Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency

Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder caused by mutations in the MVK gene resulting in decreased activity of the enzyme mevalonate kinase (MK). Although MK is required for biosynthesis of all isoprenoids, in MKD, in particular, the timely synthesis of geranylgeranyl pyro...

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Bibliographic Details
Published in:Journal of inherited metabolic disease 2010-10, Vol.33 (5), p.625-632
Main Authors: Henneman, L, Schneiders, M. S, Turkenburg, M, Waterham, H. R
Format: Article
Language:English
Subjects:
Biochemistry
Case-Control Studies
Cell Line
Cell Membrane - enzymology
Enzyme Activation
Fibroblasts - drug effects
Fibroblasts - enzymology
Human Genetics
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
Internal Medicine
Medicine
Medicine & Public Health
Metabolic Diseases
Mevalonate Kinase Deficiency - enzymology
Mevalonate Kinase Deficiency - genetics
Original
Original Article
Pediatrics
Phosphotransferases (Alcohol Group Acceptor) - deficiency
Phosphotransferases (Alcohol Group Acceptor) - genetics
Protein Prenylation
Protein Transport
rac1 GTP-Binding Protein - metabolism
rhoA GTP-Binding Protein - metabolism
Signal Transduction
Simvastatin - pharmacology
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Summary:Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder caused by mutations in the MVK gene resulting in decreased activity of the enzyme mevalonate kinase (MK). Although MK is required for biosynthesis of all isoprenoids, in MKD, in particular, the timely synthesis of geranylgeranyl pyrophosphate appears to be compromised. Because small guanosine triphosphatases (GTPases) depend on geranylgeranylation for their proper signaling function, we studied the effect of MK deficiency on geranylgeranylation and activation of the two small GTPases, RhoA and Rac1. We demonstrate that both geranylgeranylation and activation of the two GTPases are more easily disturbed in MKD cells than in control cells when the flux though the isoprenoid biosynthesis pathway is suppressed by low concentrations of simvastatin. The limited capacity of geranylgeranylation in MKD cells readily leads to markedly increased levels of nonisoprenylated and activated GTPases, which will affect proper signaling by these GTPases.
ISSN:0141-8955
1573-2665
DOI:10.1007/s10545-010-9173-8