Review
Mevalonate pathway: A review of clinical and therapeutical implications

https://doi.org/10.1016/j.clinbiochem.2007.03.016Get rights and content

Abstract

Mevalonate pathway is an important metabolic pathway which plays a key role in multiple cellular processes by synthesizing sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, such as dolichol, heme-A, isopentenyl tRNA and ubiquinone. While extensively studied in regard with cholesterol synthesis and its implications in cardiovascular diseases, in recent years the mevalonate pathway has become a challenging and, in the meantime, fascinating topic, when a large number of experimental and clinical studies suggested that inhibition of non-sterol isoprenoids might have valuable interest in human pathology. These molecules that are essential for cell growth and differentiation appear to be potential interesting therapeutic targets for many areas of ongoing research: oncology, autoimmune disorders, atherosclerosis, and Alzheimer disease. Also, considerable progress has been made in the past decade in understanding the pathophysiology of two auto-inflammatory disorders resulting from an inherited deficiency of mevalonate kinase, the first committed enzyme of the mevalonate pathway.

Here we present a brief description of the biochemistry of the mevalonate pathway, together with a review of the current knowledge of the clinical and therapeutical implications of this fascinating and complex metabolic pathway.

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)

  • A.M. Tonkin et al.

    Effects of pravastatin in 3260 patients with unstable angina: results from the LIPID study

    Lancet

    (2000)
  • J. Shepherd et al.

    PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial

    Lancet

    (2002)
  • M.S. Weber et al.

    Statins in the treatment of central nervous system autoimmune disease

    J. Neuroimmunol.

    (2006)
  • T. Vollmer et al.

    Oral simvastatin treatment in relapsing–remitting multiple sclerosis

    Lancet

    (2004)
  • X. Peng et al.

    Immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, potential therapy for relapsing remitting multiple sclerosis

    J. Neuroimmunol.

    (2006)
  • D.W. McCarey et al.

    Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial

    Lancet

    (2004)
  • D.G. Hackam et al.

    Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis

    Lancet

    (2006)
  • A.D. Basso et al.

    Lipid posttranslational modifications. Farnesyl transferase inhibitors

    J. Lipid Res.

    (2006)
  • Y.K. Peterson et al.

    A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity

    J. Biol. Chem.

    (2006)
  • Y.K. Peterson et al.

    A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity

    J. Biol. Chem.

    (2006)
  • Z. Yang et al.

    HMG-CoA reductase inhibition improves endothelial cell function and inhibits smooth muscle cell proliferation in human saphenous veins

    J. Am. Coll. Cardiol.

    (2000)
  • T. Waehre et al.

    Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease

    J. Am. Coll. Cardiol.

    (2003)
  • X. Peng et al.

    Immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, potential therapy for relapsing remitting multiple sclerosis

    J. Neuroimmunol.

    (2006)
  • J.L. Goldstein et al.

    Regulation of the mevalonate pathway

    Nature

    (1990)
  • J.D. Horton

    Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis

    Biochem. Soc. Trans.

    (2002)
  • L.W. Weber et al.

    Maintaining cholesterol homeostasis: sterol regulatory element-binding proteins

    World J. Gastroenterol.

    (2004)
  • P.O. Bonetti et al.

    Statin effects beyond lipid lowering – are they clinically relevant?

    Eur. Heart J.

    (2003)
  • P.A. Edwards et al.

    Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway

    Annu. Rev. Biochem.

    (1999)
  • J.P. Drenth et al.

    Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients

    Int. Hyper-IgD Study Group Med. (Baltimore)

    (1994)
  • G.F. Hoffmann et al.

    Clinical and biochemical phenotype in 11 patients with mevalonic aciduria

    Pediatrics

    (1993)
  • J. Frenkel et al.

    Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D

    Rheumatology (Oxford)

    (2001)
  • D. Haas et al.

    Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome

    Orphanet J. Rare Dis.

    (2006)
  • L. Obici et al.

    First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome

    Arthritis Rheum

    (2004)
  • H.J. Lachmann et al.

    AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever syndrome: a report of two cases

    Arthritis Rheum

    (2006)
  • S.M. Houten et al.

    Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome

    Nat. Genet.

    (1999)
  • J.P. Drenth et al.

    Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group

    Nat. Genet.

    (1999)
  • K.M. Gibson et al.

    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

    (1989)
  • J. Frenkel et al.

    Increased urinary leukotriene E(4) during febrile attacks in the hyperimmunoglobulinaemia D and periodic fever syndrome

    Arch. Dis. Child

    (2001)
  • J. Frenkel et al.

    Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome

    Arthritis Rheum

    (2002)
  • K. Takada et al.

    Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome

    Arthritis Rheum

    (2003)
  • P.D. Arkwright et al.

    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.

    (2002)
  • E.J. Bodar et al.

    Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model

    Neth. J. Med.

    (2005)
  • M.S. Schneiders et al.

    Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency

    Arthritis Rheum

    (2006)
  • A. Simon et al.

    Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome

    Clin. Pharmacol. Ther.

    (2004)
  • G.F. Hoffmann et al.

    Clinical and biochemical phenotype in 11 patients with mevalonic aciduria

    Pediatrics

    (1993)
  • H. Lennernas et al.

    Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences.

    Clin. Pharmacokinet.

    (1997)
  • J. Shepherd et al.

    Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group

    N. Engl. J. Med.

    (1995)
  • J.R. Downs et al.

    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

    (1998)
  • L.A. Prosser et al.

    Cost-effectiveness of cholesterol-lowering therapies according to selected patient characteristics

    Ann. Intern. Med.

    (2000)
  • Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)

    Lancet

    (1994)
  • Cited by (453)

    • Lipids in inflammasome activation and autoinflammatory disorders

      2024, Journal of Allergy and Clinical Immunology
    View all citing articles on Scopus
    View full text