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User:Glynwiki/Mevalonate Inhibition

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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 attached enzyme HMG-CoA reductase. Such inhibitors are also known as the statins. They exert their effect at the very beginning of the mevalonate pathway, the location of this key reductase step, and thereby reduce the de-novo availability of a range of terpenoid and steroid products in cell membrane. The consequences of long-term statin use are classified below according to the depletion of a mevalonate product,[1] e.g. de novo membrane cholesterol.[2] and Co-enzyme Q10 [3][4]

There are also less direct impacts from mevalonate product depletions e.g. those affecting the synthesis of Tau proteins and Rho family of GTPases to consider here. [5]

Cholesterol depletion in cholesterol-rich lipid rafts edit

Further information: [[:Cholesterol Depletion]]
 
Neuron A (transmitting) to neuron B (receiving)
1. Mitochondrion
2. synaptic vesicle with neurotransmitters
3. Autoreceptor
4. Synapse with neurotransmitter released (serotonin)
5. Postsynaptic receptors activated by neurotransmitter (induction of a postsynaptic potential)
6. Calcium channel
7. Exocytosis of a vesicle
8. Recaptured neurotransmitter
The membranes in the vesicles and synapses are very dependent on additional glial sourced cholesterol[6]

Cholesterol produced and found in the membranes of eukaryotic cells where it is facilitates their form and function. A key example is the is glial cell cholesterol synthesis [7] in our brains vital for memory function and cognition.

Cholesterol also is the substrate for our most important hormones: aldosterone, cortisone, estrogen, progesterone and testosterone as well as the quasi-hormone, vitamin D (calciferol).

Cholesterol's vital role in eukaryote biomembrane structure and function and lipid raft formation, makes it of critical importance in vesicle formation, exocytosis [8], endocytosis, lipid trafficking [9] cell signalling, cell communication and immune defense.

Potential adverse effects of glial cell inhibition of de novo cholesterol synthesis include amnesia, forgetfulness, confusion, disorientation and increased senility. [10]. [11]

CoQ10 ( Ubiquinone ) Inhibition edit

Coenzyme Q10 (CoQ10) also known Ubiquinone is an isoprenoid made from mevalonate units and found primarily in the miochondria. It is depleted by inhibiting the supply of mevalonate. This leads to depleted anti-oxidant activity as well as its important role in Electron transfer phosphorylation in the respiration. Golomb et al. [12] have extensively reviewed and documented the role of statin side effects and very strongly associated them with CoQ10 depletion. A direct causative biochemical link has been in the long term use HMG-CoA reductase and the depletion of the mevalonate required for the biosynthesis of mitochondrial CoQ10.

The correction of this deficiency is discussed in the documentation supporting two US patent applications (Nos.4,933,165 and 4,929,437) for the inclusion of CoQ10 in statin medication both filed in 1990.[13][14]

A citizen's petition for improved guidance on CoQ10 supplementation was undertaken by a journal of the Life Extension Foundation in 2002 and remains unresolved. [15]

Mitochondrial Damage, Permanent Neuropathy, Permanent Myopathy, Neurodegeneration[16] [17]

Dolichol Inhibition edit

Dolichols are vital to the process of Glycoprotein formation in the endoplasmic reticulum of cells. In this capacity it is critical to the formation of the Glycoproteins involved in neuropeptides, cell identification, cell messaging and Immunodefence. Reduced bioavailability of dolichols can affect every cellular process in the body. [18] [19] [20]


Potential side effects from altered glycoprotein synthesis include impairment of DNA error correction, dysfunction of almost any cellular process, altered cell identification, altered cell messaging, and altered immunodefense. [21] [22]

Abnormal Phosphorylation of Tau protein edit

Meske V et al have shown that when normal phosphorylation is interfered with by mevalonate blockade[23], our cells increase the production of Tau protein. Tau is the protein substance of the Neurofibrillary tangles common to Alzheimers and other neurodegenerative diseases.

Abnormal tau phosphorylation and deposition in neurones and glial cells is one of the major features in taupathies. The tauopathies are a group of neurodegenerative disorders characterized by the presence of filamentous deposits, consisting of hyperphosphorylated tau protein, in neurons and glia. Major neurodegenerative tauopathies includes sporadic and hereditary neurodegenerative diseases characterized by filamentous tau deposits in brain and spinal cord.
In prototypical tauopathies, glial and neuronal tau inclusions are the sole or predominant CNS lesions. They includes

Section References: [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38]
Alzheimer's and Parkinson Disease 9Th International Conference

Selenoprotein edit

Only recently have selenoproteins been discovered and the effects of statin use to blockade of the mevalonate pathway on their role in human physiology are just emerging. Deficiency of selenoproteins has been proven to result in various types of Myopathies formerly seen only in Selenium deficiency - ( a Trace element). Additionally some forms of cognitive dysfunction are associated with Selenium deficiency. [39]

Nuclear factor-kappa B NF-kB edit

The benefit of statin drugs in cardiovascular disease control is in their ability to inhibit this vital transcriptase. The anti-inflammatory and immunomodulation effect of statins might be mediated by such statin inhibition of Nuclear factor-kappa B (NF-kB). Repoerted improvement in atherosclerosis may result from such inhibition of the key inflammatory elements: smooth muscle migration. lymphocyte adhesion, macrophage attraction and platelet activation has been associated with inhibition of NF-kB. The immunodefense system is also keyed to NF-kB, possibly explaining associative connections with changing patterns of certain infections and cancers. [40] [41]

References edit

  1. ^ Buhaescu I & Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin. Biochem. (2007) 40: pp. 575-584
  2. ^ Salaün C, James DJ & Chamberlain LH. Lipid rafts and the regulation of exocytosis. Traffic (2004) 5: pp. 255-264
  3. ^ Brown MS. Coenzyme q.sub.10 with hmg-coa reductase inhibitors. United States Patent (1990) 4,933,165
  4. ^ Tobert JA. Coenzyme q.sub.10 with hmg-coa reductase inhibitors. United States Patent (1990) 4,929,437:
  5. ^ Meske V; et al. (2003). "Blockade of HMG-CoA reductase activity causes changes in Microtubule-stabilizing protein tau. European Journal of Neuroscience". European Journal of Neuroscience. 17: 93, 2003. {{cite journal}}: Explicit use of et al. in: |author= (help)
  6. ^ Pfrieger, F W (January 2003). "Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes?". BioEssays. 25 (1): 72–78. doi:10.1002/bies.10195. PMID 12508285.{{cite journal}}: CS1 maint: date and year (link)
  7. ^ Pfrieger, F W (January 2003). "Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes?". BioEssays. 25 (1): 72–78. doi:10.1002/bies.10195. PMID 12508285.{{cite journal}}: CS1 maint: date and year (link)
  8. ^ Salaün C, James DJ & Chamberlain LH. Lipid rafts and the regulation of exocytosis. Traffic (2004) 5: pp. 255-264
  9. ^ Ikonen E. Cellular cholesterol trafficking and compartmentalization. Nat. Rev. Mol. Cell Biol. (2008) 9: pp. 125-138
  10. ^ Ben A. Barres and Stephen J. Smith (November 2001). "Cholesterol—Making or Breaking the Synapse". Science. 294 (5545): 1296–1297. doi:10.1126/science.1066724. PMID 11701918.{{cite journal}}: CS1 maint: date and year (link)
  11. ^ Pfrieger F W (November 2001). "Brain researcher discovers bright side of ill-famed molecule". Science.{{cite journal}}: CS1 maint: date and year (link)
  12. ^ Golomb, Beatrice A;Evans, Marcella A (2008). "Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism". Am J Cardiovasc Drugs. 8 (6): 373–418. doi:10.2165/0129784-200808060-00004. PMC 2849981. PMID 19159124.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Brown MS. Coenzyme q.sub.10 with hmg-coa reductase inhibitors. United States Patent (1990) 4,933,165
  14. ^ Tobert JA. Coenzyme q.sub.10 with hmg-coa reductase inhibitors. United States Patent (1990) 4,929,437:
  15. ^ Whitaker J. (May 2002). "Citizens' petition filed with FDA to include coenzyme Q10 use recommendation in all statin drug labeling". Life Extension Foundation Magazine.{{cite journal}}: CS1 maint: date and year (link)
  16. ^ Trifunovic, A. (2004). "Premature ageing in mice expressing defective mitochondrial DNA polymerase". Nature. 429, 417–423.
  17. ^ Nadanaciva, S.; et al. (June 2007). ". Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2+/− mice: Two-stage oxidative injury". Toxicol Appl Pharmacol. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link)
  18. ^ Wilcox, Andrew; et al. (2004). "Abrogation of Insulin-like Growth Factor-I (IGF-I) and Insulin Action by Mevalonic Acid Depletion: SYNERGY BETWEEN PROTEIN PRENYLATION AND RECEPTOR GLYCOSYLATION PATHWAYS". Journal of Biological Chemistry. 279. {{cite journal}}: Explicit use of et al. in: |author= (help)
  19. ^ Selected Medical Biochemistry Pages of Michael King PhD, Indiana State University http://themedicalbiochemistrypage.org/glycoproteins.html
  20. ^ Astrand, I M;Fries, E;Chojnacki, T;Dallner, G (1986). "Inhibition of dolichyl phosphate biosynthesis by compactin in cultured rat hepatocytes". Eur J Biochem. 155 (2): 447–52. doi:10.1111/j.1432-1033.1986.tb09511.x. PMID 3956495.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Trifunovic, A. (2004). "Premature ageing in mice expressing defective mitochondrial DNA polymerase". Nature. 429, 417–423.
  22. ^ Duane Graveline MD MPH (2009). The Statin Damage Crisis. Duane E. Graveline. ISBN 9781424338696.
  23. ^ Meske V; et al. (2003). "Blockade of HMG-CoA reductase activity causes changes in Microtubule-stabilizing protein tau. European Journal of Neuroscience". European Journal of Neuroscience. 17: 93, 2003. {{cite journal}}: Explicit use of et al. in: |author= (help)
  24. ^ Dermaut B, Kumar-Singh S, Rademakers R, Theuns J, Cruts M, Van Broeckhoven C. Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum. Trends Genet. 2005 Dec;21(12):664-72. PMID 16221505
  25. ^ Laferla FM, Oddo S. Alzheimer’s disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005 Apr;11(4):170-6. PMID 15823755
  26. ^ D’Souza I, Schellenberg GD. Regulation of tau isoform expression and dementia. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):104-15. PMID 15615630
  27. ^ Goedert M, Jakes R. Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):240-50. PMID 15615642
  28. ^ Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):198-210. PMID 15615638
  29. ^ von Bergen M, Barghorn S, Biernat J, Mandelkow EM, Mandelkow E. Tau aggregation is driven by a transition from random coil to beta sheet structure. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):158-66. Epub 2004 Nov 12. PMID 15615635
  30. ^ Hyman BT, Augustinack JC, Ingelsson M. Transcriptional and conformational changes of the tau molecule in Alzheimer’s disease. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):150-7. PMID 15615634
  31. ^ Gamblin TC. Potential structure/function relationships of predicted secondary structural elements of tau. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):140-9. PMID 15615633
  32. ^ Yancopoulou D, Spillantini MG. Tau protein in familial and sporadic diseases. Neuromolecular Med. 2003;4(1-2):37-48. PMID 14528051
  33. ^ Hutton M, Lewis J, Dickson D, Yen SH, McGowan E. Analysis of tauopathies with transgenic mice. Trends Mol Med. 2001 Oct;7(10):467-70. PMID 11597522
  34. ^ Avila J. Tau aggregation into fibrillar polymers: taupathies. FEBS Lett. 2000 Jun 30;476(1-2):89-92. PMID 10878257
  35. ^ Heutink P. Untangling tau-related dementia. Hum Mol Genet. 2000 Apr 12;9(6):979-86. PMID 10767321
  36. ^ Avila J. Tau aggregation into fibrillar polymers: taupathies. FEBS Lett. 2000 Jun 30;476(1-2):89-92. PMID 10878257
  37. ^ Heutink P. Untangling tau-related dementia. Hum Mol Genet. 2000 Apr 12;9(6):979-86. PMID 10767321
  38. ^ Duane Graveline MD MPH (2009). The Statin Damage Crisis. Duane E. Graveline. ISBN 9781424338696.
  39. ^ Mooseman B and Behl C. Lancet, 2004 (2004). "Selenoprotein synthesis and side effects of statins". Lancet. 363:892-94.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  40. ^ Shovman O et al. . 25(3): 272-85, 2002 (2002). "Anti-inflammatory and immunomodulatory properties of statins". Immunol Res. 25(3): 272-85.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  41. ^ Hilgendorff A.; et al. (2003). "Statins differ in their ability to block NF-kB activation in human blood monocytes". International Journal of Clinical Pharmacology and Therapeutics. 41(9): 397-401. {{cite journal}}: Explicit use of et al. in: |author= (help)

Further reading edit

External links edit

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