Dolikolin merkityksestä: Polyprenolien ryhmää

 

Dolicholsynthesis:
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281381/
 The schematic presentation of the biosynthetic pathway leading to the synthesis of Dol-P is shown in Fig. 1. Dolichol in animals and yeast is considered as the end-product of the mevalonate (MVA) pathway. In summary, condensation of three acetyl-CoA molecules gives rise to 3-hydroxy-3-methylglutaryl-CoA which by HMG-CoA reductase (HMGR), the enzyme considered as the regulatory point of the entire MVA pathway, is converted into mevalonate. Combined activity of three subsequent enzymes leads to synthesis of isopentyl diphospate (IPP), the building block for isoprenoids. Further condensation of three IPP molecules results in formation of farnesyl diphosphate (FPP), which is considered as a critical branch-point of the pathway. It serves as substrate for four different pathways:

•  squalene synthase that catalyzes the first step leading to production of cholesterol,  
• trans-prenyltransferase involved in ubiquinone side-chain synthesis, 
• protein farnesyltransferase responsible for posttranslational farnesylation of proteins and   
• cis-prenyltransferase, the first specific enzyme in dolichol biosynthesis pathway.

https://www.researchgate.net/publication/12196198_Suppression_of_dolichol_synthesis_with_isoprenoids_and_statins_may_potentiate_the_cancer-retardant_efficacy_of_IGF-I_down-regulation

Article in Medical Hypotheses 56(1):12-6 · February 2001 with 12 Reads

DOI: 10.1054/mehy.2000.1073 · Source: PubMed

Med Hypotheses. 2001 Jan;56(1):12-6.

Suppression of dolichol synthesis with isoprenoids and statins may potentiate the cancer-retardant efficacy of IGF-I down-regulation.

McCarty MF¹. Abstract

Agents that inhibit the synthesis of mevalonate or of downstream isoprenoids block the G1-S transition and induce apoptosis in many cell lines; these agents include statins, phenylacetate, and a range of cyclic and acyclic isoprenoids. This cytostatic effect is mediated primarily by decreased availability of dolichol; this deficit impedes the glycosylation of nascent IGF-I receptors, preventing their transfer to the cell surface. In most tissues as well as transformed cell lines, IGF-I activity is crucial for transition to S phase, and also prevents apoptosis.
Thus, down-regulation of serum levels of free IGF-I - as may be achieved by caloric restriction, low-fat vegan diets, and various estrogen agonists/antagonists - may represent a useful strategy for preventing and controlling cancer; however, a compensatory up-regulation of tissue expression of IGF-I receptors limits the efficacy of such an approach.
 Concurrent use of agents that inhibit dolichol synthesis can be expected to prevent an increase in plasma membrane IGF-I receptors, thus potentiating the cancer-retardant efficacy of IGF-I down-regulation. Since dolichol and IGF-I appear to be essential for angiogenesis, these measures may also prove useful for control of pathogenic neovascularization.

PMID:

 

DOI:

10.1054/mehy.2000.1073

https://www.ncbi.nlm.nih.gov/pubmed/29297247

Biosci Biotechnol Biochem. 2018 Jun;82(6):947-955. doi: 10.1080/09168451.2017.1411775. Epub 2018 Jan 3.

The history and recent advances in research of polyprenol and its derivatives.Sagami H¹, Swiezewska E², Shidoji Y³. Abstract

The reduction pathway leading to the formation of dolichol was clarified in 2010 with the identification of SRD5A3, which is the polyprenol reductase. The finding inspired us to reanalyze the length of the major chain of polyprenol and dolichol from several plant leaves, including mangrove plants, as well as from animal and fish livers by 2D-TLC. Polyprenol- and dolichol-derived metabolites such as polyprenylacetone and epoxydolichol were found together with rubber-like prenol. This review focuses on analyses of polyprenol and its derivatives, including recently found epoxypolyprenol and polyprenylacetone. Attention has also been paid to the chromatographic behavior of rubber-like prenol on TLC. KEYWORDS: Prenol; acetone; dolichol; epoxide; rubberPMID:

DOI:

10.1080/09168451.2017.1411775

[Indexed for MEDLINE] 

REDUKTAASI löytö 2010

SRD5A3
 https://www.ncbi.nlm.nih.gov/gene/79644

Also known as

CDG1P; CDG1Q; KRIZI; SRD5A2L; SRD5A2L1

Summary

The protein encoded by this gene belongs to the steroid 5-alpha reductase family, and polyprenol reductase subfamily. It is involved in the production of androgen 5-alpha-dihydrotestosterone (DHT) from testosterone, and maintenance of the androgen-androgen receptor activation pathway. This protein is also necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins. Mutations in this gene are associated with congenital disorder of glycosylation type Iq. [provided by RefSeq, Mar 2011]

Expression

Ubiquitous expression in gall bladder (RPKM 7.7), endometrium (RPKM 4.5) and 25 other tissues See more

Orthologs  mouse all

Preferred Names

polyprenol reductase

Names

3-oxo-5-alpha-steroid 4-dehydrogenase 3

S5AR 3

SR type 3

probable polyprenol reductase

Related articles in PubMed

1. 5α-Reductase isozymes and aromatase mRNA levels in plucked hair from young women with female pattern hair loss. Sánchez P, et al. Arch Dermatol Res, 2018 Jan. PMID 29185104
2. Association of Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation With Early-Onset Retinal Dystrophy. Taylor RL, et al. JAMA Ophthalmol, 2017 Apr 1. PMID 28253385
3. SRD5A3-CDG: Expanding the phenotype of a congenital disorder of glycosylation with emphasis on adult onset features. Wheeler PG, et al. Am J Med Genet A, 2016 Dec. PMID 27480077, Free PMC Article
4. Adult phenotype and further phenotypic variability in SRD5A3-CDG. Kara B, et al. BMC Med Genet, 2014 Jan 16. PMID 24433453, Free PMC Article
5. A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Morava E, et al. Brain, 2010 Nov. PMID 20852264, Free PMC Article

See all (19) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. Study revealed for the first time the presence of 5alpha-reductase-R3 mRNA in human hair.
2. Findings suggest that 5alpha-reductases (5-AR) isoenzymes could be explored as a therapeutic target for urothelial bladder cancer (UBC) with 5alpha-reductase inhibitors (5-ARI).
3. We present the features of five individuals (three children and two adults) with mutations in SRD5A3 focusing on the variable eye and skin involvement
4. Although 4-dione is the main source of 5alpha-dihydrotestosterone in human preadipocytes, production of this steroid by 5 alpha-reductase isoenzymes (SRD5A1, 2 and 3) mediates the inhibitory effect of both 4-dione and testosterone on preadipocyte differentiation.
5. Mutations in the SRD5A3 gene may cause early-onset retinal dystrophy, a previously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious visual impairment.
6. the spectrum of phenotypes resulting from SRD5A3 mutations and the clinical variability of SRD5A3-CDG
7. Findings suggest that overexpression of 5alpha-reductase, through a higher inactivation of cortisol in the liver, could have a protective role in preserving hepatic sensitivity to insulin.
8. Next generation sequencing identified a homozygous frameshift mutation (c.203dupC; p.Phe69LeufsX2) SRD5A3 as the disease-causing change in Kahrizi syndrome.
9. A novel syndrome is identified in families with cerebellar ataxia and congenital eye malformations due to steroid 5 alpha-reductase type 3 disorders of glycosylation.
10. Study of a large consanguineous Emirati family showed that loss of function mutations of the SRD5A3 gene cause a multisystemic syndrome with eye malformations, cerebellar vermis hypoplasia, and psychomotor delay.