-
Glycoconjugate Journal Jan 2013In the majority of congenital disorders of glycosylation, the assembly of the glycan precursor GlcNAc(2)Man(9)Glc(3) on the polyprenol carrier dolichyl-pyrophosphate is... (Review)
Review
In the majority of congenital disorders of glycosylation, the assembly of the glycan precursor GlcNAc(2)Man(9)Glc(3) on the polyprenol carrier dolichyl-pyrophosphate is compromised. Because N-linked glycosylation is essential to life, most types of congenital disorders of glycosylation represent partial losses of enzymatic activity. Consequently, increased availability of substrates along the glycosylation pathway can be beneficial to increase product formation by the compromised enzymes. Recently, we showed that increased dolichol availability and improved N-linked glycosylation can be achieved by inhibition of squalene biosynthesis. This review summarizes the current knowledge on the biosynthesis of dolichol-linked glycans with respect to deficiencies in N-linked glycosylation. Additionally, perspectives on therapeutic treatments targeting dolichol and dolichol-linked glycan biosynthesis are examined.
Topics: Carbohydrate Sequence; Congenital Disorders of Glycosylation; Dolichol Phosphates; Dolichols; Glycosylation; Humans; Polysaccharides
PubMed: 22717794
DOI: 10.1007/s10719-012-9417-y -
Journal of Inherited Metabolic Disease Jan 2015Congenital disorders of glycosylation (CDG) comprise a group of inborn errors of metabolism with abnormal glycosylation of proteins and lipids. Patients with defective... (Review)
Review
Congenital disorders of glycosylation (CDG) comprise a group of inborn errors of metabolism with abnormal glycosylation of proteins and lipids. Patients with defective protein N-glycosylation are identified in routine metabolic screening via analysis of serum transferrin glycosylation. Defects in the assembly of the dolichol linked Glc(3)Man(9)GlcNAc(2) glycan and its transfer to proteins lead to the (partial) absence of complete glycans on proteins. These defects are called CDG-I and are located in the endoplasmic reticulum (ER) or cytoplasm. Defects in the subsequent processing of protein bound glycans result in the presence of truncated glycans on proteins. These defects are called CDG-II and the enzymes involved are located mainly in the Golgi apparatus. In recent years, human defects have been identified in dolichol biosynthesis genes within the group of CDG-I patients. This has increased interest in dolichol metabolism, has resulted in specific recognizable clinical symptoms in CDG-I and has offered new mechanistic insights in dolichol biosynthesis. We here review its biosynthetic pathways, the clinical and biochemical phenotypes in dolichol-related CDG defects, up to the formation of dolichyl-P-mannose (Dol-P-Man), and discuss existing evidence of regulatory networks in dolichol metabolism to provide an outlook on therapeutic strategies.
Topics: Animals; Congenital Disorders of Glycosylation; Cytoplasm; Dolichols; Endoplasmic Reticulum; Glycosylation; Golgi Apparatus; Humans; Mice; Oxidoreductases; Phenotype; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 25270028
DOI: 10.1007/s10545-014-9760-1 -
Biochemistry and Cell Biology =... Jun 1992Dolichol, a homologous series of alpha-saturated polyisoprenoid alcohols containing 14-24 isoprene units, was first isolated and characterized about 30 years ago. The... (Review)
Review
Dolichol, a homologous series of alpha-saturated polyisoprenoid alcohols containing 14-24 isoprene units, was first isolated and characterized about 30 years ago. The phosphorylated form, dolichyl phosphate, is required for the biosynthesis of biologically important N-linked glycoproteins. Dolichol itself is synthesized by a common isoprenoid pathway from acetate and synthesis can be inhibited by some of the factors that inhibit cholesterol biosynthesis. It is metabolized very slowly and accumulates in tissues during aging and in certain lipid storage diseases. Dolichyl phosphate and cholesterol also accumulate in tissues during aging, but to a lesser extent than dolichol. Although dolichol and cholesterol have important metabolic functions, their accumulation in tissues can have deleterious effects.
Topics: Adult; Aging; Animals; Dolichols; Glycoproteins; Glycosylation; Humans; Infant, Newborn; Mice; Organ Specificity; Protein Processing, Post-Translational; Rats
PubMed: 1449704
DOI: 10.1139/o92-059 -
Biochemistry and Cell Biology =... Jun 1992Dolichols were first described about 30 years ago when animal tissues were being examined for the presence of a putative precursor to the polyisoprenoid side chain of... (Review)
Review
Dolichols were first described about 30 years ago when animal tissues were being examined for the presence of a putative precursor to the polyisoprenoid side chain of ubiquinone. These long-chain 2,3-dihydro-polycis-isoprenoid alcohols are found in all eukaryotic organisms. In many plant tissues they are accompanied by families of other polyisoprenoid alcohols that are usually similar molecules and possess an unsaturated alpha-isoprene residue. Analogy with the role of bactoprenyl phosphates in the synthesis of bacterial wall glycans led to the discovery that the mono- and di-phosphates of dolichols function as cofactors in protein N-glycosylation, involving the formation of glycosylated derivatives of dolichol as intermediates. Variation of the concentration of dolichyl phosphate was shown to be one way of controlling protein N-glycosylation. This can be achieved by modification of the relative activities of dolichol kinase and dolichol phosphate phosphatase. Modulation of the biosynthetic pathway, still not fully understood, of dolichyl phosphate may also be an important factor. Several disease conditions involve aberrations in these pathways.
Topics: Carbohydrate Sequence; Dolichol Phosphates; Dolichols; Glycosylation; History, 20th Century; Humans; Kidney; Molecular Sequence Data; Plants; Protein Processing, Post-Translational
PubMed: 1449703
DOI: 10.1139/o92-058 -
FEMS Yeast Research Aug 2002Dolichol, an isoprenoid lipid, known mainly for its function in protein glycosylation, is synthesised in the mevalonate pathway. The pathway is highly regulated, on... (Review)
Review
Dolichol, an isoprenoid lipid, known mainly for its function in protein glycosylation, is synthesised in the mevalonate pathway. The pathway is highly regulated, on multiple levels, by sterol and non-sterol derivatives of mevalonic acid. Farnesyl diphosphate (FPP) and/or FPP-derived molecules have been identified as the main non-sterol compounds regulating degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, one of the regulatory enzymes in the mevalonate pathway. In the present review we concentrate on the effect of overexpression of farnesyl diphosphate synthase on dolichol biosynthesis in yeast. In this context the role of the Yta7 protein, belonging to the AAA ATPase family, in the regulation of FPP flux to the dolichol branch of the mevalonate pathway is discussed, and the effect of FPP and/or derived molecules on the transcription of genes encoding the first enzyme committed to dolichol biosynthesis, i.e. cis-prenyl transferase.
Topics: Alkyl and Aryl Transferases; Dolichols; Gene Expression Regulation, Fungal; Geranyltranstransferase; Saccharomyces cerevisiae
PubMed: 12702274
DOI: 10.1016/S1567-1356(02)00110-1 -
Advances in Experimental Medicine and... 2023De novo synthesis of dolichol (Dol) and dolichyl phosphate (Dol-P) is essential for protein glycosylation. Herein, we provide a brief overview of Dol and Dol-P synthesis... (Review)
Review
De novo synthesis of dolichol (Dol) and dolichyl phosphate (Dol-P) is essential for protein glycosylation. Herein, we provide a brief overview of Dol and Dol-P synthesis and the maintenance of their cellular content. Retinal Dol metabolism and the requirement of Dol-linked oligosaccharide synthesis in the neural retina also are discussed. There are recently discovered and an emerging class of rare congenital disorders that affect Dol metabolism, involving the genes DHDDS, NUS1, SRD5A3, and DOLK. Further understanding of these congenital disorders is evolving, based upon studies utilizing yeast and murine models, as well as clinical reports of these rare disorders. We summarize the known visual deficits associated with Dol metabolism disorders, and identify the need for generation and characterization of suitable animal models of these disorders to elucidate the underlying molecular and cellular mechanisms of the associated retinopathies.
Topics: Animals; Mice; Dolichols; Glycosylation; Oligosaccharides; Retina; Saccharomyces cerevisiae
PubMed: 37440071
DOI: 10.1007/978-3-031-27681-1_66 -
Biochemistry and Cell Biology =... Jun 1992The addition of oligosaccharide to asparagine residues of soluble and membrane-associated proteins in eukaryotic cells involves a polyisoprenoid lipid carrier, dolichol.... (Review)
Review
The addition of oligosaccharide to asparagine residues of soluble and membrane-associated proteins in eukaryotic cells involves a polyisoprenoid lipid carrier, dolichol. In Chinese hamster ovary cells, the major isomer of this polyisoprenol has 19 isoprenyl units, the terminal one being saturated. Our laboratory has developed a procedure to analyze the levels and nature of the cell's dolichyl derivatives. Chinese hamster ovary cells contain predominately activated, anionic dolichol derivatives, such as oligosaccharyl pyrophosphoryldolichol, monoglycosylated phosphoryldolichols, and dolichyl phosphate. Our studies show that in growing cells there is continual synthesis of total dolichol. Also, preliminary data suggest there is no catabolism or secretion of this lipid. The level of dolichyl phosphate did not change significantly under a variety of conditions where the levels of enzyme activities utilizing dolichyl phosphate did change. These results suggested that these enzymes had access to the same pool of dolichyl phosphate and had similar Km values for this lipid.
Topics: Amino Acid Sequence; Animals; Asparagine; CHO Cells; Consensus Sequence; Cricetinae; Cricetulus; Dolichol Phosphates; Dolichols; Glycosylation; Molecular Sequence Data; Phosphorylation; Protein Processing, Post-Translational; Tunicamycin
PubMed: 1449705
DOI: 10.1139/o92-060 -
Biochimie 1993Isolated rat liver peroxisomes contain the complete enzymatic machinery required for the synthesis of both cholesterol and dolichol from farnesyl pyrophosphate.... (Review)
Review
Isolated rat liver peroxisomes contain the complete enzymatic machinery required for the synthesis of both cholesterol and dolichol from farnesyl pyrophosphate. Additionally, the whole or part of the initial portion of the mevalonate pathway between acetyl-CoA and farnesyl pyrophosphate is also present in peroxisomes. Cholesterol and dolichol biosynthesis in peroxisomes is more complete than in ER since peroxisomes contain high concentrations of sterol carrier protein-2, a protein that stimulates both dolichol and cholesterol biosynthesis. Approximately 50 and 20% of the total hepatic dolichol and cholesterol biosynthesis is associated with rat liver peroxisomes, respectively. Upon dietary and drug treatments the synthesis of these lipids displays different regulation in peroxisomes and ER.
Topics: Animals; Carrier Proteins; Cholesterol; Dolichols; Humans; Lipids; Liver; Microbodies; Plant Proteins; Polyisoprenyl Phosphates; Rats; Sesquiterpenes; Sterols
PubMed: 8507678
DOI: 10.1016/0300-9084(93)90074-3 -
Journal of Inherited Metabolic Disease Aug 2011Polyisoprenoid alcohols are membrane lipids that are present in every cell, conserved from archaea to higher eukaryotes. The most common form, alpha-saturated polyprenol... (Review)
Review
Polyisoprenoid alcohols are membrane lipids that are present in every cell, conserved from archaea to higher eukaryotes. The most common form, alpha-saturated polyprenol or dolichol is present in all tissues and most organelle membranes of eukaryotic cells. Dolichol has a well defined role as a lipid carrier for the glycan precursor in the early stages of N-linked protein glycosylation, which is assembled in the endoplasmic reticulum of all eukaryotic cells. Other glycosylation processes including C- and O-mannosylation, GPI-anchor biosynthesis and O-glucosylation also depend on dolichol biosynthesis via the availability of dolichol-P-mannose and dolichol-P-glucose in the ER. The ubiquity of dolichol in cellular compartments that are not involved in glycosylation raises the possibility of additional functions independent of these protein post-translational modifications. The molecular basis of several steps involved in the synthesis and the recycling of dolichol and its derivatives is still unknown, which hampers further research into this direction. In this review, we summarize the current knowledge on structural and functional aspects of dolichol metabolites. We will describe the metabolic disorders with a defect in known steps of dolichol biosynthesis and recycling in human and discuss their pathogenic mechanisms. Exploration of the developmental, cellular and biochemical defects associated with these disorders will provide a better understanding of the functions of this lipid class in human.
Topics: Animals; Congenital Disorders of Glycosylation; Dolichols; Glycosylation; Humans; Metabolic Diseases; Models, Biological; Protein Processing, Post-Translational
PubMed: 21384228
DOI: 10.1007/s10545-011-9301-0 -
The Biochemical Journal Apr 1988
Review
Topics: Animals; Biological Transport; Diterpenes; Dolichol Phosphates; Dolichols; Humans
PubMed: 3291859
DOI: 10.1042/bj2510001