Mevalonate pathway

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HMG-CoA synthase

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HMG-CoA reductase reaction

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Mevalonate kinase reaction

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Mevalonate pathway is a crucial metabolic pathway present in eukaryotes, archaea, and some bacteria. This pathway is vital for the biosynthesis of isoprenoids or terpenoids, including cholesterol, steroid hormones, and vitamin K. The mevalonate pathway involves a series of enzymatic reactions that convert acetyl-CoA to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are the building blocks for the synthesis of more complex isoprenoids.

Overview

The mevalonate pathway begins in the cytosol, where acetyl-CoA is converted into 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction is catalyzed by the enzyme HMG-CoA synthase. Subsequently, HMG-CoA is reduced to mevalonate by HMG-CoA reductase, a key regulatory enzyme and the target of statins, drugs used to lower cholesterol levels. Mevalonate is then phosphorylated and decarboxylated to yield isopentenyl pyrophosphate (IPP), which can be isomerized to dimethylallyl pyrophosphate (DMAPP). These two five-carbon molecules serve as the precursors for the synthesis of all other isoprenoids.

Key Enzymes

• HMG-CoA Synthase: Catalyzes the synthesis of HMG-CoA from acetyl-CoA.
• HMG-CoA Reductase: Reduces HMG-CoA to mevalonate, a rate-limiting step in the pathway.
• Mevalonate Kinase: Phosphorylates mevalonate to mevalonate-5-phosphate.
• Phosphomevalonate Kinase: Converts mevalonate-5-phosphate to mevalonate-5-diphosphate.
• Mevalonate-5-diphosphate Decarboxylase: Decarboxylates mevalonate-5-diphosphate to IPP.

Biological Significance

The mevalonate pathway is essential for the synthesis of numerous biomolecules that play critical roles in various biological processes. For example, cholesterol is a vital component of cell membranes and a precursor for the synthesis of steroid hormones, bile acids, and vitamin D. Isoprenoids produced via this pathway are also involved in protein prenylation, a post-translational modification that affects protein localization and function.

Regulation

The mevalonate pathway is tightly regulated, primarily at the step catalyzed by HMG-CoA reductase. This enzyme is subject to both transcriptional and post-translational regulation. Statins, which are inhibitors of HMG-CoA reductase, effectively reduce cholesterol synthesis, demonstrating the importance of this regulatory point.

Clinical Significance

Disruptions in the mevalonate pathway can lead to various metabolic disorders. For instance, mutations in the gene encoding mevalonate kinase can cause mevalonate kinase deficiency, which is characterized by recurrent fever episodes and inflammatory symptoms. Furthermore, the pathway's role in cholesterol biosynthesis makes it a target for therapeutic intervention in cardiovascular diseases.

See Also

• Isoprenoid
• Cholesterol
• Statins
• Metabolic pathway