ReviewMevalonate pathway: A review of clinical and therapeutical implications
Introduction
Mevalonate pathway is an important metabolic pathway that provides cells with essential bioactive molecules, vital in multiple cellular processes. This pathway converts mevalonate into sterol isoprenoids, such as cholesterol, indispensable precursor of bile acids, lipoproteins, and steroid hormones, and into a number of hydrophobic molecules, nonsterol isoprenoids. These intermediates of the mevalonate biosynthetic pathway play important roles in the post-translational modification of a multitude of proteins involved in intracellular signaling and are essential in cell growth/differentiation, gene expression, protein glycosylation and cytoskeletal assembly [1], [2].
Section snippets
Biochemistry of the mevalonate pathway
The mevalonate–isoprenoid pathway involves first the synthesis of 3-hydroxy-3-methylglutaryl-CoA (HMG)-CoA from acetyl-CoA through acetoacetylCoA. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), one of the most highly regulated enzymes in nature, catalyzes the conversion of HMG-CoA to mevalonic acid. HMGR is the rate-limiting enzyme of mevalonate pathway [1]. In the absence of sterol isoprenoids in the cell, HMGR gene transcription is directly activated by a family transcription factors, named
Clinical implications
The clinical importance of isoprenoid biosynthesis for human health has been extensively demonstrated. The decreased activity of one of the key enzymes of the mevalonate pathway, mevalonate kinase (MK), has been identified as the direct biochemical and molecular cause of two inherited human autoinflammatory disorders: mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS). MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia,
Mevalonate pathway as a therapeutic target
Rational therapeutical manipulation of the mevalonate pathway and downstream isoprenoid biosynthesis pathway by statins and bisphosphonates has been intensively studied and found to be an interesting and revolutionary option in a variety of diseases, by mechanisms unrelated to changes of cholesterol and bone metabolism, respectively. Although this mechanism has yet to be fully elucidated and many controversies still exist, essentially because of the observed differences between the experimental
References (133)
- et al.
Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways
J. Lipid Res.
(1997) - et al.
Sterol regulatory element-binding proteins induce an entire pathway of cholesterol synthesis
Biochem. Biophys. Res. Commun.
(2001) - et al.
Regulation of isoprenoid/cholesterol biosynthesis in cells from mevalonate kinase-deficient patients
J. Biol. Chem.
(2003) Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase
Am. Heart J.
(2002)Statin inhibition of HMG-CoA reductase: a 3-dimensional view
Atheroscler. Suppl.
(2003)- et al.
The structure of the catalytic portion of human HMG-CoA reductase
Biochim. Biophys. Acta
(2000) - et al.
Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study)
Am. J. Cardiol.
(1998) - et al.
Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial)
Am. J. Cardiol.
(2003) - et al.
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial
Lancet
(2003) - et al.
CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicenter randomised placebo-controlled trial
Lancet
(2004)
Effects of pravastatin in 3260 patients with unstable angina: results from the LIPID study
Lancet
PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial
Lancet
Statins in the treatment of central nervous system autoimmune disease
J. Neuroimmunol.
Oral simvastatin treatment in relapsing–remitting multiple sclerosis
Lancet
Immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, potential therapy for relapsing remitting multiple sclerosis
J. Neuroimmunol.
Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial
Lancet
Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis
Lancet
Lipid posttranslational modifications. Farnesyl transferase inhibitors
J. Lipid Res.
A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity
J. Biol. Chem.
A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity
J. Biol. Chem.
HMG-CoA reductase inhibition improves endothelial cell function and inhibits smooth muscle cell proliferation in human saphenous veins
J. Am. Coll. Cardiol.
Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease
J. Am. Coll. Cardiol.
Immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, potential therapy for relapsing remitting multiple sclerosis
J. Neuroimmunol.
Regulation of the mevalonate pathway
Nature
Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis
Biochem. Soc. Trans.
Maintaining cholesterol homeostasis: sterol regulatory element-binding proteins
World J. Gastroenterol.
Statin effects beyond lipid lowering – are they clinically relevant?
Eur. Heart J.
Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway
Annu. Rev. Biochem.
Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients
Int. Hyper-IgD Study Group Med. (Baltimore)
Clinical and biochemical phenotype in 11 patients with mevalonic aciduria
Pediatrics
Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D
Rheumatology (Oxford)
Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome
Orphanet J. Rare Dis.
First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome
Arthritis Rheum
AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever syndrome: a report of two cases
Arthritis Rheum
Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome
Nat. Genet.
Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group
Nat. Genet.
Mevalonate kinase in lysates of cultured human fibroblasts and lymphoblasts: kinetic properties, assay conditions, carrier detection and measurement of residual activity in a patient with mevalonic aciduria
Enzyme
Increased urinary leukotriene E(4) during febrile attacks in the hyperimmunoglobulinaemia D and periodic fever syndrome
Arch. Dis. Child
Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome
Arthritis Rheum
Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome
Arthritis Rheum
Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept
Clin. Exp. Immunol.
Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model
Neth. J. Med.
Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency
Arthritis Rheum
Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome
Clin. Pharmacol. Ther.
Clinical and biochemical phenotype in 11 patients with mevalonic aciduria
Pediatrics
Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences.
Clin. Pharmacokinet.
Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group
N. Engl. J. Med.
Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study
JAMA
Cost-effectiveness of cholesterol-lowering therapies according to selected patient characteristics
Ann. Intern. Med.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
Lancet
Cited by (453)
Short-term test for the toxicogenomic assessment of ecotoxic modes of action in Myriophyllum spicatum
2024, Science of the Total EnvironmentCoenzyme Q deficiency in endothelial mitochondria caused by hypoxia; remodeling of the respiratory chain and sensitivity to anoxia/reoxygenation
2024, Free Radical Biology and MedicineLipids in inflammasome activation and autoinflammatory disorders
2024, Journal of Allergy and Clinical ImmunologyAn updated review of chemical compounds with anti-Toxoplasma gondii activity
2023, European Journal of Medicinal ChemistryRole of Panax ginseng and ginsenosides in regulating cholesterol homeostasis
2023, Food Bioscience