803 80

Amyloidoses are characterized by the deposition of non soluble proteins in tissues. Clinical aspects of hereditary amyloidoses are very diverse, and they offer many diagnosis problems to the physician. Biochemical and genetic aspects are also various. Several proteins are implicated in these hereditary diseases mainly: transthyretin, apolipoprotein A1, gelsolin, fibrinogen alpha chain and lysozyme. Studies on structural changes induced by the mutations in the transthyretin should bring new data relevant to our understanding of the amyloidogenic process. Transgenic mice with mutated transthyretin are a good model and will allow new pathogenic approach and therapeutic intervention.
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PMID:[Hereditary amyloidosis]. 805 45

Metabolic processing of amyloid precursor proteins is an important factor in the genesis of practically all forms of amyloidosis. Of the three major forms of systemic amyloidosis, reactive amyloid (amyloid A protein; AA) formation shows the most consistent role of partial proteolysis of serum amyloid A (SAA) to AA proteins which form fibrils. Immunoglobulin amyloidosis is also usually associated with C-terminal degradation of the fibril precursor light chain protein. Although it is commonly thought that transthyretin amyloidosis is associated with fibril formation from the tetrameric circulating plasma transthyretin, chemical analyses of transthyretin fibril deposits show significant fragmentation of the fibril protein constituents. In addition, it has been documented that proteolytic fragments are the fibril subunit proteins in gelsolin, cystatin C. Alzheimer's beta-amyloid precursor protein and apolipoprotein AI (apoAI) amyloidoses. Notable exceptions to the role of proteolysis in amyloid fibril formation would appear to be the lysozyme and beta 2-microglobulin amyloidoses. Few studies have examined the metabolism of amyloid-forming proteins. Perhaps the best data are on apoAI, which show decreased plasma residence time for the amyloidogenic Gly26Arg apoAI (1.8 d vs. normal 4.5 d). Similarly, preliminary data show increased clearance of Val30Met transthyretin when compared with the wild-type protein (18 h vs. 26 h). Also, biosynthetically 35S-labelled SAA proteins reconstituted with HDL show increased plasma clearance of murine SAA2, the amyloid fibril subunit protein, when compared with murine SAA1. Few data are available on metabolism of amyloid immunoglobulin light chain proteins, but it has been shown that radiolabelled Bence-Jones proteins are cleared very rapidly from the circulation. A better understanding of the metabolism of precursor proteins in each of the amyloid deposition diseases will give insight into the mechanisms of fibril formation and pathogenesis of amyloidosis.
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PMID:Metabolism of amyloid proteins. 891 6

Clinical aspects of hereditary amyloidoses are very diverse, and they pose many diagnostic problems to the physician. Biochemical and genetic aspects are also various. Several proteins are implicated in these hereditary diseases: transthyretin, apolipoprotein A1, gelsolin, fibrinogen alpha chain and lysozyme. Studies on structural changes induced by the mutations in these proteins should bring new data relevant to our understanding of the amyloidogenic process. Familial mediterranean fever is a hereditary disease of the inflammatory reaction which is associated with AA amyloidosis.
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PMID:[Hereditary amyloidosis]. 945 3

The physiological metabolism of proteins guarantees that different cellular compartments contain the appropriate concentration of proteins to perform their biological functions and, after a variable period of wear and tear, mediates their natural catabolism. The equilibrium between protein synthesis and catabolism ensures an effective turnover, but hereditary or acquired abnormalities of protein structure can provoke a premature loss of biological function, an accelerated catabolism and diseases caused by the loss of an irreplaceable function. In certain proteins, abnormal structure and metabolism are associated with a strong tendency to self-aggregation into a polymeric fibrillar structure, and in these cases the disease is not principally caused by the loss of an irreplaceable function but by the action of this new biological entity. Amyloid fibrils are an apparently inert, insoluble, mainly extracellular protein polymer that kills the cell without tissue necrosis but by activation of the apoptotic mechanism. We analyzed the data reported so far on the structural and functional properties of four prototypic proteins with well-known biological functions (lysozyme, transthyretin, beta 2-microglobulin and apolipoprotein AI) that are able to create amyloid fibrils under certain conditions, with the perspective of evaluating whether the achievement of biological function favors or inhibits the process of fibril formation. Furthermore, studying the biological functions carried out by amyloid fibrils reveals new types of protein-protein interactions in the transmission of messages to cells and may provide new ideas for effective therapeutic strategies.
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PMID:Biological activity and pathological implications of misfolded proteins. 1041 75

Tissue deposition of normally soluble proteins, or their fragments, as insoluble amyloid fibrils causes the usually fatal, acquired and hereditary systemic amyloidoses and is associated with the pathology of Alzheimer's disease, type 2 diabetes and the transmissible spongiform encephalopathies. Although each type of amyloidosis is characterised by a specific amyloid fibril protein, the deposits share pathognomonic histochemical properties and the structural morphology of all amyloid fibrils is very similar. We have previously demonstrated that transthyretin amyloid fibrils contain four constituent protofilaments packed in a square array. Here, we have used cross-correlation techniques to average electron microscopy images of multiple cross-sections in order to reconstruct the sub-structure of ex vivo amyloid fibrils composed of amyloid A protein, monoclonal immunoglobulin lambda light chain, Leu60Arg variant apolipoprotein AI, and Asp67His variant lysozyme, as well as synthetic fibrils derived from a ten-residue peptide corresponding to the A-strand of transthyretin. All the fibrils had an electron-lucent core but the packing arrangement comprised five or six protofilaments rather than four. The structural similarity that defines amyloid fibres thus exists principally at the level of beta-sheet folding of the polypeptides within the protofilament, while the different types vary in the supramolecular assembly of their protofilaments.
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PMID:The protofilament substructure of amyloid fibrils. 1090 51

Atomic force microscopy has been employed to investigate the structural organization of amyloid fibrils produced in vitro from three very different polypeptide sequences. The systems investigated are a 10-residue peptide derived from the sequence of transthyretin, the 90-residue SH3 domain of bovine phosphatidylinositol-3'-kinase, and human wild-type lysozyme, a 130-residue protein containing four disulfide bridges. The results demonstrate distinct similarities between the structures formed by the different classes of fibrils despite the contrasting nature of the polypeptide species involved. SH3 and lysozyme fibrils consist typically of four protofilaments, exhibiting a left-handed twist along the fibril axis. The substructure of TTR(10-19) fibrils is not resolved by atomic force microscopy and their uniform appearance is suggestive of a regular self-association of very thin filaments. We propose that the exact number and orientation of protofilaments within amyloid fibrils is dictated by packing of the regions of the polypeptide chains that are not directly involved in formation of the cross-beta core of the fibrils. The results obtained for these proteins, none of which is directly associated with any human disease, are closely similar to those of disease-related amyloid fibrils, supporting the concept that amyloid is a generic structure of polypeptide chains. The detailed architecture of an individual fibril, however, depends on the manner in which the protofilaments assemble into the fibrillar structure, which in turn is dependent on the sequence of the polypeptide and the conditions under which the fibril is formed.
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PMID:Ultrastructural organization of amyloid fibrils by atomic force microscopy. 1110 31

Hereditary systemic amyloidosis may be caused by mutations in a number of plasma proteins including transthyretin, apolipoprotein AI, fibrinogen Aalpha-chain, lysozyme, and gelsolin. Each type of amyloidosis is inherited as an autosomal dominant disease and is associated with a structurally altered protein that aggregates to form amyloid fibrils. Here we report that the amyloid protein in a family with previously uncharacterized hereditary renal amyloidosis is apolipoprotein AII (apoAII) with a 21-residue peptide extension on the carboxyl terminus. Sequence analysis of the apoAII gene of affected individuals showed heterozygosity for a single base substitution in the apoAII stop codon. The mutation results in extension of translation to the next in-frame stop codon 60 nucleotides downstream and is predicted to give a 21-residue C-terminal extension of the apoAII protein identical to that found in the amyloid. This mutation produces a novel BstNI restriction site that can be used to identify individuals with this gene by restriction fragment length polymorphism analysis. This is the first report of apoAII amyloid in humans and the first mutation identified in apoAII protein. Amyloid fibril formation from apoAII suggests that this lipoprotein, which is predicted to have an amphipathic helical structure, must undergo a transition to a beta-pleated sheet by a mechanism shared by other lipoproteins that form amyloid.
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PMID:A new human hereditary amyloidosis: the result of a stop-codon mutation in the apolipoprotein AII gene. 1140 42

Amyloid beta-protein (Abeta) fibril assembly is a defining characteristic of Alzheimer's disease. Fibril formation is a complex nucleation-dependent polymerization process characterized in vitro by an initial lag phase. To a significant degree, this phase is a consequence of the energy barrier that must be overcome in order for Abeta monomers to fold and oligomerize into fibril nuclei. Here we show that low concentrations of 2,2,2-trifluoroethanol (TFE) convert predominately unstructured Abeta monomers into partially ordered, quasistable conformers. Surprisingly, this results in a temporal decrease in the lag phase for fibril formation and a significant increase in the rate of fibril elongation. The TFE effect is concentration dependent and is maximal at approximately 20% (v/v). In the presence of low concentrations of TFE, fibril formation is observed in Abeta samples at nanomolar concentration, well below the critical concentration for Abeta fibril formation in the absence of TFE. As the amount of TFE is increased above 20%, helix content progressively rises to approximately 80%, a change paralleled first by a decrease in elongation rate and then by a complete cessation of fibril growth. These findings are consistent with the hypothesis that a partially folded helix-containing conformer is an intermediate in Abeta fibril assembly. The requirement that Abeta partially folds in order to assemble into fibrils contrasts with the mechanism of amyloidogenesis of natively folded proteins such as transthyretin and lysozyme, in which partial unfolding is a prerequisite. Our results suggest that in vivo, factors that affect helix formation and stability will have significant effects on the kinetics of Abeta fibril formation.
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PMID:Kinetic studies of amyloid beta-protein fibril assembly. Differential effects of alpha-helix stabilization. 1214 56


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