Overview of Dolichol or Dolichyl-phosphate

All tissues of eukaryotic organisms contain dolichol metabolites. In humans, they occur in the form of dolichol (Dol) or dolichol-phosphate (Dol-P). Apart from studies showing that Dol-P is used for protein N-glycosylation in the endoplasmic reticulum, almost all organelle membranes such as Golgi, mitochondria, and lysosomes contain dolichol metabolites. Very limited knowledge is available about the functions of dolichol metabolites in these organelles, such as the role of Dol and Dol-P in regulating the physicochemical properties of lipid bilayers and the protection of cellular lipids against oxidative damage caused by ROS. In recent years, the metabolism of dolichol has gained considerable interest in the context of protein glycosylation, since the physiological consequences of disruptions in this process, especially in congenital disorders of glycosylation (CDG), have been identified. The identification of such genetic defects has led to significant advances in the understanding of the molecular context of dolichol biosynthesis.

Fig.1 Dolichol cycle in the endoplasmic reticulum in humans. (Cantagrel & Lefeber, 2011)

Biosynthesis of Dolichol

In the biosynthetic pathway of Dol-P synthesis, Dolichol in animals and yeast is thought to be the end product of the mevalonate (MVA) pathway. The condensation of three acetyl CoA molecules produces 3-hydroxy-3-methylglutaryl CoA, which is converted to mevalonate by HMG-CoA reductase (HMGR). The combined activity of the three subsequent enzymes leads to the synthesis of isopentyl diphosphate (IPP), a component of isoprenoids. Further condensation of the three IPP molecules leads to the formation of farnesyl diphosphate (FPP), which is considered to be a key branching point in the pathway. It serves as a substrate for four different pathways: (a) squalene synthase, which catalyzes the first step leading to the production of cholesterol; (b) trans-isopentenyltransferase, involved in the synthesis of ubiquinone side chains; (c) protein farnesyltransferase, responsible for the post-translational farnesylation of proteins; (d) cis-isopentenyltransferase, the first specific enzyme of the polyhydroxy compound biosynthetic pathway.

Cis-isopentenyltransferases in yeast and animals use FPP as an initiator and catalyze its subsequent multiple condensations with IPP molecules to form polypentenyl diphosphates of the desired chain length, in effect a mixture of several homologs. The range of IPP amounts added depends on the species. In yeast, the polyhydroxy compound molecule contains 14-18 isoprene units (i.u.). Mammalian cells synthesize longer chains consisting of 18-21 units, and plant roots produce a broad mixture of homologs. Dolichol is further phosphorylated by dolichol kinase, which may then serve as a carrier for mannose and glucose monosaccharides, and further as a donor for N-glycosylation, O- and C-mannosylation, and GPI anchor synthesis. In addition, Dol-P is used as a carrier for the GlcNAc₂Man₉Glc₃ oligosaccharide precursor for protein N-glycosylation. Dol-P-Man is synthesized by Dol-P-Man synthase via the human DPM1-3 protein complex. Dolichyl-P-glucose (Dol-P-Glc) is synthesized by dolichol-phosphate β-glucosyltransferase (ALG5 in humans). synthesis of DolPP-GlcNAc₂Man₉Glc₃ starts on the cytoplasmic side of the ER, after which the intermediate DolPP-GlcNAc₂Man₅ is flipped into the ER lumen by RFT1 to complete the assembly of the oligosaccharide chain. Finally, the fully formed oligosaccharide structure GlcNAc₂Man₉Glc₃ is co-translationally transferred to the asparagine residues of the growing peptide and releases the recovered Dol-PP.

Phenotypes Resulting from Dolichol Biosynthesis Defects

Studies of CDG have increased our understanding of the consequences of defects in the dolichol cycle. Recently, several diseases resulting from defects in bile acid biosynthesis have been described (SRD5A3, DOLK), while other defects are closely related to bile acid metabolism (MPDU1, DPM synthase). In contrast to the disruption of genes strictly involved in the N-glycosylation process, defects in dolichol metabolism are expected to affect several cellular pathways.

Here we describe one of the disorders in the Disorders of Multiple Glycosylation and Other Pathways. CD BioGlyco provides comprehensive and deep insights into disorders of dolichol(-phosphate) synthesis and utilization. We provide various relevant services including but not limited to Custom Complex N-linked Oligosaccharides Synthesis, Custom Glycosylation Service, Custom Carbohydrate Synthesis, Custom Glycosylation of Proteins, Custom Phosphatidylinositol Synthesis. If you are interested in our services, please contact us for more details without any hesitation. 

Reference:

1. Cantagrel, V.; Lefeber, D.J. From glycosylation disorders to dolichol biosynthesis defects: a new class of metabolic diseases. Journal of inherited metabolic disease. 2011, 34(4): 859-867.