Abstract
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 Glc3Man9GlcNAc2 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.
Highlights
Congenital disorders of glycosylation (CDG) comprise a group of inborn errors of metabolism with abnormal glycosylation of proteins and lipids
Further condensation of three isopentyl diphospate (IPP) molecules results in formation of farnesyl diphosphate (FPP), which is considered as a critical branch-point of the pathway
It serves as substrate for four different pathways: squalene synthase that catalyzes the first step leading to production of cholesterol, transprenyltransferase involved in ubiquinone side-chain synthesis, protein farnesyltransferase responsible for posttranslational farnesylation of proteins and cis-prenyltransferase, the first specific enzyme in dolichol biosynthesis pathway
Summary
Congenital disorders of glycosylation (CDG) comprise a group of inborn errors of metabolism with abnormal glycosylation of proteins and lipids. Dolichol metabolism gained considerably increased interest in the context of protein glycosylation due to the identified physiological consequences of disruptions in this process, especially in the congenital disorders of glycosylation (CDG). Identification of such gene defects resulted in. Further condensation of three IPP molecules results in formation of farnesyl diphosphate (FPP), which is considered as a critical branch-point of the pathway It serves as substrate for four different pathways: squalene synthase that catalyzes the first step leading to production of cholesterol, transprenyltransferase involved in ubiquinone side-chain synthesis, protein farnesyltransferase responsible for posttranslational farnesylation of proteins and cis-prenyltransferase, the first specific enzyme in dolichol biosynthesis pathway
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