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Ziqiang Guan - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE N-Linked Glycans Are Assembled on Highly Reduced Dolichol Phosphate Carriers in the
2016Co-Authors: Hyperthermophilic Archaea Pyrococcus, Jerry Eichler, Michelle M. Chang, Barbara Imperiali, Ziqiang GuanAbstract:In all three domains of life, N-glycosylation begins with the assembly of glycans on phos-phorylated polyisoprenoid carriers. Like eukaryotes, archaea also utilize phosphorylated dolichol for this role, yet whereas the assembled oligosaccharide is transferred to target pro-teins from dolichol pyrophosphate in eukaryotes, archaeal N-linked glycans characterized to date are derived from a dolichol monophosphate carrier, apart from a single example. In this study, glycan-charged dolichol phosphate from the hyperthermophile Pyrococcus furio-sus was identified and structurally characterized. Normal and reverse phase liquid chroma-tography-electrospray ionization mass spectrometry revealed the existence of dolichol phosphate charged with the heptasaccharide recently described in in vitro studies of N-gly-cosylation on this species. As with other described archaeal dolichol phosphates, the α-andω-terminal isoprene subunits of the P. furiosus lipid are saturated, in contrast to eukaryal phosphodolichols that present only a saturated α-position isoprene subunit. Inter-estingly, an additional 1-4 of the 12-14 isoprene subunits comprising P. furiosus dolichol phosphate are saturated, making this lipid not only the longest archaeal dolichol phosphate described to date but also the most highly saturated
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n linked glycans are assembled on highly reduced dolichol phosphate carriers in the hyperthermophilic archaea pyrococcus furiosus
PLOS ONE, 2015Co-Authors: Michelle M. Chang, Jerry Eichler, Barbara Imperiali, Ziqiang GuanAbstract:In all three domains of life, N-glycosylation begins with the assembly of glycans on phosphorylated polyisoprenoid carriers. Like eukaryotes, archaea also utilize phosphorylated dolichol for this role, yet whereas the assembled oligosaccharide is transferred to target proteins from dolichol pyrophosphate in eukaryotes, archaeal N-linked glycans characterized to date are derived from a dolichol monophosphate carrier, apart from a single example. In this study, glycan-charged dolichol phosphate from the hyperthermophile Pyrococcus furiosus was identified and structurally characterized. Normal and reverse phase liquid chromatography-electrospray ionization mass spectrometry revealed the existence of dolichol phosphate charged with the heptasaccharide recently described in in vitro studies of N-glycosylation on this species. As with other described archaeal dolichol phosphates, the α- and ω-terminal isoprene subunits of the P. furiosus lipid are saturated, in contrast to eukaryal phosphodolichols that present only a saturated α-position isoprene subunit. Interestingly, an additional 1-4 of the 12-14 isoprene subunits comprising P. furiosus dolichol phosphate are saturated, making this lipid not only the longest archaeal dolichol phosphate described to date but also the most highly saturated.
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mutation of nogo b receptor a subunit of cis prenyltransferase causes a congenital disorder of glycosylation
Cell Metabolism, 2014Co-Authors: Eon Joo Park, Kariona A Grabinska, Hana Hartmannova, Jana Sovova, Levente Jozsef, Viktor Stránecký, Kateřina Hodaňova, Veronika Baresova, Ziqiang Guan, Nina OndruskovaAbstract:Summary Dolichol is an obligate carrier of glycans for N-linked protein glycosylation, O-mannosylation, and GPI anchor biosynthesis. cis -prenyltransferase ( cis -PTase) is the first enzyme committed to the synthesis of dolichol. However, the proteins responsible for mammalian cis -PTase activity have not been delineated. Here we show that Nogo-B receptor (NgBR) is a subunit required for dolichol synthesis in yeast, mice, and man. Moreover, we describe a family with a congenital disorder of glycosylation caused by a loss of function mutation in the conserved C terminus of NgBR-R290H and show that fibroblasts isolated from patients exhibit reduced dolichol profiles and enhanced accumulation of free cholesterol identically to fibroblasts from mice lacking NgBR. Mutation of NgBR-R290H in man and orthologs in yeast proves the importance of this evolutionarily conserved residue for mammalian cis -PTase activity and function. Thus, these data provide a genetic basis for the essential role of NgBR in dolichol synthesis and protein glycosylation.
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life with too much polyprenol polyprenol reductase deficiency
Molecular Genetics and Metabolism, 2012Co-Authors: J E H Grundahl, N Ortizbruchle, Sabine Rudnikschoneborn, Steven Rust, J. Reunert, I Du Chesne, Klaus Zerres, B Muller, Ziqiang Guan, Martin HäuslerAbstract:Abstract Congenital disorders of glycosylation (CDG) are caused by a dysfunction of glycosylation, an essential step in the manufacturing process of glycoproteins. This paper focuses on a 6-year-old patient with a new type of CDG-I caused by a defect of the steroid 5α reductase type 3 gene (SRD5A3). The clinical features were psychomotor retardation, pathological nystagmus, slight muscular hypotonia and microcephaly. SRD5A3 was recently identified encoding the polyprenol reductase, an enzyme catalyzing the final step of the biosynthesis of dolichol, which is required for the assembly of the glycans needed for N-glycosylation. Although an early homozygous stop-codon (c.57G > A [W19X]) with no functional protein was found in the patient, about 70% of transferrin (Tf) was correctly glycosylated. Quantification of dolichol and unreduced polyprenol in the patient's fibroblasts demonstrated a high polyprenol/dolichol ratio with normal amounts of dolichol, indicating that high polyprenol levels might compete with dolichol for the initiation of N-glycan assembly but without supporting normal glycosylation and that there must be an alternative pathway for dolichol biosynthesis.
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A predicted geranylgeranyl reductase reduces the ω-position isoprene of dolichol phosphate in the halophilic archaeon, Haloferax volcanii.
Biochimica et biophysica acta, 2012Co-Authors: Shai Naparstek, Ziqiang Guan, Jerry EichlerAbstract:Abstract In N-glycosylation in both Eukarya and Archaea, N-linked oligosaccharides are assembled on dolichol phosphate prior to transfer of the glycan to the protein target. However, whereas only the α-position isoprene subunit is saturated in eukaryal dolichol phosphate, both the α- and ω-position isoprene subunits are reduced in the archaeal lipid. The agents responsible for dolichol phosphate saturation remain largely unknown. The present study sought to identify dolichol phosphate reductases in the halophilic archaeon, Haloferax volcanii. Homology-based searches recognize HVO_1799 as a geranylgeranyl reductase. Mass spectrometry revealed that cells deleted of HVO_1799 fail to fully reduce the isoprene chains of H. volcanii membrane phospholipids and glycolipids. Likewise, the absence of HVO_1799 led to a loss of saturation of the ω-position isoprene subunit of C55 and C60 dolichol phosphate, with the effect of HVO_1799 deletion being more pronounced with C60 dolichol phosphate than with C55 dolichol phosphate. Glycosylation of dolichol phosphate in the deletion strain occurred preferentially on that version of the lipid saturated at both the α- and ω-position isoprene subunits.
Gustav Dallner - One of the best experts on this subject based on the ideXlab platform.
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changes in the levels of dolichol and dolichyl phosphate in a murine model of niemann pick s type c disease
Journal of Neurochemistry, 2002Co-Authors: Sophia Schedin, Gustav Dallner, Peter G Pentchev, U BrunkAbstract:The distributions of mevalonate pathway lipids in various organs of a mouse strain used as a model for Niemann-Pick's type C disease were analyzed. Extensive accumulation of cholesterol was observed in all tissues with the exception of the brain, where the content of this lipid was decreased. The changes in total dolichol contents of most organs varied from a 50% decrease in the lung to a twofold increase in kidney and heart. There was relative enrichment of longer-chain dolichols, but no increase in the relative amount of alpha-unsaturated polyprenols was observed. The levels of dolichyl phosphate in all organs were increased, and most of this lipid was associated with bound oligosaccharides or proteins. Ubiquinone levels were largely unchanged. Subfractionation studies revealed that heavy and light lysosomes exhibited a 10-fold increase in cholesterol level, the amount of dolichol was decreased in lysosomes and increased in microsomes, and there was an increase in the dolichyl phosphate levels of all three of these subfractions. These results indicate that in diseased mice cholesterol accumulation in various organs is paralleled by an increase in the dolichyl phosphate concentration, whereas dolichol transport from the endoplasmic reticulum to lysosomes is inhibited.
Ewa Swiezewska - One of the best experts on this subject based on the ideXlab platform.
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the history and recent advances in research of polyprenol and its derivatives
Bioscience Biotechnology and Biochemistry, 2018Co-Authors: Hiroshi Sagami, Ewa Swiezewska, Yoshihiro ShidojiAbstract:AbstractThe reduction pathway leading to the formation of dolichol was clarified in 2010 with the identification of SRD5A3, which is the polyprenol reductase. The finding inspired us to reanalyze the length of the major chain of polyprenol and dolichol from several plant leaves, including mangrove plants, as well as from animal and fish livers by 2D-TLC. Polyprenol- and dolichol-derived metabolites such as polyprenylacetone and epoxydolichol were found together with rubber-like prenol. This review focuses on analyses of polyprenol and its derivatives, including recently found epoxypolyprenol and polyprenylacetone. Attention has also been paid to the chromatographic behavior of rubber-like prenol on TLC.
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polyprenol reductase2 deficiency is lethal in arabidopsis due to male sterility
The Plant Cell, 2015Co-Authors: Adam Jozwiak, Katarzyna Gawarecka, Malgorzata Gutkowska, Liliana Surmacz, Anna Buczkowska, Malgorzata Lichocka, Julita Nowakowska, Ewa SwiezewskaAbstract:Dolichol is a required cofactor for protein glycosylation, the most common posttranslational modification modulating the stability and biological activity of proteins in all eukaryotic cells. We have identified and characterized two genes, PPRD1 and -2, which are orthologous to human SRD5A3 (steroid 5α reductase type 3) and encode polyprenol reductases responsible for conversion of polyprenol to dolichol in Arabidopsis thaliana. PPRD1 and -2 play dedicated roles in plant metabolism. PPRD2 is essential for plant viability; its deficiency results in aberrant development of the male gametophyte and sporophyte. Impaired protein glycosylation seems to be the major factor underlying these defects although disturbances in other cellular dolichol-dependent processes could also contribute. Shortage of dolichol in PPRD2-deficient cells is partially rescued by PPRD1 overexpression or by supplementation with dolichol. The latter has been discussed as a method to compensate for deficiency in protein glycosylation. Supplementation of the human diet with dolichol-enriched plant tissues could allow new therapeutic interventions in glycosylation disorders. This identification of PPRD1 and -2 elucidates the factors mediating the key step of the dolichol cycle in plant cells which makes manipulation of dolichol content in plant tissues feasible.
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srd5a3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder
Cell, 2010Co-Authors: Vincent Cantagrel, Ludwig Lehle, Hans Hombauer, Bobby G Ng, Maciej Adamowicz, Jennifer L Silhavy, Stephanie L Bielas, Dirk Lefeber, Ziqiang Guan, Ewa SwiezewskaAbstract:N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5α-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.
P K Pandey - One of the best experts on this subject based on the ideXlab platform.
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cloning restriction mapping and phylogenetic relationship of genomic components of mymiv from lablab purpureus
Bioresource Technology, 2006Co-Authors: Sudheer Kumar Singh, Swastika Chakraborty, A K Singh, P K PandeyAbstract:The present work describes cloning of genomic components of whitefly transmitted geminivirus infecting Lablab purpureus syn. Dolichos lablab (commonly known as Dolichos bean or Hyacinth bean). The genome characterization using PCR with geminiviral degenerate primers and DNA sequencing were used to describe the bipartite virus associated with yellow mosaic disease of Dolichos lablab. Full-length DNA-A and DNA-B clones were obtained. The DNA-A sequence analysis showed that the isolate was similar to other Mungbean yellow mosaic India virus (MYMIV) isolates reported earlier. The nucleotide sequence analysis of the full-length DNA-A of virus isolate revealed more than 97% homology with Mungbean yellow mosaic India virus-[Cowpea] (AF481865), while the DNA-B also showed >95% homology with MYMIV-[Cp] (AF503580) and MYMIV-[Sb] (AY049771). The phylogenetic analysis of present isolate showed close relationship to legume geminiviruses. The nucleotide sequence analysis showed presence of six open reading frames (ORFs) in DNA-A, with 2 ORFs aligned in sense and 4 ORFs in antisense orientation. Similarly, DNA-B contained two open reading frames (ORFs), one in sense and another in antisense orientation.
Mateusz Juchimiuk - One of the best experts on this subject based on the ideXlab platform.
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candida albicans cis prenyltransferase rer2 is required for protein glycosylation cell wall integrity and hypha formation
Fungal Genetics and Biology, 2014Co-Authors: Mateusz Juchimiuk, Jacek Orlowski, Katarzyna Gawarecka, Ewa świezewska, Joachim F Ernst, Grazyna PalamarczykAbstract:cis-Prenyltransferase is the first enzyme of the mevalonate pathway committed to the biosynthesis of dolichol in eukaryotes. The RER2 gene encoding cis-prenyltransferase (Rer2p) in the human fungal pathogen Candida albicans was characterized. In addition, the ORF19.5236 encoding the second cis-prenyltransferase, which putatively is responsible for the synthesis of longer polyisoprenoids chains, was identified. When cultivated under repressive conditions, the conditional mutant strain expressing the RER2 gene from the regulatable MET3 promoter contained only 4% of cis-prenyltransferase activity and markedly diminished amounts of dolichols, as compared to the wild-type strain. Moreover, transcriptomal analyses revealed changes in the expression of 300 genes, mainly involved in transport, response to stress, filamentous growth and organelle organization. Growth of the conditional strain was blocked completely at 37 °C. The strain was hypersensitive to a wide range of inhibitors, which suggested glycosylation defects and compromised cell wall integrity. Moreover, the rer2 conditional mutant grown in the repressive conditions, unlike the same strain in the absence of repressor, failed to form hyphae. The results indicate that dolichols are essential not only for protein glycosylation and cell wall integrity but also for growth and development of C. albicans.