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At least 703 records · Page 39Linked to original sources
PubMed1999

Structure and biogenesis of topaquinone and related cofactors.

The structure of a new biological redox cofactor-topaquinone (TPQ), the quinone of 2,4,5-trihydroxyphenylalanine-was elucidated in 1990. TPQ is the cofactor in most copper-containing amine oxidases. It is produced by post-translational modification of a strictly conserved active-site tyrosine residue. Recent work has established that TPQ biogenesis proceeds via a novel self-processing pathway requiring only the protein, copper, and molecular oxygen. The oxidation of tyrosine to TPQ by dioxygen is a six-electron process, which has intriguing mechanistic implications because copper is a one-electron redox agent, and dioxygen can function as either a two-electron or four-electron oxidant. This review adopts an historical perspective in discussing the structure and reactivity of TPQ in amine oxidases, and then assesses what is currently understood about the mechanism of the oxidation of tyrosine to produce TPQ. Aspects of the structures and chemistry of related cofactors, such as the Tyr-Cys radical in galactose oxidase and the lysine tyrosylquinone of lysyl oxidase, are also discussed.

Amine Oxidase (Copper-Containing)↗
PubMed2001

The peroxin Pex6p gene is impaired in peroxisomal biogenesis disorders of complementation group 6.

Human genetic peroxisomal biogenesis disorders (PBDs), such as Zellweger syndrome, comprise 13 different complementation groups (CGs). Eleven peroxin genes, termed PEXs, responsible for PBDs have been identified, whereas pathogenic genes for PBDs of 2CGs, CG-A (the same CG as CG8 in the United States and Europe) and CG6, remained unidentified. We herein provide several lines of novel evidence indicating that PEX6, the pathogenic gene for CG4, is impaired in PBD of CG6. Expression of PEX6 restored peroxisome assembly in fibroblasts from a CG6 PBD patient. This patient was a compound heterozygote for PEX6 gene alleles. Accordingly, by merging CG6 with CG4, human PBDs are now classified into 12CGs.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2005

Orthotopic liver transplantation from a living-related donor in an infant with a peroxisome biogenesis defect of the infantile Refsum disease type.

Peroxisomal biogenesis defects include a number of severe neurodevelopmental disorders, among which infantile Refsum disease (IRD) occupies the mildest end of the spectrum. Although high docosahexaenoic acid (DHA) and low phytanic acid diets can correct some of the biochemical defects, they have not consistently altered the progressive course of the disease. We carried out orthotopic liver transplantation (OLT) in a mildly symptomatic 6-month-old infant who was a sibling of a severely neurologically impaired older sister. After transplantation the clinical course of this young child appeared much improved by comparison to her older sister. She walked alone at 4 years, had acceptable social interaction and had a noticeable recovery of audition. After transplantation her biochemical parameters were significantly improved: phytanic acid and very long-chain fatty acid (VLCFA) serum concentrations decreased. Abnormal bile acids disappeared from plasma. Although the OLT did not result in a cure of the disorder, the clinical and biochemical results suggest that OLT should be considered in mildly symptomatic patients.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2005

Peroxisome biogenesis disorders: the role of peroxisomes and metabolic dysfunction in developing brain.

Peroxisome biogenesis disorders, of which Zellweger syndrome is the most severe, result in severe neurological dysfunction associated with abnormal CNS neuronal migrations due to the lack of functional peroxisomes. The PEX2-/- mouse model for Zellweger syndrome has enabled us to evaluate the role of peroxisomes in the development and functioning of the nervous system. These studies have shown that, in addition to disturbances in neuronal migration in developing cerebral cortex and cerebellum, defects in neuronal differentiation, proliferation and survival may also contribute to the CNS malformations. However, owing to the multiorgan dysfunction in peroxisomal disorders, it has been difficult to clearly define an intrinsic role for the peroxisome in brain cells. The use of several in vitro cell culture assays to evaluate the migration and differentiation of cerebellar neurons demonstrates a persistence of defects in peroxisome-deficient neurons. The absence of potential systemically derived, extrinsic factors in these in vitro systems indicates that CNS intrinsic defects contribute to the pathogenesis of disease in these disorders. However, bile acid treatment also increases the survival and growth of PEX2-/- mice and improves some aspects of cerebellar development, indicating that extrinsic factors also affect the developing peroxisome-deficient brain. Therefore, the final phenotype of nervous system dysfunction in peroxisomal disorders will reflect a combination of both CNS intrinsic and extrinsic factors.

Animals↗
PubMed2006

The role of presenilin and its interacting proteins in the biogenesis of Alzheimer's beta amyloid.

The biogenesis and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterises Alzheimer's disease. The presenilins and its interacting proteins play a pivotal role in the generation of Abeta from the amyloid precursor protein (APP). In particular, three proteins (nicastrin, aph-1 and pen-2) interact with presenilins to form a large multi-subunit enzymatic complex (gamma-secretase) that cleaves APP to generate Abeta. Reconstitution studies in yeast and insect cells have provided strong evidence that these four proteins are the major components of the gamma-secretase enzyme. Current research is directed at elucidating the roles that each of these protein play in the function of this enzyme. In addition, a number of presenilin interacting proteins that are not components of gamma-secretase play important roles in modulating Abeta production. This review will discuss the components of the gamma-secretase complex and the role of presenilin interacting proteins on gamma-secretase activity.

Alzheimer Disease↗
PubMed1987

Proapolipoprotein-converting enzymes and high-density lipoprotein early events in biogenesis.

The early events in high-density lipoprotein biogenesis involve the extracellular action of two converting enzymes affecting the cleavage of the prosegment of either proapolipoprotein A-I or proapolipoprotein A-II and the generation of mature apolipoprotein (apo) A-I and apo A-II, the main apolipoprotein of high-density lipoproteins. These two converting enzymes differ from each other in mechanism of action and specificity. The observation that they can be secreted by human hepatocarcinoma G2 cells in culture provides an experimental basis for examining the possible coordination between the synthesis and secretion of these two converting enzymes and the events attending the production and cellular export of apo A-I and apo A-II.

Apolipoprotein A-I↗
PubMed1975

Renal biogenesis of erythropoietin.

The widespread and ever expanding use of dialysis in the maintenance of patients with chronic renal disease has added an urgency to the study of the biogenesis of erythropoietin. It seems almost certain that erythropoietin could ameliorate, if not eliminate, the anemia of uremia, but unfortunately, erythropoietin is still not available in therapeutic quantities. Initially, erythropietin was though to be produced by the kidneys" but then the attention became directed at the liver. It was proposed that erythropoietin was produced there as an inactive precursor and that the kidney only acted as an oxygen sensor and as a producer of an erythropoietin-activating enzyme. Recent studies summarized here show that an isolated perfused kidney in the absence of any extrarenal substrate or precursor can synthesize erythropoietin. Consequently, it appears almost certain that the kidney is the endocrine organ of origin of erythropoietin. Further studies suggest that erythropoietin formation involves a phase of oxygen sensing and programming and a phase of synthesis. These phases probably occur in the same cell, and the renal cortex appears to be the most likely location for such cells. The current inability to extract erythropoietin from kidney homogenates is discussed but, unfortunately, not adequately explained.

Animals↗
PubMed1988

Site-directed antibodies for probing the structure and biogenesis of phosphatidylinositol glycan-linked membrane proteins: application to placental alkaline phosphatase.

An immunological approach to the study of the structure and biogenesis of the phosphatidylinositol glycan (PI-G) membrane anchor at the carboxyl terminus of human placental alkaline phosphatase (PLAP) is described. Based on the protein sequence predicted from full length PLAP cDNA, two epitopes were chosen in the region of the carboxyl terminus for the production of site-directed antibodies. The exo site represents the last nine residues of preproPLAP, (res. 505-513), which is part of the sequence that is expected to be cleaved from the nascent protein during processing and addition of the PI-G tail. A second site, the endo sequence, was selected close to the expected carboxyl terminus in mature PI-G-tailed PLAP (res. 474-484 of proPLAP). The two peptides were synthesized, polyclonal antibodies to the conjugated peptides were prepared, and the antisera were characterized. Analytical methods for both synthetic peptides and proteins are presented. Preliminary applications to the isolation and characterization of the PI-G-linked carboxyl terminus of mature PLAP and to the characterization of nascent PLAP are described. The application of both carboxyl terminal-directed antibodies, and a third antibody directed to the amino terminus of mature PLAP, in studies employing mutant forms of PLAP and to the PI-G tailing process itself are discussed. The immunological approach used here for PLAP should be applicable generally to the study of other PI-G-tailed proteins.

Alkaline Phosphatase↗
PubMed1984

Effect of exogenous addition of hemin on the biogenesis of mitochondrial membranes during glucose repression in Saccharomyces cerevisiae.

Exogenous addition of hemin alleviated glucose repression by promoting mitochondrial membrane functions. It prevented the release of mitochondrial proteins into the cytosol by decreasing the activities of phospholipase C and phospholipase D. It restored oligomycin sensitivity of mitochondrial ATPase associated with repressed mitochondria. It enhanced cardiolipin content twofold, and decreased the sterol:phospholipid ratio. Studies on the amino acid incorporation into isolated mitochondria showed that hemin can also promote biogenesis of the organelle by stimulating amino acid incorporation into mitochondrial proteins, and this stimulation appeared to be mediated through some cytosolic factor(s).

Cycloheximide↗
PubMed1989

Membrane biogenesis in Escherichia coli: effects of a secA mutation.

In Escherichia coli K-12, temperature-sensitive mutations in the secA gene have been shown to interfere with protein export. Here we show that the effect of a secA mutation is strongly pleiotropic on membrane biogenesis. Freeze-fracture experiments as well as cryosections of the cells revealed the appearance of intracytoplasmic membranes upon induction of the SecA phenotype. The permeability barrier of the outer membrane to detergents was lost. Two alterations in the outer membrane may be responsible for this effect, namely the reduced amounts of outer membrane proteins, or the reduction of the length of the core oligosaccharide of the lipopolysaccharide, which was observed in phage-sensitivity experiments and by SDS-polyacrylamide gel electrophoresis. Phospholipid analysis of the secA mutant, grown under restrictive conditions, revealed a lower content of the negatively charged phospholipid cardiolipin and of 18:1 fatty acid compared to those of the parental strain grown under identical conditions. These results are in line with the hypothesis that protein export and lipid metabolism are coupled.

Bacterial Outer Membrane Proteins↗
PubMed1983

Evidence for a negative modulating effect of erucic acid on the peroxisomal beta-oxidation enzyme system and biogenesis in rat liver.

In male rats fed a 30 cal% high-erucic acid (22:1 (13) (cis] rapeseed oil diet for 4 weeks a transient, small increase in peroxisomal beta-oxidation was observed in liver homogenates and isolated peroxisomes after approximately 1 week. Morphometric analysis revealed a progressive decrease in the average size of the liver peroxisomes (by approx. 20%), as well as their volume fraction (by more than 40%). A negative dose-response was observed when peroxisomal beta-oxidation was determined in animals fed rapeseed oil diets with a variable content of erucic acid. When erucic acid was given as subcutaneous injections the peroxisomal beta-oxidation decreased, in both liver homogenates and isolated peroxisomes. In contrast to recent proposals, our findings indicate that the amount of erucic acid cannot account for the small increase in peroxisomal beta-oxidation observed in the liver of rats adapted to a diet containing 30 cal% rapeseed oil with a high content of this fatty acid. In fact, by the selected criteria erucic acid seems to have a negative modulating effect on both the peroxisomal beta-oxidation enzyme system and biogenesis.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1981

Biogenesis of the mitochondrial enzyme, carbamyl phosphate synthetase. Appearance during fetal development of rat liver an rapid repression in freshly dispersed hepatocytes.

Synthesis of carbamyl phosphate synthetase was undetectable in fetal rat liver at 16 days gestation but by 4-5 days after birth (11-12 days later), this single protein accounted for approx. 5% of total liver protein and roughly 1% of total liver protein synthesis. Likewise, translatable mRNA coding for the enzyme was absent from 16-day fetal livers but then rapidly accumulated reaching maximum levels just after birth. The in vitro primary translation product of carbamyl phosphate synthetase mRNA corresponded to a higher molecular weight biosynthetic precursor of the enzyme; peptide maps obtained from the precursor synthesized both in vivo and in vitro and from the mature enzyme made in vivo were the same. When livers of neonatal rats were perfused with collagenase and further treated to yield a preparation of freshly dispersed hepatocytes highly active in general protein synthesis, a procedure which took about 45 min to complete, biosynthesis of carbamyl phosphate synthetase was found to be completely absent in these cells. The mRNA coding for the enzyme, however, could be extracted from the dispersed hepatocytes and was actively translatable in vitro, at levels approximately 75% of those for mRNA obtained from intact liver. Repression of biogenesis of carbamyl phosphate synthetase in dispersed hepatocytes, therefore, must involve a mechanism which shifts the mRNA coding for the enzyme out of active polysomal complexes and renders it further untranslatable in vivo but not in vitro.

Animals↗
PubMed1983

Biogenesis of mitochondrial proteins regulation of maturation of delta-aminolevulinate synthase by hemin.

The effect of hemin on the biogenesis of delta-aminolevulinate (ALA) synthase was examined in primary cultures of chick embryo hepatocytes. Hemin (0.010 mM) in the culture medium significantly inhibited the induction of ALA synthase activity in hepatocytes exposed to the porphyrogenic agent allylisopropylacetamide. In hepatocytes pulse-labeled with [35S]methionine for 45 min in the presence and absence of hemin, it was determined by immunechemical analyses that hemin blocked the processing of the precursor of ALA synthase.

5-Aminolevulinate Synthetase↗
PubMed1983

Changes in D-loop frequency and superhelicity among the mitochondrial DNA molecules in relation to organelle biogenesis in oocytes of Xenopus laevis.

Changes in mitochondrial DNA (mtDNA) replication activity are known to occur during oogenesis in Xenopus laevis. Electron microscopic and electrophoretic analyses carried out on mtDNA molecules at different vitellogenic stages show that 1. The frequency of displacement loop (D-loop) forms is correlated with the intensity of mitochondrial biogenesis. 2. Most of the native molecules as well as the D-loop carrying ones are superhelical. 3. Four families of different superhelicity may be distinguished and D-loops are found only in the most superhelical ones. To account for the changes in the frequencies of the D-loop forms and of the different topological types during cell differentiation, it is suggested that the initiation of a new replication occurs only on the most superhelical molecules and that some control of superhelicity may exist in mitochondria.

Animals↗
PubMed1992

Biogenesis of endoplasmic reticulum transport vesicles transferring gastric apomucin from ER to Golgi.

Rough endoplasmic reticulum (RER) transport vesicles were generated from gastric mucous cell RER microsomes in the presence of labeled precursors of phospholipids. The vesicles contained 7-10% of their proteins in the form of apomucin (cargo), and 80% of de novo synthesized phosphatidylcholine (PC) was incorporated into the vesicular membrane. In the absence of choline and ethanolamine precursors or in the presence of 3 mM N-ethylmaleimide (NEM), an inhibitor of CTP:phosphocholine cytidylyltransferase, formation of the transport vesicles, their enrichment in the newly synthesized PC, and the total synthesis of PC decreased by 86%, whereas in the presence of 3 mM Zn2+, complete blockage of vesicle formation and PC synthesis was observed. Analysis of the mucin-transporting vesicles indicated that the CTP:phosphocholine cytidylyltransferase and 1,2-diacyl-sn-glycerol:CDP-choline phosphotransferase remained associated with transport vesicles released from ER. The enzymes and other proteins separated from the vesicle surface prior to vesicle fusion with Golgi and the process was induced by phosphorylation. Based on the results of this study, it is proposed that the formation of the ER transport vesicles of gastric mucosal cells is in concert with synthesis of phospholipids and thus in part is regulated by phospholipid-synthesizing enzymes that reside on the membrane during its biogenesis and dissociate from its surface once the task is completed.

Animals↗
PubMed1992

A new gene of the f1 operon of Y. pestis involved in the capsule biogenesis.

The DNA sequence determination of the f1 operon between the genes encoding the F1 subunit (caf1) and chaperone-like protein (caf1M) revealed a large open reading frame that codes for a polypeptide similar to some E. coli proteins involved in the biogenesis of fimbria. The deletion and in trans complementation analyses showed that this gene is not necessary for extracellular transport of the F1 subunit but plays a role in the capsule assembly.

Amino Acid Sequence↗
PubMed1993

Importance of Arg-219 for correct biogenesis of alpha 1 homooligomeric glycine receptors.

The inhibitory glycine receptor is characterized by a pentameric arrangement of subunits with four predicted transmembrane segments (M1-M4) each. Here, we have mutagenized arginine residues located at both termini of the alpha 1 subunit segment, M2, which lines the receptor's anion channel. No glycine-gated channel formation could be detected in the plasma membrane of expressing cells for any of the mutants. In addition, mutating the arginine at the cytoplasmic terminus of M2 (R219) generated proteins which were only core-glycosylated, retained within intracellular compartments, and aggregated to high molecular weight complexes. Thus, residue R219, which corresponds to an arginine/lysine conserved in other ligand-gated ion channel polypeptides, is essential for correct biogenesis of the receptor.

Amino Acid Sequence↗
PubMed1994

Myelin membrane biogenesis by oligodendrocytes. Developmental regulation of low molecular weight GTP-binding proteins.

Oligodendrocytes synthesize dramatic amounts of myelin membrane. We hypothesized that this requires unique aspects of vesicular trafficking. Specific stages of the oligodendrocyte lineage were assayed for low molecular weight GTP-binding proteins implicated in the regulation of vesicular transport pathway (two dimensional gel electrophoresis, [alpha-32P]GTP overlay). Consistent with the hypothesis, as oligodendrocytes differentiate from early progenitors to mature myelin-producing cells, > or = 12 small GTP-binding proteins become up-regulated. Myelin membrane also has a complex pattern of GTP-binding proteins. Several of these proteins may be specific to oligodendrocytes, suggesting that oligodendrocytes may utilize cell-type specific GTP-binding proteins for biogenesis and maintenance of the myelin membrane.

Animals↗