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Dolichol
Identifiers
CAS Number	11029-02-0 ; 2067-66-5 (dolichol-20);
ChEBI	CHEBI:16091;
KEGG	C00381;
MeSH	Dolichol
PubChem CID	6433320 (dolichol-20);
Properties
Chemical formula	Variable; Dolichol-20: C100H164O
Molar mass	Variable; Dolichol-20: 1382.37 g/mol
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

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 post-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 (where Glc is glucose, Man is mannose, and GlcNAc is N-acetylglucosamine). This oligosaccharide is transferred from the dolichol donor onto certain asparagine 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, 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.^[1] Dolichol phosphate was discovered at the University of Liverpool in the 1960s, although researchers did not know its function at the time of discovery.^[2]

Role in aging

Dolichol has been suggested to be used as a biomarker for aging.^[3] 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.^[4] 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.^[5]

Synthesis

Dolichol is a product of the HMG-CoA reductase pathway (also known as the 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.^[6]

Other

Dolichols are found in eukaryotes and in archaea,^[7] 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.^[8]

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 (already pharmaceutically registered as a hepatoprotector) in relation to neurodegenerative diseases (including Alzheimer's disease) in both Russia^[9] and Australia^[10] indicate considerable potential as a safe and effective treatment.

References

^ Fedorow, Heidi; Pickford, Russell; Hook, James M.; Double, Kay L.; Halliday, Glenda M.; Gerlach, Manfred; Riederer, Peter; Garner, Brett (February 2005). "Dolichol is the major lipid component of human substantia nigra neuromelanin". Journal of Neurochemistry. 92 (4): 990–995. doi:10.1111/j.1471-4159.2004.02975.x. PMID 15686500.
^ Chojnacki, T; Dallner, G (1 April 1988). "The biological role of dolichol". The Biochemical Journal. 251 (1): 1–9. doi:10.1042/bj2510001. PMC 1148956. PMID 3291859.
^ "J Gerontol A Biol Sci Med Sci. 2005 Jan;60(1):39-43".
^ Edlund C, Söderberg M, Kristensson K (1994). "Isoprenoids in aging and neurodegeneration". Neurochem. Int. 25 (1): 35–38. doi:10.1016/0197-0186(94)90050-7. PMID 7950967. S2CID 34009482.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Edlund C, Söderberg M, Kristensson K. Neurochem Int, 1994 Jul,25(1), 35-8
^ Schenk, B.; Fernandez, F.; Waechter, C. J. Glycobiology, 2001, 11(5), 61R-70R.
^ Meyer, Benjamin H.; Albers, Sonja-Verena (2013-02-01). "Hot and sweet: protein glycosylation in Crenarchaeota". Biochemical Society Transactions. 41 (1): 384–392. doi:10.1042/BST20120296. ISSN 0300-5127. PMID 23356316.
^ Bełtowski J, Wójcicka G, Jamroz-Wiśniewska A (September 2009). "Adverse effects of statins - mechanisms and consequences". Curr Drug Saf. 4 (3): 209–28. doi:10.2174/157488609789006949. PMID 19534648. Archived from the original on 2013-10-29.
^ Company announcement 20 September 2005.
^ Company announcement 21 February 2007.