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PubMed1986

Nuclear functions required for cytochrome c oxidase biogenesis in Saccharomyces cerevisiae. Characterization of mutants in 34 complementation groups.

To identify nuclear functions required for cytochrome c oxidase biogenesis in yeast, recessive nuclear mutants that are deficient in cytochrome c oxidase were characterized. In complementation studies, 55 independently isolated mutants were placed into 34 complementation groups. Analysis of the content of cytochrome c oxidase subunits in each mutant permitted the definition of three phenotypic classes. One class contains three complementation groups whose strains carry mutations in the COX4, COX5a, or COX9 genes. These genes encode subunits IV, Va, and VIIa of cytochrome c oxidase, respectively. Mutations in each of these structural genes appear to affect the levels of the other eight subunits, albeit in different ways. A second class contains nuclear mutants that are defective in synthesis of a specific mitochondrial-encoded cytochrome c oxidase subunit (I, II, or III) or in both cytochrome c oxidase subunit I and apocytochrome b. These mutants fall into 17 complementation groups. The third class is represented by mutants in 14 complementation groups. These strains contain near normal amounts of all cytochrome c oxidase subunits examined and therefore are likely to be defective at some step in holoenzyme assembly. The large number of complementation groups represented by the second and third phenotypic classes suggest that both the expression of the structural genes encoding the nine polypeptide subunits of cytochrome c oxidase and the assembly of these subunits into a functional holoenzyme require the products of many nuclear genes.

Cell Nucleus↗
PubMed1988

Apolipoproteins of the orotic acid fatty liver: implications for the biogenesis of plasma lipoproteins.

Rats fed orotic acid develop fatty livers characterized by triglyceride-laden, membrane-bounded vesicles designated "liposomes." We have measured the levels of apolipoproteins in isolated liposomes and other subcellular fractions by SDS-polyacrylamide gel electrophoresis, electrotransfer, and immunodecoration. Apolipoproteins Bh, Bl, E, and C appear to cofractionate; for these proteins, the liposomal pool represents a large portion of their total intracellular mass. However, liposomes are deficient in both variants of apoB relative to apoE and apoC when compared with rat plasma very low density lipoprotein (VLDL). Albumin and apolipoproteins A-I and A-IV are also found in liposomes, but this organelle represents a minor fraction of their total intracellular mass. The liposomal apolipoproteins show varying degrees of association with cisternal lipid and with organelle membranes. Orotic acid may selectively block VLDL production at the level of particle assembly or transorganellar movement. We conclude that liposomal contents probably represent exaggerated accumulations of VLDL assembly intermediates, and that the intracellular partitioning of high density lipoprotein-destined from VLDL-destined components occurs at an early stage in particle biogenesis. Moreover, some unique structural feature of apoB may effect movement of VLDL assembly intermediates through secretory organelles.

Animals↗
PubMed1988

Comparative metabolism of branched-chain amino acids to precursors of juvenile hormone biogenesis in corpora allata of lepidopterous versus nonlepidopterous insects.

Comparative studies were performed on the role of branched-chain amino acids (BCAA) in juvenile hormone (JH) biosynthesis using several lepidopterous and nonlepidopterous insects. Corpora cardiaca-corpora allata complexes (CC-CA, the corpora allata being the organ of JH biogenesis) were maintained in culture medium containing a uniformly 14C-labeled BCAA, together with [methyl-3H]methionine as mass marker for JH quantification. BCAA catabolism was quantified by directly analyzing the medium for the presence of 14C-labeled propionate and/or acetate, while JHs were extracted, purified by liquid chromatography, and subjected to double-label liquid scintillation counting. Our results indicate that active BCAA catabolism occurs within the CC-CA of lepidopterans, and this efficiently provides propionyl-CoA (from isoleucine or valine) for the biosynthesis of the ethyl branches of JH I and II. Acetyl-CoA, formed from isoleucine or leucine catabolism, is also utilized by lepidopteran CC-CA for biosynthesizing JH III and the acetate-derived portions of the ethyl-branched JHs. In contrast, CC-CA of nonlepidopterans fail to catabolize BCAA. Consequently, exogenous isoleucine or leucine does not serve as a carbon source for the biosynthesis of JH III by these glands, and no propionyl-CoA is produced for genesis of ethyl-branched JHs. This is the first observation of a tissue-specific metabolic difference which in part explains why these novel homosesquiterpenoids exist in lepidopterans, but not in nonlepidopterans.

Amino Acids, Branched-Chain↗
PubMed1987

Biogenesis of peroxisomes in regenerating rat liver. I. Sequential changes of catalase and urate oxidase detected by ultrastructural cytochemistry.

The biogenesis of peroxisomes has been investigated in the model of regenerating rat liver after partial hepatectomy using ultrastructural cytochemical staining methods: catalase as a marker of the peroxisomal matrix and uricase for the cores. The peroxisomes in regenerating rat liver showed several distinctive features: a) marked variation in shape and size, e.g., peroxisomes with tail-like extensions and tortuously elongated rod-shaped ones, b) formation of peroxisomal clusters and, c) interconnections between adjacent peroxisomes suggesting cleavage or budding. Whereas the reaction product for catalase was present at all intervals after hepatectomy in the matrix of all peroxisomes, the pattern of localization of uricase case varied with the time. It was confined to the cores in controls and at 10 days after the operation, while at 24 and 48 h it showed, in addition, a diffuse reaction in the matrix of some peroxisomes. In interconnected apparently dividing peroxisomes, the core with positive uricase reaction was present only in one half, while the other half was devoid of the reaction product. Similarly, the diffuse uricase staining was confined to the half which contained the core with the other half remaining unstained. These observations are consistent with the concept that new peroxisomes are formed from preexisting ones by budding and segmentation. While catalase is transferred uniformly to all new segments, uricase is compartmentalized in certain portions, of the apparently growing "peroxisomal reticulum".

Animals↗
PubMed1979

[Biogenesis of chromatin in animal cells. Stimulation of nuclear protein and DNA synthesis in hepatocytes after brief inhibition of translation by cycloheximide].

A drastic and brief inhibition of protein synthesis (up to 95% for 3--6 hrs) by cycloheximide in the liver of rats starved for 24 hrs results in a recovery and subsequent marked stimulation of non-histone proteins, histone chromosomal proteins and DNA. The stimulation of non-histone protein synthesis was observed after 1 hr (inhibition) 12--24 hrs (recovery and stimulation of protein synthesis) and 48--60 hrs (stimulation of DNA synthesis) following the administration of cycloheximide. Two periods of histone biosynthesis were observed. The first one (24--36 hrs) was not coupled and the second one (48--60 hrs) was coupled with DNA replication. During the recovery and stimulation of protein synthesis acetylation of the histone and non-histone proteins proceeds at an increased rate. Possible applicability of the model in question for investigations of chromatin biogenesis is discussed.

Animals↗
PubMed1972

Intracellular sites of lipid synthesis and the biogenesis of mitochondria.

Experimental data are presented on the intracellular localization in rat liver of three enzymes which are involved in the biosynthesis of phosphatidylethanolamine and diphosphatidylglycerol. These enzymes are phosphatidylserine decarboxylase, CDP-diglyceride-l-alpha-glycerophosphate phosphatidyl transferase, and phosphatidylethanolamine-l-serine phosphatidyl transferase. It was found that the first two enzymes are primarily mitochondrial while the latter enzyme is primarily microsomal. The intracellular sites for the biosynthesis of phosphatidylcholine, phosphatidylethanolamine, and diphosphatidylglycerol are discussed, and the implications of their sites of biosynthesis on the assembly processes involved in the biogenesis of mitochondria are considered.

Amino Alcohols↗
PubMed1980

Biogenesis of plasma membrane glycoproteins. Purification and properties of two rat liver plasma membrane glycoproteins.

As a preliminary to a study of the biogenesis of individual plasma membrane glycoproteins, the marker enzyme nucleotide pyrophosphatase (NPPase) and a major rat liver plasma membrane sialoprotein, subsequently found to be identical with the enzyme dipeptidyl peptidase IV (DPP IV), were purified 10,000- and 2,000-fold, respectively, from rat liver. Both were amphipathic proteins which formed defined micellar complexes with detergents and aggregated in their absence. Gel filtration, sucrose density gradient centrifugation, and polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate showed the Triton X-100 complex of NPPase to contain a single 150,000-dalton peptide, while that of DPP IV was composed of two 120,000-dalton subunits; each complex also contained about 150,000-dalton Triton X-100. Trypsin cleaved the detergent complexes with release of major hydrophilic fragments which no longer bound detergent micelles; the accompanying change in peptide size was small for NPPase and undetectable for DPP IV, which also retained the dimer structure of its native form. DPP IV was the only major glycoprotein in rat liver plasma membrane which bound strongly to wheat germ agglutinin. Monospecific rabbit antibodies against NPPase and DPP IV precipitated the antigens without affecting their enzymatic activities.

Alkaline Phosphatase↗
PubMed1980

Biogenesis of plasma membrane glycoproteins. Tracer kinetic study of two rat liver plasma membrane glycoproteins in vivo.

Antibodies to purified nucleotide pyrophosphatase (NPPase) and dipeptidyl peptidase IV (DPP IV) were used to study the biogenesis of these rat liver plasma membrane glycoproteins in vivo. Following injection of tritiated leucine, the radioactivity in NPPase and DPP IV decayed at markedly different rates in the plasma membrane, with apparent half-lives of about 1 and 5 days, respectively. In short term experiments, labeling of total plasma membrane proteins was rapid and insensitive to colchicine, while labeling of both NPPase and DPP IV showed a lag of about 15 min, followed by colchcine-sensitive/cycloheximide-insensitive increases to half-maximal and maximal values at about 1 and 2 h, respectively. A peak of labeled DPP IV in rough microsomes at 15 min showed increased mobility on polyacrylamide gels and was largely inaccessible to antibodies in intact microsomes, consistent with its being an underglycosylated precursor, exposed on the cisternal side of the rough endoplasmic reticulum. In contrast, the behavior of unlabeled DPP IV in preparations of rough microsomes and Golgi was consistent with its being contributed by contaminating right-side-out plasma membrane vesicles. This conclusion was also necessary to fit the tracer kinetic data to a simple membrane-flow model, which gave precursor pools (1 microgram/g of liver) and fluxes (1 microgram/h/g of liver) for both DPP IV and NPPase which were about 3 orders of magnitude less than those for the synthesis of rat serum albumin. Thus, unlike hepatoma tissue culture cells (Doyle, D., Baumann, H., England, B., Friedman, E., Hou, E., and Tweto, J. (1978) J. Biol. Chem. 253, 967-973), normal rat liver does not contain large amounts of preformed intracellular plasma membrane precursors.

Animals↗
PubMed1982

Co-and post-translational events in the biogenesis of pig small intestinal aminopeptidase N.

The biogenesis of pig small intestinal aminopeptidase N (EC 3. 4. 11. 2) was studied by cell-free translation of intestinal mRNA and by labelling of organ cultured intestinal explants. In cell-free translation, the primary mRNA translation product of aminopeptidase N was a polypeptide of Mr 115,000. When translation was performed in the presence of dog pancreatic microsomes, a Mr 140,000 polypeptide was also observed. A polypeptide of Mr 115,000 was seen for the enzyme, purified from tunicamycin exposed explants. This result suggests that aminopeptidase N is co-translationally inserted into the membrane without cleavage of the signal. Pulse-chase labelling of explants gave the following results: 1. Immediately after a 10 min pulse with [35S] methionine, aminopeptidase N was detected in the Ca2+-precipitated membrane fraction. 2. The earliest detectable form of the enzyme, a polypeptide of Mr 140,000, was "high mannose" glycosylated as judged by its sensitivity to endoglycosidase H. After 40 min of chase, a re-glycosylation, yielding the mature form of Mr 166,000, occurred. 3. Aminopeptidase N was expressed at the microvillar membrane after 60-90 min of chase. Monensin inhibited the conversion from high mannose to complex glycosylation and the appearance of the enzyme in the microvillar membrane, indicating a role of the Golgi complex in these processes. Colchicine prevented aminopeptidase N from reaching the microvillar membrane, suggesting the involvement of microtubules in the transport.

Aminopeptidases↗
PubMed1980

[Effect of hyperoxia on erythropoietin biogenesis in the "endocrine" kidney model].

The erythropoietin plasma level and RNA synthesis in both kidneys were studied in rats with the H. Selye "endocrine" kidney under 4-hour hyperoxia. It was shown that a short period of hyperoxia leads to a 2-fold decrease in erythropoietin plasma level and to the fall of RNA synthesis in the "endocrine" and intact kidneys. From the evidence obtained it is concluded that hyperoxia inhibits erythropoietin production in the kidneys. Changes in high-polymeric RNA synthesis suggest that DNA-dependent RNA synthesis is one of the mechanisms of the hormone biogenesis.

Animals↗
PubMed1984

Biogenesis and cytochemistry of unspecialized peroxisomes in root cortical cells of Yucca torreyi L.

Microbodies containing bipyramidal crystalline nucleoid inclusions occur within every cortical cell in roots of Yucca torreyi. Reaction product deposition attributable to catalase, glycolate oxidase, and urate oxidase activities are cytochemically localized to Yucca root microbodies and classifies them as unspecialized peroxisomes on the basis of their enzyme complement and tissue origin. Crystalline nucleoids do not stain for glycolate or urate oxidase activities, appearing as negatively-stained inclusions, but are apparently reactive for catalase activity. Development of unspecialized peroxisomes in Yucca roots is consistent with all evidence for glyoxysome and leaf-type peroxisome biogenesis from ER. Dilated ends of ER cisternae accumulate cytochemically detectable glycolate oxidase activity. After considerable dilation, paracrystalline precursors to nucleoids form within the bulge, and the inclusion enlarges to comprise the majority of peroxisomal volume. Peroxisomes that are not attached to ER are observed with high voltage electron microscopy and in serial thin sections, implying that eventually the budding peroxisomes are vesiculated. The functions of these unspecialized peroxisomes are suggested based upon cytochemical detection of their partial enzyme complement and their spatial and developmental timing relationships within developing Yucca root cortical parenchyma cells.

Alcohol Oxidoreductases↗
PubMed1980

The biogenesis of erythropoietin.

Aerobic living demands a constant supply of oxygen at the cellular mitochondrial level. Numerous interlocking feedback mechanisms insure the constancy of this supply by adapting the supply lines to changes in the intra and extracellular milieu. Among these mechanisms is the feedback circuit which, triggered by an intracellular decrease in oxygen supply, initiates the production of a polypeptide hormone, erythropoietin, which in turn augments the production of an oxygen carrier, the hemoglobin-containing red cell. The biogenesis of this hormone is an important biologic process which is being studied intensively and slowly unravelled.

Animals↗
PubMed1981

Membrane biogenesis. Evidence that a soluble chimeric polypeptide can serve as a precursor of a mutant lac permease in Escherichia coli.

A mutant in the Escherichia coli lac permease, called Yf, appears to be defective in the biogenesis and proper assembly of this membrane protein. It was proposed that this defect led to the accumulation of a precursor of the mutant permease (Fried, V. A. (1977) J. Mol Biol. 114, 477-490). In this communication, evidence is presented that the lacYf mutant accumulates a novel lac-specific soluble polypeptide with a molecular weight of 87,000. Detected by double-label analysis on sodium dodecyl sulfate gels, and identified as a lac-specific polypeptide on a two-dimensional gel system, this polypeptide is immunoprecipitated by anti-transacetylase antibody. Pulse-chase experiments are consistent with the hypothesis that it is converted in vivo into a lac-specific membrane protein with an apparent molecular weight of 28,000, which appears to be the mutant lac permease. The results suggest that the 87,000-dalton soluble protein is a precursor of the mutant lac permease. It is proposed that this precursor is a polyprotein chimera containing both the lacY and lacA gene products.

Cell Membrane↗
PubMed1994

Intracellular sites involved in the biogenesis of bile canaliculi in hepatic cells.

Studies in hepatoma cells and hepatocytes have revealed that the biogenesis of bile canalicular membrane involves microvilli-lined vesicles (MLV), which are formed in well differentiated cells. The vesicles grow as a function of time and are presumably vectorially transported to cell surface contact sites of attached cells. We demonstrate that a fluorescent head group-labeled lipid analog, N-(lissamine rhodamine B sulfonyl)phosphatidylethanolamine (N-Rh-PE), after its exogenous insertion into the plasma membrane of HepG2 cells at 4 degrees C, accumulates in these microvilli-lined vesicles at 37 degrees C. This shows that the MLV are a target for plasma membrane-derived lipids. Furthermore, also the Golgi apparatus is involved in the formation of the vesicles. After initial accumulation of the fluorescent sphingolipid precursor, 6-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoic acid (C6-NBD)-ceramide in the Golgi apparatus at 37 degrees C, prolonged incubation at 37 degrees C results in the appearance of NBD fluorescence in the microvilli-lined vesicles. The transport route for the Golgi-derived material to the developing bile canalicular vesicle is not an indirect pathway, i.e. involving transcytosis via the basolateral plasma membrane. This could be demonstrated by including bovine serum albumin (BSA) in the incubation media, a lipid scavenger that will remove any C6-NBD-lipids exposed at the basolateral membrane. At these conditions, lipid trafficking between the Golgi complex and MLV still occurred. We further demonstrate that the targeting from the Golgi apparatus to the bile canaliculus is also operational in isolated human hepatocytes. The latter results suggests that the Golgi complex is involved in both the formation of bile canaliculi and in bile secretion in fully differentiated cells.

Bile Canaliculi↗
PubMed1993

Evidence for an alternate model of human P-glycoprotein structure and biogenesis.

We have studied the transmembrane topology of human P-glycoprotein (MDR1) using protein chimeras in Xenopus oocytes and full-length native protein in a cell-free translation system. We find both in vivo and in vitro, that the peptide region between putative transmembrane helices (TM) 8 and 9 resides in the endoplasmic reticulum lumen not in the cytosol as predicted. The topology of the carboxyl-terminal half of MDR1 therefore appears distinct from the homologous amino-terminal half in which the corresponding region between TM2 and TM3 is cytosolic. Thus, topogenic sequences encoded in the homologous amino and carboxyl domains of MDR1 direct fundamentally different events in biogenesis of the two halves of MDR1. We conclude that the transmembrane topology of MDR1, an important member of the ATP binding cassette (ABC) transporter superfamily, is not as predicted and should be revised.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Translocational pausing is a common step in the biogenesis of unconventional integral membrane and secretory proteins.

Signal, stop transfer, and signal-anchor sequences direct a nascent polypeptide to a single topology with respect to the membrane of the endoplasmic reticulum. However, other types of sequences direct nascent proteins, either transiently or permanently, to more than one topologic form. Pause transfer sequences direct nascent apolipoprotein B to pause during its translocation, resulting in nonintegrated, transmembrane intermediates that become fully translocated over time. The stop transfer effector sequence (STE) directs the nascent prion protein either to integrate at the hydrophobic domain which immediately follows (TM1) or to become fully translocated, in a manner dependent on cytosolic factors. Although the action of pause transfer sequences has been dissected into stop and restart steps, the mechanism of STE action is unknown. Using chimeric proteins expressed in vitro, we show that STE, independent of TM1, acts as a pause transfer sequence. We also demonstrate that translocational pausing at STE is a common step preceding either complete translocation or integration into the membrane of a chimeric protein containing STE and TM1. These findings have implications for the role of pausing in the biogenesis of both secretory and membrane proteins.

Amino Acid Sequence↗
PubMed1993

A Chinese hamster ovary cell line with a temperature-conditional defect in receptor recycling is pleiotropically defective in lysosome biogenesis.

We have previously described the isolation of a Chinese hamster ovary cell line, TfT1.11, that has a pleiotropic, temperature-conditional defect in receptor recycling (Cain, C. C., Wilson, R. B., and Murphy, R. F. (1991) J. Biol. Chem. 266, 11746-11752). These cells show a rapid loss of cell surface receptors upon temperature shift due to a reduction in the rate of receptor recycling. We show here that, in addition to altered receptor recycling, TfT1.11 cells show three defects in lysosome biogenesis. At the nonpermissive temperature, they 1) redistribute at least one lysosomal enzyme from lysosomes to endosomes, 2) fail to transfer fluid-phase material from early endosomes to later compartments, and 3) fail to accumulate fluid-phase markers due to increased efflux of internalized material. The results suggest that the processes of recycling from the endosome and movement of material from endosomes to lysosomes are tightly linked.

Animals↗
PubMedDate not supplied

[Features of the biogenesis of Escherichia coli alkaline phosphatase during its supersynthesis].

The oversynthesis of the secreted alkaline phosphatase (PhoA) in E.coli K12802 cells due to transformation with the PhoA+ plasmid pHI-7 leads to a change in its biogenesis--alternative localization and accumulation of the enzyme intermediate forms corresponding to different stages of the its post-translational modification. Instead of the soluble PhoA available in the parent strain mostly as a completely processed mature metazyme III localized in the periplasm, five enzyme forms were discovered in the PhoA overproducer: a cytoplasmic PhoA precursor (prePhoA) as insoluble aggregates; three soluble metazymes of a mature active form localized in the periplasm as in well as in culture medium; and a soluble high-molecular form in the periplasm. PrePhoA was isolated and purified by removal of soluble cell fractions using differential centrifugation, solubilization of membrane proteins with Triton X100, dissolution of the aggregates in the buffer with 8M urea and FPLC on MonoQ. Extracellular PhoA was purified by ultrafiltration, thermal treatment, and gel chromatography on Sepharose CL-4B. It was shown that the isolated prePhoA can be transformed into a mature form in the presence of a leader peptidase in 0.8 urea and is completely cleaved with proteinase K. Three forms of the mature PhoA vary in resistance to proteinase K and trypsin. Metazyme I, the unprocessed mature PhoA, is the most resistant to proteolysis.

Alkaline Phosphatase↗