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At least 19 recordsLinked to original sources
PubMed1984

Asparagine-linked glycosylation in Saccharomyces cerevisiae: genetic analysis of an early step.

Asparagine-linked glycosylation is a form of covalent modification that distinguishes proteins that are either membrane bound or are in cellular compartments topologically outside of the cell from those proteins that remain soluble in the cytoplasm. This type of glycosylation occurs stepwise, with core oligosaccharide added in the endoplasmic reticulum and subsequent modifications occurring in the golgi. We used tunicamycin, an inhibitor of one of the earliest steps in the synthesis of N-linked oligosaccharide, to select for mutants that are resistant to this antibiotic. Genetic, biochemical, and physiological experiments led to the following conclusions. The synthesis of N-linked oligosaccharide is an essential function in cells. In contrast to mammalian cells, yeast cells do not transport tunicamycin by a glucosamine transport function. We identified a gene, ALG7, that is probably the structural gene for UDP-N-acetylglucosamine-1-P transferase, the enzyme inhibited by tunicamycin. Dominant mutations in this gene result in increased activity of the transferase and loss of the ability of the cell to sporulate. In addition, we identified another gene, TUN1, in which recessive mutations result in resistance to tunicamycin. The ALG7 and TUN1 genes both map on chromosome VII.

Asparagine↗
PubMed1991

Synthesis of phosphatidylinositol 4,5-bisphosphate in the endoplasmic reticulum of Chinese hamster ovary cells.

We have investigated the intracellular localization and synthesis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2) in Chinese hamster ovary (CHO) cells by analyzing membrane fractions that were obtained by sucrose density gradient centrifugation. After labeling the cells for 24 h with [3H]inositol, the bulk of [3H] PtdInsP2 was found in the plasma membrane fraction, yet this lipid was also distinctly present in the microsomal fraction (20% of total cellular [3H]PtdInsP2). To determine the origin of this microsomal PtdInsP2, gradient fractions from unlabeled CHO cells were incubated with [3H]inositol in the presence of an ATP-generating system. Under these conditions of labeling, [3H]PtdIns was exclusively present in the microsomal fractions and found to be partially converted to [3H] phosphatidylinositol 4-phosphate ([3H]PtdInsP) and phosphatidylinositol 4-phosphate ([3H]PtdInsP) and [3H]PtdInsP2. The ability of microsomes to synthesize PtdInsP and PtdInsP2 was confirmed by assaying the gradient fractions for PtdIns and PtdInsP kinase activity using endogenous substrate and [gamma-32P]ATP. In the presence of exogenous substrate and Triton X-100, PtdInsP kinase activity was particularly high in the plasma membrane fractions. When phosphoinositide synthesis was studied in permeabilized CHO cells under conditions of sustained membrane vesicle flow (Helms, J. B., Karrenbauer, A., Wirtz, K. W. A., Rothman, J. E., and Wieland, F. T. (1990) J. Biol. Chem. 265, 20027-20032), no lag-time could be detected between the synthesis of [3H]PtdIns and the formation of [3H]PtdInsP2. Moreover, when lipid transport pathways were blocked in these permeabilized cells either by omission of membrane-free cytosol, addition of GTP gamma S and brefeldin A, or temperature block, PtdInsP2 formation still occurred at normal levels. These results strongly suggest that PtdInsP2 can be formed at the site of PtdIns synthesis, i.e. the endoplasmic reticulum (ER). The relationship between PtdInsP2, generated in the ER, and PtdInsP2 present in the plasma membrane, remains to be established.

1-Phosphatidylinositol 4-Kinase↗
PubMed1999

Characterization of a novel GDP-mannose:Serine-protein mannose-1-phosphotransferase from Leishmania mexicana.

Protozoan parasites of the genus Leishmania secrete a number of glycoproteins and mucin-like proteoglycans that appear to be important parasite virulence factors. We have previously proposed that the polypeptide backbones of these molecules are extensively modified with a complex array of phosphoglycan chains that are linked to Ser/Thr-rich domains via a common Manalpha1-PO4-Ser linkage (Ilg, T., Overath, P., Ferguson, M. A. J., Rutherford, T., Campbell, D. G., and McConville, M. J. (1994) J. Biol. Chem. 269, 24073-24081). In this study, we show that Leishmania mexicana promastigotes contain a peptide-specific mannose-1-phosphotransferase (pep-MPT) activity that adds Manalpha1-P to serine residues in a range of defined peptides. The presence and location of the Manalpha1-PO4-Ser linkage in these peptides were determined by electrospray ionization mass spectrometry and chemical and enzymatic treatments. The pep-MPT activity was solubilized in non-ionic detergents, was dependent on Mn2+, utilized GDP-Man as the mannose donor, and was expressed in all developmental stages of the parasite. The pep-MPT activity was maximal against peptides containing Ser/Thr-rich domains of the endogenous acceptors and, based on competition assays with oligosaccharide acceptors, was distinct from other leishmanial MPTs involved in the initiation and elongation of lipid-linked phosphoglycan chains. In subcellular fractionation experiments, pep-MPT was resolved from the endoplasmic reticulum marker BiP, but had an overlapping distribution with the cis-Golgi marker Rab1. Although Man-PO4 residues in the mature secreted glycoproteins are extensively modified with mannose oligosaccharides and phosphoglycan chains, similar modifications were not added to peptide-linked Man-PO4 residues in the in vitro assays. Similarly, Man-PO4 residues on endogenous polypeptide acceptors were also poorly extended, although the elongating enzymes were still active, suggesting that the pep-MPT activity and elongating enzymes may be present in separate subcellular compartments.

Amino Acid Sequence↗
PubMed1990

Phosphoinositide metabolism in cultured glioma and neuroblastoma cells: subcellular distribution of enzymes indicate incomplete turnover at the plasma membrane.

The hypothesis that the small portion of cellular phosphoinositide participating in signal transduction might be preferentially recycled within the plasma membrane was tested in rat glioma (C6) and murine neuroblastoma (N1E-115) cells. Percoll density gradient centrifugation was used to isolate a purified plasma membrane fraction and the subcellular distribution of all enzymes mediating phosphoinositide turnover was assessed. A small but significant proportion of PtdInsP2-specific phosphodiesterase was located in the plasma membrane but only two of the five enzymes required to replace PtdInsP2 (diacylglycerol kinase and PtdInsP kinase) also were present. CTP:phosphatidate cytidylyltransferase and CMP-phosphatidate:inositol phosphatidyltransferase were located exclusively in a microsomal fraction containing enriched levels of endoplasmic reticulum markers. Thus, diacylglycerol from agonist-stimulated cleavage of PtdInsP2, or phosphatidic acid formed from it, must be transferred to the endoplasmic reticulum for conversion to PtdIns. Plasma membrane also lacked PtdIns kinase. If the soluble PtdIns kinase has access to membrane-bound substrate, PtdIns may be phosphorylated to PtdInsP before or during transport to the plasma membrane. Phosphorylation by the predominantly plasma membrane PtdInsP kinase to form PtdInsP2 completes the cycle. PtdInsP phosphatase was present in all membrane fractions suggesting that PtdInsP can be returned to the PtdIns pool in plasma membrane and elsewhere. PtdInsP2 phosphatase was almost exclusively in the cytosol suggesting that reversible interchange between PtdInsP and PtdInsP2 in the plasma membrane may be modulated by the ability of this phosphatase to act on PtdInsP2 in the membrane. Thus, PtdIns resynthesis in the plasma membrane of these cells does not occur and is not required for phosphoinositide-mediated signal transduction.

Animals↗
PubMed1997

Regulation of phospholipid biosynthetic enzymes by the level of CDP-diacylglycerol synthase activity.

Amine-containing phospholipid synthesis in Saccharomyces cerevisiae starts with the conversion of CDP-diacylglycerol (CDP-DAG) and serine to phosphatidylserine (PS), whereas phosphatidylinositol (PI) is formed from CDP-DAG and inositol (derived from inositol 1-phosphate). In this study the regulation of PS synthase (encoded by CHO1/PSS), PI synthase (encoded by PIS1), and inositol 1-phosphate synthase (encoded by INO1) activities by the in vivo level of CDP-DAG synthase activity (encoded by CDS1) is described. Reduction in the level of CDP-DAG synthase activity from 10-fold over wild type levels to 10% of wild type levels results in a 7-fold increase in PS synthase activity, which follows a similar change in the CHO1/PSS mRNA level. INO1 mRNA also increases but only after CDP-DAG synthase activity falls below the wild type level. PI synthase activity follows the decrease of the CDP-DAG synthase activity, but there is no parallel change in the level of PIS1 mRNA. These changes in CHO1/PSS and INO1 mRNA levels are mediated by a mechanism not dependent on changes in the expression of the INO2-OPI1 regulatory genes. CDS1 expression is repressed in concert with INO2 expression in response to inositol.

CDP-Diacylglycerol-Inositol 3-Phosphatidyltransfer↗
PubMed1983

Phospholipid synthesis in the squid giant axon: enzymes of phosphatidylinositol metabolism.

We examined the properties of several enzymes of phospholipid metabolism in axoplasm extruded from squid giant axons. The following synthetic enzymes, CDP-diglyceride: inositol transferase (EC 2.7.8.11), ATP:diglyceride phosphotransferase, diglyceride kinase (EC 2.7.2.-), and phosphatidylinositol kinase (EC 2.7.1.67), were all present in axoplasm. Phospholipid exchange proteins, which catalyzed the transfer of phosphatidylinositol and phosphatidylcholine between membrane preparations and unilamellar lipid vesicles, were also found. However, we did not find conditions under which the synthesis of CDP-diglyceride, phosphatidylserine, and phosphatidylinositol-4,5-diphosphate could be measured. Subcellular fractionation by differential centrifugation showed that the axoplasmic inositol transferase and phosphatidylinositol kinase activities were largely "microsomal," while the diglyceride kinase and exchange protein activities were primarily "cytosolic."

1-Phosphatidylinositol 4-Kinase↗
PubMed2005

Resveratrol inhibits polyphosphoinositide metabolism in activated platelets.

The effects of resveratrol (trans-3,4',5-trihydroxystilbene) on activation responses and the polyphosphoinositide metabolism in human blood platelets have been studied. Resveratrol partially inhibited secretory responses (liberation of dense granule nucleotides and lysosomal acid hydrolases), microparticle formation and protein phosphorylations induced by thrombin. The effects of resveratrol on phosphoinositide metabolites, phosphatidate (PtdOH), phosphatidylinositol (PtdIns), phosphatidylinositol-4-phosphate (PtdIns-4(5)-P), phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P2), phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P2) and phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3) were monitored in blood platelets prelabelled with [32P]Pi. Resveratrol not only inhibited the marked increase in levels of PtdOH in platelets activated by thrombin (0.1 U/ml) but it decreased the steady state levels of the other polyphosphoinositide metabolites. The distribution of 32P in phosphoinositides in activated platelets was consistent with inhibition of CDP-DAG inositol transferase and a weak inhibition of PtdIns-4(5)-P kinase. These observations show that resveratrol has a profound effect on phospholipids, particularly on polyphosphoinositide metabolism, and may decrease the amount of PtdIns-4,5-P2 available for signalling in these cells.

Blood Platelets↗
PubMed1981

Topography of glycerolipid synthetic enzymes. Synthesis of phosphatidylserine, phosphatidylinositol and glycerolipid intermediates occurs on the cytoplasmic surface of rat liver microsomal vesicles.

The topography of glycerolipid biosynthetic enzymes within the transverse plane of rat liver microsomal vesicles was investigated: (1) by use of the impermeant inhibitor, mercury-dextran; (2) by use of proteases; and (3) by determining whether the enzyme activities are latent. The seven enzyme activities investigated (dihydroxyacetone-phosphate acyltransferase, acyldihydroxyacetone-phosphate oxidoreductase, phosphatidic acid : CTPcytidyltransferase, CDPdiacylglycerol : inositol phosphatidyltransferase, 2-monoacylglycerol acyltransferase, diacylglycerol kinase, and the serine base exchange enzyme) function in phosphatidylinositol and phosphatidylserine synthesis and at intermediate levels in glycerolipid synthesis including steps of ether lipid synthesis. Mercury-dextran inhibited four of these enzymes greater than 60% in intact microsomal vesicles. One or more of the proteases employed (chymotrypsin, trypsin and pronase) inactivated each of the seven enzyme activities in intact microsomal vesicles. These two approaches indicate that each of these enzymes has important domains located on the cytoplasmic surface of microsomal vesicles. These enzyme activities could be assayed in intact microsomal vesicles. None appeared to be highly latent, indicating that substrates have free access to active sites. One substrate for each of these enzymes had been shown previously to be unable to cross the microsomal membrane. These data indicate that the active sites of these enzymes are located on the cytoplasmic surface of microsomal vesicles. It is concluded that the synthesis of phosphatidylserine and phosphatidylinositol, intermediates of ether lipid formation and other intermediates of glycerolipid synthesis occur asymmetrically on the cytoplasmic surface of the endoplasmic reticulum. These findings and our previous investigations on the topography of seven enzymes of triacylglycerol, phosphatidylcholine and phosphatidylethanolamine biosynthesis (Ballas, L.M. and Bell, R.M., Biochim. Biophys. Acta 602, (1980) 578-590) indicate that the synthesis of the major cellular glycerolipids occurs asymmetrically on the cytoplasmic surface of the endoplasmic reticulum.

Acyltransferases↗
PubMed1984

Incorporation of serine into the phospholipids of phosphatidylethanolamine-depleted Tetrahymena.

Phosphatidylserine formation and decarboxylation are decreased in Tetrahymena in which phosphatidylethanolamine has been replaced by its isosteric analog 3-aminopropylphosphonolipid (1,2-diacylglyceryl-3-O-(3-aminopropylphosphonate). The combined activity of the phosphatidylethanolamine: serine phosphatidyltransferase/ phosphatidylserine decarboxylase complex in isolated mitochondria from lipid-altered cells [J. D. Smith and D. A. Giegel (1981) Arch. Biochem, Biophys. 206, 420-423] is about 20% of the activity in mitochondria from control cells. The enzyme activity in the lipid-altered mitochondria is stimulated by the addition of exogenous phosphatidylethanolamine to the assay system while the enzymes of the control mitochondria are not. In vivo the lipid-altered cells are able to incorporate radioactivity from [3-14C]- or [3-3H]serine into phosphatidylserine and phosphatidylcholine in amounts comparable to normal cells. Thus, under conditions of "stress" (e.g., the depletion of phosphatidylethanolamine), the phosphatidyltransferase is apparantly capable of utilizing other phospholipids besides its normal substrate phosphatidylethanolamine.

Animals↗
PubMed1984

Factors regulating the specific activity of galactose-1-phosphate uridyltransferase during perfusion of suckling rat liver.

The regulation of the specific activity of galactose-1-phosphate uridyltransferase (E.C.2.7.7.12) has been studied using the hexose-perfused suckling rat liver as a model. Perfusion in the recirculating mode with galactose concentrations up to 4mM resulted in enzyme activity which fluctuated significantly during a 90-min experimental period. A concentration of 10 mM galactose stabilized the enzyme activity at levels found in unperfused liver. The same stabilizing effect was seen with 10 mM glucose. The elevated transferase specific activity observed after 30 min recirculating perfusion was not seen when the nonrecirculation mode was employed suggesting a factor in the recirculating medium may mediate this effect.

Animal Population Groups↗
PubMed1996

Progesterone triggers the rapid activation of phospholipase D in the amphibian oocyte plasma membrane when initiating the G2/M transition.

Previous reports indicate that, in the Rana pipiens oocyte, progesterone triggers a rapid rise in 1,2-diacylglycerol (DAG) derived from phosphatidylcholine (PC) in the plasma membranes. This DAG transient, which appears and is terminated within 60-90 s, is derived both from a phospholipase which we assumed to be phospholipase C and from sphingomyelin (SM) synthase. We now find that progesterone stimulates PC and DAG turnover primarily via the phospholipase D (PLD) and phosphatidic acid phosphohydrolase (PAP) pathways as well as via the SM-ceramide pathway. Rana oocytes were prelabeled with [3H]choline chloride under conditions in which about 70% is incorporated into PC of the plasma membrane of the intact oocyte or with [3H]lysoplatelet activating factor (1-O-octadecyl-sn-glycero-3-phosphocholine, lysoPAF) which is selectively incorporated into plasma membrane PC. Progesterone induced the release of [3H]choline from intact oocytes into the medium within 60-90 s. This choline release was dose-dependent and was not inhibited by a putative PC-specific phospholipase C inhibitor, D609. Progesterone also induced a transient rise in [3H]lysoPAF-derived [3H]DAG within 1-2 min followed by a rise in [3H]PA. In the presence of 20 mM ethanol, progesterone stimulated formation of [3H]lysoPAF-derived phosphatidylethanol, indicating progesterone activation of PC-specific PLD and concomitant formation of PA. A DGK inhibitor (D102) reduced the level of [3H]PA, produced a sustained rise in [3H]DAG and was a weak inducer of meiosis in oocytes not exposed to progesterone. A PA phosphohydrolase inhibitor (propranolol) elevated [3H]PA and completely inhibited the progesterone-induced rise in DAG. Progesterone thus acts at oocyte plasma membrane receptors to release PC-derived DAG via both SM synthase and PC-PLD. The duration of the DAG signal is regulated by the coordinate action of DGK and PAP.

Animals↗
PubMed1995

[I-cell disease and pseudo-Hurler polydystrophy].

I-cell disease (ML II) and pseudo-Hurler poly-dystrophy (ML-III) are lysosomal storage diseases caused by abnormal lysosomal enzyme phosphorylation and localization. In both diseases, newly synthesized lysosomal enzymes are secreted into the extra-cellular medium instead of being targeted correctly to lysosomes. All cells and tissues of affected medium instead of being targeted correctly to lysosomes. All cells and tissues of affected patients are deficient in UDP-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase activity. However, we have demonstrated that liver cells from ML II patients have normal lysosomal enzyme contents. In Japan, ML II is a relatively common disorder whereas ML III is very rare as compared to Western Countries. The natural history of 21 cases with ML II, as well as 5 prenatally diagnosed cases of ML II, have been reported by our research group.

Female↗
PubMed1994

Enhancement of CDP-DG:inositol transferase activity in src- and erbB2-transformed cells.

Phosphatidylinositol (PI) synthesis was activated in Rous sarcoma virus-infected NIH3T3 or activated erbB2-transformed NIH3T3 cells. The in vitro activity of CDP-DG:inositol transferase prepared from these cells was also higher than that from normal parent NIH3T3 cells, although phospholipase C and PI kinase activities were not significantly different among these cells. A tyrosine kinase inhibitor, erbstatin, inhibited the PI synthesis in cultured cells, suggesting that Src and ErbB2-associated tyrosine kinases are involved in activation of CDP-DG:inositol transferase in these cell lines.

1-Phosphatidylinositol 4-Kinase↗
PubMed1995

Isolation and biological activities of signal transduction inhibitors from microorganisms and plants.

Microorganisms and plants are treasuries of secondary metabolites having unique structures and biological activities. We have isolated inhibitors of cellular signal transduction from them. Phosphatidylinositol turnover inhibitors include inostamycin, piericidins and echiguanines. Erbstatin and lavendustin A were isolated as tyrosine kinase inhibitors, and dephostatin was isolated as a tyrosine phosphatase inhibitor. Recently, we have isolated a new vinca alkaloid having anti-ras activity. These signal transduction inhibitors will be useful for mechanistic studies and suppression of cancer.

1-Phosphatidylinositol 4-Kinase↗
PubMed2002

Cardiolipin and apoptosis.

Cardiolipin (CL) is recognized to be an essential phospholipid in eukaryotic energy metabolism so that physiological and pathological perturbations in its synthetic and catabolic pathways play key roles in maintaining mitochondrial structure and function, and ultimately cell survival. This review describes potential regulatory mechanisms in CL synthesis and the effects of de-acylation pathways on steady state levels of CL and its interaction with cytochrome c. The latter interaction is significant in the initiation of programmed cell death. Physiological factors that modify CL acylation include ageing, dietary influences and ischemia/reperfusion where the terminal events may be either necrosis or apoptosis. In various pathologies, phospholipase activity increases in response to production of peroxidized CL. The cell may use lysosomal or mitochondrial pathways for CL degradation. However, the manner by which CL and cytochrome c leave the mitochondria is not well understood. The lipid (CL)-bound form of cytochrome c is thought to initiate apoptosis via a lipid transfer step involving mitochondrially targeted Bid. A direct relationship between CL loss and cytochrome c release from the mitochondria has been identified as an initial step in the pathway to apoptosis. An absolute requirement for CL in the function of crucial mitochondrial proteins, e.g., cytochrome oxidase and the adenine nucleotide translocase, are likely additional factors impacting apoptosis and cellular energy homeostasis. This is reflected in the occurrence of both oncotic and apoptotic events in ischemia and reperfusion injury. Other potential clinical manifestations of perturbations of CL synthesis are discussed with particular emphasis on Barth Syndrome where a primary defect can be attributed to CL metabolism and is associated with dilated cardiomyopathy. Finally, the model of fatty acid induced apoptosis is used as a paradigm to our understanding of the temporal relationship between decreased mitochondrial CL, release of cytochrome c, and initiation of apoptosis.

Acylation↗
PubMed2004

Sequence-specific assignments of methyl groups in high-molecular weight proteins.

A new 3D multiple-quantum (H)CCmHm-TOCSY experiment is proposed to assign methyl resonances in high-molecular weight proteins, on the basis of spectral patterns and prior backbone assignments. The favorable relaxation properties of the multiple-quantum coherences and the slow decays of in-phase methyl 13C magnetizations optimize performance of the proposed experiment for application to large proteins. The experiment has been demonstrated on an acyl carrier protein synthase (trimer, 42 kDa, overall correlation time of 26 ns) at 25 degrees C, and 63 out of 67 nonmethionine methyl groups have been assigned.

Carbon Isotopes↗
PubMed1993

Glycogen contains phosphodiester groups that can be introduced by UDPglucose: glycogen glucose 1-phosphotransferase.

Rabbit-muscle glycogen contains covalently bound phosphorus, equivalent to 1 phosphate group per 208 glucose residues. This often disputed, minor component was previously thought to represent a phosphomonoester group at C-6 of a glucose residue. Here we show that more than half the phosphorus is present as a phosphodiester, the remainder being monoester. A novel enzyme activity has been found in muscle that can account for the presence of the phosphodiester in glycogen. This is a UDPglucose: glycogen glucose 1-phosphotransferase that positions glucose 1-phosphate on C-6 of glucose residues in glycogen, forming a diester. The phosphomonoester groups present may arise by removal of the glucose residue originally transferred as glucose 1-phosphate.

Animals↗