From glycosylation disorders to dolichol biosynthesis defects: a new class of metabolic diseases

Abstract

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.

Fig. 1

Dolichol cycle in the endoplasmic reticulum in human. The Dol-P pool available for glycosylation reactions originates from de novo synthesis of dolichol phosphate and its recycling from the lumenal leaflet to the cytoplasmic leaflet of the ER. Cellular functions of dolichol are indicated including known functions in N-glycosylation (1–2), O-mannosylation (3), GPI-anchor biosynthesis (4) and suspected effects on membrane biophysical properties (5–6). Abbreviations: FPP, farnesyl pyrophosphate; DHDDS, dehydrodolichyl diphosphate synthase; SRD5A3, steroid 5-alpha reductase 3; DOLK, dolichol kinase; DPM1-3, dolichyl-phosphate mannosyltransferase polypeptide 1–3; MDPU1, mannose-P-dolichol utilization defect 1; ALG5, asparagine-linked glycosylation 5; DOLPP1, dolichyl pyrophosphate phosphatase 1; LLO, lipid-linked oligosaccharide

Fig. 2

De novo biosynthesis of dolichol phosphate in human. Polyisoprenoids are generated by the condensation of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), the 5-carbon building blocks of all isoprenoids. The mevalonate pathway is responsible for the synthesis of IPP and DMAPP. The first step dedicated to dolichol biosynthesis is the elongation of farnesyl pyrophosphate by the dehydrodolichyl diphosphate synthase (DHDDS) . This cis-prenyl transferase uses IPP as substrates to produce polyprenol pyrophosphate. It is believe that this polyprenol pyrophosphate is then dephosphorylated into polyprenol before its reduction by SRD5A5. Finally, the dolichol kinase (DOLK) transfers a phosphate from CTP to dolichol