Dolichol


Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol functional group.

Functions

Dolichols play a role in the co-translational modification of proteins known as N-glycosylation in the form of dolichol phosphate. Dolichols function as a membrane anchor for the formation of the oligosaccharide Glc3-Man9-GlcNAc2. This oligosaccharide is transferred from the dolichol donor onto certain asparagine residues of newly forming polypeptide chains. Dolichol is also involved in transfer of the monosaccharides to the forming Glc3-Man9-GlcNAc2-Dolichol carrier.
In addition, dolichols can be adducted to proteins as a posttranslational modification, a process in which branched carbohydrate trees are formed on a dolichol moiety and then transferred to an assembly of proteins to form a large glycoprotein in the rough endoplasmic reticulum.
Dolichols are the major lipid component of human substantia nigra neuromelanin.
Dolichol phosphate was discovered at the University of Liverpool in the 1960s, although researchers did not know its function at the time of discovery.

Role in aging

Dolichol has been suggested to be used as a biomarker for aging. During aging, the human brain shows a progressive increase in levels of dolichol, a reduction in levels of ubiquinone, but relatively unchanged concentrations of cholesterol and dolichyl phosphate. In the neurodegenerative disease Alzheimer's disease, the situation is reversed, with decreased levels of dolichol and increased levels of ubiquinone. The concentrations of dolichyl phosphate are also increased, while cholesterol remains unchanged. The isoprenoid changes in Alzheimer's disease differ from those occurring during normal aging, and, therefore, this disease cannot be regarded as a result of premature aging. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of glycosylation in the diseased brain, and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from oxidative stress, for instance, induced by lipid peroxidation.

Synthesis

Dolichol is a product of the HMG-CoA reductase pathway, and as such their creation and availability are affected by mevalonate inhibition. First, a cis -prenyltransferase catalyzes the condensation of farnesyl diphosphate with a varying number of isopentenyl diphosphate molecules, resulting in the formation of a polyprenyl diphosphate. This subsequently undergoes loss of both phosphate groups, resulting in a polyprenol. Lastly, the α isoprenoid unit is saturated by α-saturase, and this α-saturated polyprenyl alcohol is known as dolichol.

Other

Dolichols are found in eukaryotes and in archaea, although similar polyprenols molecules are found in bacteria. Polyprenols in bacteria do not contain an α-saturated isoprenoid and are typically smaller in terms of isoprenoid units or carbon length. Polyprenols perform similar functions within bacteria; that is, they function as glycosyl carrier lipids involved in formation of complex branched polysaccharide. However, the cellular process they are involved in is not glycosylation, but instead cell wall biosynthesis. Statins decrease dolichol levels in the body.

Medical Significance

The Australian pharmaceutical company Solagran has been investigating the medical significance of polyprenols and their substitution with dolichols when ingested where there is a deficiency. Trials of Ropren in relation to neurodegenerative diseases in both Russia and Australia indicate considerable potential as a safe and effective treatment.