Dolichol
Encyclopedia
Dolichol refers to any of a group of long-chain mostly unsaturated
organic compound
s that are made up of varying numbers of isoprene
units terminating in an α-saturated isoprenoid group, containing an alcohol
functional group.
in the form of dolichol phosphate
. Dolichols function as a membrane anchor for the formation of the oligosaccharide
Glc3-Man9-GlcNAc2 (where Glc is glucose
, Man is mannose
, and GlcNAc is N-acetylglucosamine
). 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 protein
s 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 (14% by mass) of human substantia nigra (SN) neuromelanin.
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. This study http://www.ncbi.nlm.nih.gov/pubmed/7950967 shows that 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
.
(also known as the mevalonate pathway), and as such their creation and availability are affected by mevalonate inhibition
. First, a cis (or Z) -prenyltransferase catalyzes the condensation of farnesyl diphosphate (FPP) with a varying number (dependent on the particular cis-prenyltransferase) of isopentenyl diphoshate (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). Last, the α isoprenoid unit is saturated by α-saturase (still a hypothetical enzyme), and this α-saturated polyprenyl alcohol is known as dolichol.
s molecules are found in other organisms including bacteria. Polyprenol
s in bacteria do not contain an α-saturated isoprenoid and are typically smaller in terms of isoprenoid units or carbon length. Polyprenol
s perform similar functions within bacteria; that is, they function as glycosyl carrier lipids involved in formation of complex branched polysacharide. However, the cellular process they are involved in is not glycosylation, but instead cell wall biosynthesis .
has been investigating the medical significance of polyprenol
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 http://www.asx.com.au/asxpdf/20050920/pdf/3sd7g0mczqbnc.pdf and Australia http://www.asx.com.au/asxpdf/20070221/pdf/3111ztwcbqzkk9.pdf indicate considerable potential as a safe and effective treatment.
Unsaturated compound
In organic chemistry, a saturated compound is a chemical compound that has of a chain of carbon atoms linked together by single bonds and has hydrogen atoms filling all of the other bonding orbitals of the carbon atoms. Alkanes are an example of saturated compounds...
organic compound
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
s that are made up of varying numbers of isoprene
Isoprene
Isoprene , or 2-methyl-1,3-butadiene, is a common organic compound with the formula CH2=CCH=CH2. Under standard conditions it is a colorless liquid...
units terminating in an α-saturated isoprenoid group, containing an alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
functional group.
Functions
Dolichols play a role in the co-translational modification of proteins known as N-glycosylationGlycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
in the form of dolichol phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
. Dolichols function as a membrane anchor for the formation of the oligosaccharide
Oligosaccharide
An oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...
Glc3-Man9-GlcNAc2 (where Glc is glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
, Man is mannose
Mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. Mannose is a C-2 epimer of glucose. It is not part of human metabolism, but is a component of microbial cell walls, and is therefore a target of the immune system and also of antibiotics....
, and GlcNAc is N-acetylglucosamine
N-Acetylglucosamine
N-Acetylglucosamine is a monosaccharide derivative of glucose. It is an amide between glucosamine and acetic acid...
). This oligosaccharide is transferred from the dolichol donor onto certain asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
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 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s as a posttranslational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
, 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
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
in the rough endoplasmic reticulum.
Dolichols are the major lipid component (14% by mass) of human substantia nigra (SN) neuromelanin.
Role in aging
Dolichol has been suggested to be used as a biomarker for aging. During aging, the human brainHuman brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
shows a progressive increase in levels of dolichol, a reduction in levels of ubiquinone, but relatively unchanged concentrations of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
and dolichyl phosphate. In the neurodegenerative disease Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, the situation is reversed, with decreased levels of dolichol and increased levels of ubiquinone. The concentrations of dolichyl phosphate are also increased, while cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
remains unchanged. This study http://www.ncbi.nlm.nih.gov/pubmed/7950967 shows that the isoprenoid changes in Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
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
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
in the diseased brain, and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, for instance, induced by lipid peroxidation
Lipid peroxidation
Lipid peroxidation refers to the 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 chain reaction mechanism...
.
Synthesis
Dolichol is a product of the HMG-CoA reductase pathwayHMG-CoA reductase pathway
The mevalonate pathway or HMG-CoA reductase pathway or mevalonate-dependent route or isoprenoid pathway, is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria...
(also known as the mevalonate pathway), and as such their creation and availability are affected by mevalonate inhibition
Mevalonate inhibition
Mevalonate inhibition is used to define the effects of medicines based on HMG-CoA reductase enzyme inhibitors to control the products of the mevalonate pathway. This term addresses the effects of long-term restriction of mevalonate production in cell membranes by the inhibition of the membrane...
. First, a cis (or Z) -prenyltransferase catalyzes the condensation of farnesyl diphosphate (FPP) with a varying number (dependent on the particular cis-prenyltransferase) of isopentenyl diphoshate (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). Last, 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, although similar polyprenolPolyprenol
Polyprenols are natural long-chain isoprenoid alcohols of the general formula H-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 natural bioregulators and are found in small quantities in...
s molecules are found in other organisms including bacteria. Polyprenol
Polyprenol
Polyprenols are natural long-chain isoprenoid alcohols of the general formula H-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 natural bioregulators and are found in small quantities in...
s in bacteria do not contain an α-saturated isoprenoid and are typically smaller in terms of isoprenoid units or carbon length. Polyprenol
Polyprenol
Polyprenols are natural long-chain isoprenoid alcohols of the general formula H-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 natural bioregulators and are found in small quantities in...
s perform similar functions within bacteria; that is, they function as glycosyl carrier lipids involved in formation of complex branched polysacharide. However, the cellular process they are involved in is not glycosylation, but instead cell wall biosynthesis .
Medical Significance
The Australian pharmaceutical company SolagranSolagran
Solagran Limited is an Australian pharmaceutical company which has developed a range of biologically-active multifaceted 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
Polyprenol
Polyprenols are natural long-chain isoprenoid alcohols of the general formula H-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 natural bioregulators and are found in small quantities in...
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 http://www.asx.com.au/asxpdf/20050920/pdf/3sd7g0mczqbnc.pdf and Australia http://www.asx.com.au/asxpdf/20070221/pdf/3111ztwcbqzkk9.pdf indicate considerable potential as a safe and effective treatment.
See also
- Dolichol kinaseDolichol kinaseIn enzymology, a dolichol kinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are CTP and dolichol, whereas its two products are CDP and dolichyl phosphate....
- PolyprenolPolyprenolPolyprenols are natural long-chain isoprenoid alcohols of the general formula H-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 natural bioregulators and are found in small quantities in...
s - SolagranSolagranSolagran Limited is an Australian pharmaceutical company which has developed a range of biologically-active multifaceted therapeutic substances derived from the live elements of the green needles of certain species of conifer tree known as Bioeffectives....
- Mevalonate inhibition#Dolichol Inhibition
External links
- Overview at Birkbeck, University of LondonBirkbeck, University of LondonBirkbeck, University of London is a public research university located in London, United Kingdom and a constituent college of the federal University of London. It offers many Master's and Bachelor's degree programmes that can be studied either part-time or full-time, though nearly all teaching is...