The end points of mevalonate pathway are
- tRNA isopentenylation (addition to the heterocyclic ring of purine bases)
- farnesyl- and/or geranylgeranyl- proteins
- Coenzyme Q
- Steroid hormones
- sex steroids
- cardioactive steroid hormones
The mevalonate pathway activity is correlated with other activities:
what are the feedback and feedforward mechanisms of this pathway?
one more cartoon
Details of the single metabolic steps are described elsewhere.
Mevalonate pathway details
Lung Cancer. 2007 Mar;55(3):271-7. Epub 2006 Dec 4.
Ethnic differences in frequencies of gene polymorphisms in the MYCL1 region and modulation of lung cancer patients' survival. 2007
Spinola M, Falvella FS, Galvan A, Pignatiello C, Leoni VP, Pastorino U, Paroni R, Chen S, Skaug V, Haugen A, Dragani TA.
Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Milan, Italy.
Linkage disequilibrium (LD) analysis to refine a region associated with lung cancer progression on chromosome 1p34 identified a 106 kb LD block that includes MYCL1, TRIT1 (tRNA isopentenyltransferase 1) and MFSD2 (major facilitator superfamily domain-containing 2). Case-only association study on SNPs mapping in TRIT1 and MFSD2 indicated that the rare Leu allele (frequency: 0.04) of the TRIT1 Phe202Leu variation predicts short survival as compared to the common Phe/Phe genotype (hazard ratio (HR)=1.7; 95% CI, 1.03-2.86; P=0.039) in 335 Italian lung adenocarcinoma samples. A replication study in an independent population of 246 Norwegian lung cancer patients confirmed the significant association of the Phe202Leu polymorphism with patients' survival, but the rare allele was associated with better survival rate (HR=0.5; 95% CI, 0.26-0.91; P=0.023). The rare allele of TRIT1 Phe202Leu SNP was approximately seven-fold more frequent in Asian than in Caucasian subjects and three additional SNPs in the TRIT1 and MFSD2 genes showed ethnic differences in allelic frequencies. These results suggest that polymorphisms in the MYCL1 LD region affect lung cancer survival but that the functional element(s) may show population-specific patterns.
Cholesterol synthesis steps
Cholesterol synthesis requires:
- Farnesyl diphosphate (= 2 isoprenoid units)
1 isoprenoid units ( 2 NADPH + 3 ATP each )
- 2 AcetylCoA + 2 NADPH --> mevalonate
- mevalonate + 3 ATP --> isopentenyl pirophosphate + 3 ADP + 1 CO2
Cholesterol and bile acids synthesis
The HMG-CoA reductase (or HMGR) is the rate controlling enzyme of the mevalonate pathway, and it is inhibited by statins
Cofactor requirements differ according to the final product.
Requirements from farnesyl-PP to:
- Coenzyme Q
- farnesyl- and/or geranylgeranyl- proteins
Dolichol synthesis and cell proliferation
Dolichol and cell proliferation
Deciphering peripheral nerve myelination by using Schwann cell expression profiling 2002
Serum cholesterol and death rate
Kegg; Terpenoids backbone biosynthesis
Statin-associated neuromyotoxicity 2005
Drugs Today 2005, 41(4): 267
Baker, S.K., Tarnopolsky, M.A.
The sequelae of cardiovascular disease contribute significantly to morbidity and mortality in developed nations. As a class, the statins have been shown to measurably reduce the burden of atherosclerotic illness. However, muscle- and, more recently, nerve-related toxicity have emerged as potential complications leading to treatment withdrawal. Generally, the myopathic signs and symptoms of tenderness, myalgias, cramping and elevated serum creatine kinase (CK) activity are fully reversible after drug discontinuation. Growing evidence suggests that latent or previously minimal symptomatic muscle disease may predispose to the development of myopathy. Less information is available regarding the natural history of the sensorimotor neuropathy, but it appears to be less reversible if large fiber function is clinically manifest. Pathophysiologic clues regarding the potential causes of statin myopathy with or without neuropathy are discussed with particular attention paid to the implications of disrupted mevalonate metabolism. For example, secondary defects in isoprenoid biosynthesis are expected to impair the production of a variety of intermediaries such as dolichols, which are crucial for N-linked glycosylation; geranylgeranyl pyrophosphate, which is necessary for coenzyme Q10 and G-protein synthesis; farnesyl-pyrophosphate, which facilitates the endoproteolytic cleavage and maturation of prelamin A and modifies B-type lamins and G-proteins; and isopentenylpyrophosphate, which is involved in a nucleoside modification of selenocysteinyl-tRNA and thus indirectly related to the synthesis of all selenoproteins (estimated at 35). The nature of statin neuromyotoxicity remains unresolved; however, investigating the cellular corollaries of deranged isoprenoid metabolism may uncover clues that lead to a more complete understanding of the elusive pathophysiology.
Regulation by AMPK
Cell compartmentalization of cholesterol biosynthesis.
Cell compartmentalization of cholesterol biosynthesis. 1996
Ann N Y Acad Sci. 1996 Dec 27;804:142-64.
Thus, the results showing the presence of cholesterol synthetic enzymes in peroxisomes (see references 1, 4, 5, 6, 7, 8, 12, 13, 20, 21, 22, 24, 25, and 26), the reduced levels of cholesterol synthesis enzymes and cholesterol synthetic capacity of cells and tissues lacking peroxisomes, 26, 37, 39 and the low serum cholesterol levels in patients suffering from peroxisomal deficiency diseases40-43 demonstrate that peroxisomes are essential for normal cholesterol synthesis. A number of metabolic pathways require co-participation of enzymes located in both peroxisomes as well as enzymes found in other intracellular compartments. For example, the first steps of plasmalogen synthesis occur in the peroxisomes, while the terminal reactions are completed in the endoplasmic reticulum. Similarly, the oxidation of cholesterol to bile acids requires the participation of enzymes localized in the endoplasmic reticulum as well as peroxisomes. Little is known about the regulation of such pathways or about the shuttling of intermediates between compartments. The physiological importance of peroxisomal enzymes in the regulation of sterol metabolism remains to be clarified.
Regulation by hypoxia
High altitude and serum cholesterol
Hypoxia increases HDL cholesterol and CoQ10?
Regulation of cholesterol synthesis by nuclear factors SREBP'S
- Macrophage cholesterol biosynthesis was then studied in cells from diabetic mice treated with insulin and in glucose-enriched macrophages incubated with insulin. Insulin treatment of diabetic mice significantly reduced macrophage cholesterol biosynthesis, HMG-CoA reductase mRNA expression, and protein expression by 81%, 54%, and 31% respectively, compared to macrophages isolated from nontreated diabetic mice. Similarly, insulin incubation with glucose-enriched macrophages significantly reduced macrophage cholesterol biosynthesis, HMG-CoA reductase mRNA expression, and protein expression by 84%, 42%, and 18%, respectively, compared to macrophages incubated with high glucose but without insulin. These effects were mediated by glucose and insulin ability to regulate the transcription factor SREBP-1. Whereas glucose upregulated SREBP-1 expression and maturation, insulin blocked SREBP1 cleavage,
High glucose concentration increases macrophage cholesterol biosynthesis in diabetes through activation of the sterol regulatory element binding protein 1 (SREBP1): inhibitory effect of insulin. 2008
One more figure
Regulated expression of the SREBPs is complex in that the effects of sterols are different on the SREBP-1 gene versus the SREBP-2 gene.
a deeper insight
Papers Insulin HMG-CoA reductase
Promoter analysis of the murine squalene epoxidase gene. Identification of a 205 bp homing region regulated by both SREBP'S and NF-Y.
Squalene synthase: structure and regulation.
Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and of incorporation of acetate into cholesterol in homozygous hypercholesterolemic fibroblasts by ferritin-low density lipoprotein conjugates. 1978
PPAR gamma ligand troglitazone lowers cholesterol synthesis in HepG2 and Caco-2 cells via a reduced concentration of nuclear SREBP-2.
Involvement of retinoid X receptor alpha in coenzyme Q metabolism.
Effects of granulocyte-macrophage colony-stimulating factor on the levels of VLDL and LDL receptor mRNAs in vivo.
Metabolism and function of coenzyme Q.
Serum Cholesterol sources
Liver (Pgp) induction by rifampicin (RFP), dexamethasone (DEX) and St. John's Wort
Infertility and coenzyme Q
Regulation of macrophage cholesterol efflux through hydroxymethylglutaryl-CoA reductase inhibition: a role for RhoA in ABCA1-mediated cholesterol efflux. 2005
cholesterol synthesis in diabetes
Prenylation inhibitors: a novel class of antiviral agents.
Highly unsaturated fatty acids suppress lipogenic gene transcription by reducing the DNA binding activity of several transcription factors
- sterol regulatory-element binding protein 1 (HUFA inhibit the proteolytic release of sterol regulatory-element binding protein 1 from its membrane-anchored precursor through a ceramide-dependent signal)
- nuclear factor Y (HUFA impart a post-translational modification to nuclear factor Y)
The multi-dimensional regulation of gene expression by fatty acids: polyunsaturated fats as nutrient sensors.
Inhibitors of mevalonate pathway
- inhibitors of HMG CoA reductase (the statins)
- of mevalonic acid-pyrophosphate decarboxylase (sodium phenylacetate and sodium phenylbutyrate)
- farnesyl protein transferase (R115777, SCH66336, BMS-214662, Tipifarnib, L-778,123, and, prematurely, perillyl alcohol)
are dimmed by dose-limiting toxicities.
ref(this, 'jour', 'Exp Biol Med (Maywood).'
Sirolimus modifies cholesterol homeostasis in hepatic cells: a potential molecular mechanism for sirolimus-associated dyslipidemia.
Hyperphosphorylation regulates the activity of SREBP1 during mitosis.
Vascular endothelial growth factor activation of sterol regulatory element binding protein: a potential role in angiogenesis. 2004
Sterol-responsive element-binding protein (SREBP) 2 down-regulates ATP-binding cassette transporter A1 in vascular endothelial cells: a novel role of SREBP in regulating cholesterol metabolism.
Maternal dietary iron restriction modulates hepatic lipid metabolism in the fetuses 2005
Control of gene expression by fatty acids. 2004
The mevalonate pathway during acute tubular injury: selected determinants and consequences. 2000
Tipo 2, niacina migliora attività dell'HDL
Nei pazienti con diabete mellito di tipo 2 e sindrome metabolica, l'impiego di niacina oltre che incrementare i livelli plasmatici di colesterolo Hdl sembrerebbe in grado di recuperare la perdita delle proprietà vasoprotettive di questa importante classe di lipoproteine. La conferma arriva da un gruppo di ricerca di Zurigo che, in uno studio pubblicato su Circulation, ha messo in evidenza i principali vantaggi offerti da terapie a rilascio prolungato di niacina in questi pazienti. In particolare, dopo aver isolato, da 10 individui sani e 33 diabetici, la frazione plasmatica contenente colesterolo Hdl, gli autori ne hanno misurato l'effetto sulla produzione di ossido nitrico e superossido mediante analisi spettroscopiche. In aggiunta, queste misurazioni sono state condotte nei pazienti dopo trattamento per tre mesi con niacina (1.500 mg/giorno) oppure con placebo. In breve, la somministrazione di niacina è risultata in grado di ristorare nei diabetici la capacità del colesterolo Hdl, osservata negli individui sani, di stimolare la produzione di ossido nitrico, di ridurre quella di superossido e di promuovere la riparazione di danni endoteliali (L.A.).
Circulation 2009, published online before print December 21
Human liver alcohol dehydrogenases catalyze the oxidation of the intermediary alcohols of the shunt pathway of mevalonate metabolism. 1991
Biochem Biophys Res Commun. 1991 Jan 31;174(2):701-7.
Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Boston, Massachusetts.
Human liver alcohol dehydrogenase (ADH) catalyzes the oxidation of 3,3-dimethylallyl alcohol, the intermediary alcohol of the shunt pathway of mevalonate metabolism. ADH isozymes differ in their activities toward this alcohol in the order gamma 1 gamma 1 greater than gamma 2 gamma 2 approximately alfa alfa greater pi pi approximately beta 2 beta 2 approximately beta 1 beta 1 much greater than chi chi; kcat/Km values are 1.4 × 10(8), 1.9 × 10(7), 1.4 × 10(7), 5.6 × 10(6), 3.6 × 10(6), 1.6 × 10(6) and 2.5 × 10(3) M-1 min-1, respectively. The intermediary alcohols geraniol and farnesol of the proposed branch pathways of mevalonate metabolism are also oxidized by these isozymes with similar relative efficiencies. The genetic determinants of ADH isozymes may contribute to the observed differences in serum cholesterol levels among and within various populations.
P53 Barsotti A
Novel aspects of mevalonate pathway inhibitors as antitumor AGENTS, 2012