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

Abstract

OBJECTIVE:

In cells from patients with the autoinflammatory disorder mevalonate kinase (MK) deficiency, which includes the hyperimmunoglobulin D with periodic fever syndrome, MK becomes the rate-limiting enzyme in the isoprenoid biosynthesis pathway. This suggests that up-regulation of residual MK activity in these patients could be a way in which to prevent or alleviate the associated symptoms. We studied the effect of 2 specific inhibitors of isoprenoid biosynthetic enzymes on the residual activity of MK in cells from patients with MK deficiency.

METHODS:

Skin fibroblasts from MK-deficient patients and from controls were cultured for 7 days with either simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, or zaragozic acid A, an inhibitor of squalene synthase. Following culture, MK activity, MK protein levels, MVK messenger RNA levels, and the effect on the pathway flux toward non-sterol isoprenoid biosynthesis were determined.

RESULTS:

Treatment of the fibroblasts with either of the inhibitors led to a marked increase in residual MK enzyme activity, which was largely attributable to increased MVK gene transcription. This effect was even more pronounced when the cells were cultured in lipoprotein-depleted medium. The flux toward nonsterol isoprenoid end-product synthesis was reduced when cells were treated with simvastatin but was partly restored by concomitant treatment with zaragozic acid A.

CONCLUSION:

Our results indicate that manipulations of the isoprenoid biosynthesis pathway that promote the synthesis of nonsterol isoprenoids may provide an interesting therapeutic option for the treatment of MK deficiency.

• Authors: Marit S Schneiders, Sander M Houten, Marjolein Turkenburg, Ronald J A Wanders, Hans R Waterham
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 54 Issue 7 Pg. 2306-13 (Jul 2006) ISSN: 0004-3591 [Print] United States
• PMID: 16802371 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Immunoglobulin D
• RNA, Messenger
• Terpenes
• Tricarboxylic Acids
• squalestatin 1
• Squalene
• Simvastatin
• Phosphotransferases (Alcohol Group Acceptor)
• mevalonate kinase

Topics

• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line
• Familial Mediterranean Fever (genetics, metabolism, therapy)
• Fibroblasts (drug effects, metabolism, pathology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Immunoglobulin D (metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (deficiency, genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Simvastatin (pharmacology)
• Squalene (antagonists & inhibitors)
• Terpenes (metabolism)
• Tricarboxylic Acids (pharmacology)