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Dolichol refers to any of a group of long-chain mostly unsaturated
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The s ...
s that are made up of varying numbers of
isoprene Isoprene, or 2-methyl-1,3-butadiene, is a common volatile organic compound with the formula CH2=C(CH3)−CH=CH2. In its pure form it is a colorless volatile liquid. Isoprene is an unsaturated hydrocarbon. It is produced by many plants and animals ...
units terminating in an α-saturated isoprenoid group, containing an
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of se ...
functional group.


Functions

Dolichols play a role in the co-translational modification of proteins known as ''N''-glycosylation in the form of dolichol
phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from pho ...
. Dolichols function as a membrane anchor for the formation of the
oligosaccharide An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sugar ...
Glc3-Man9-GlcNAc2 (where Glc is
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
, Man is
mannose Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylation ar ...
, and GlcNAc is ''N''-acetylglucosamine). This oligosaccharide is transferred from the dolichol donor onto certain
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
residues (onto a specific sequence that is "Asn-X-Ser/Thr") 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 Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribos ...
, 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 Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
in the
rough endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
. Dolichols are the major lipid component (14% by mass) of human substantia nigra (SN)
neuromelanin Neuromelanin (NM) is a dark pigment found in the brain which is structurally related to melanin. It is a polymer of 5,6-dihydroxyindole monomers. Neuromelanin is found in large quantities in catecholaminergic cells of the substantia nigra pars c ...
. 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 The human brain is the central organ of the human nervous system, and with the spinal cord makes up the central nervous system. The brain consists of the cerebrum, the brainstem and the cerebellum. It controls most of the activities of the ...
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 A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
, 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 The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes", ...
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 Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term ''progeroid syndrome'' does not necessarily imply progeria (Hutchinson–Gilford ...
. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of
glycosylation Glycosylation is the reaction in which a carbohydrate (or 'glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not a ...
in the diseased brain, and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...
, for instance, induced by
lipid peroxidation Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chai ...
.


Synthesis

Dolichol is a product of the
HMG-CoA reductase pathway The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl ...
(also known as the
mevalonate Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonate ...
pathway), and as such their creation and availability are affected by mevalonate inhibition. First, a cis (or Z) -prenyltransferase ( Dehydrodolichyl diphosphate synthase in humans) catalyzes the condensation of farnesyl diphosphate (FPP) with a varying number (dependent on the particular cis-prenyltransferase) of isopentenyl diphosphate (IPP) molecules, resulting in the formation of a polyprenyl diphosphate (also known as dehydrodolichyl diphosphate). This subsequently undergoes loss of both phosphate groups, resulting in a polyprenol (dehydrodolichol). Lastly, the α isoprenoid unit is saturated by α-saturase (still a hypothetical enzyme), and this α-saturated polyprenyl alcohol is known as dolichol.


Other

Dolichols are found in eukaryotes and in archaea, although similar
polyprenol Polyprenols are natural long-chain isoprenoid alcohols of the general formula H-(C5H8)n-OH where n is the number of isoprene units. Any prenol with more than 4 isoprene units is a polyprenol. Polyprenols play an important function acting as natura ...
s 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 Solagran Limited is an Australian pharmaceutical company which has developed a range of biologically active therapeutic substances derived from the live elements of the green needles of certain species of conifer tree known as ''Bioeffectives ...
has been investigating the medical significance of
polyprenol Polyprenols are natural long-chain isoprenoid alcohols of the general formula H-(C5H8)n-OH where n is the number of isoprene units. Any prenol with more than 4 isoprene units is a polyprenol. Polyprenols play an important function acting as natura ...
s and their substitution with dolichols when ingested where there is a deficiency. Trials of Ropren (already pharmaceutically registered as a hepatoprotector) in relation to neurodegenerative diseases (including Alzheimer's disease) in both Russia and AustraliaCompany announcement
21 February 2007. indicate considerable potential as a safe and effective treatment.


See also

* Dolichol kinase *
Polyprenol Polyprenols are natural long-chain isoprenoid alcohols of the general formula H-(C5H8)n-OH where n is the number of isoprene units. Any prenol with more than 4 isoprene units is a polyprenol. Polyprenols play an important function acting as natura ...
s *
Solagran Solagran Limited is an Australian pharmaceutical company which has developed a range of biologically active therapeutic substances derived from the live elements of the green needles of certain species of conifer tree known as ''Bioeffectives ...
* Mevalonate inhibition#Dolichol Inhibition


References

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External links


Overview
at
Birkbeck, University of London , mottoeng = Advice comes over nightTranslation used by Birkbeck. , established = , type = Public research university , endowment = £4.3 m (2014) , budget = £109 ...
Cell biology Alkene derivatives Primary alcohols Fatty alcohols Terpenes and terpenoids