The mevalonate (MVA) pathway is a fundamental metabolic process found in all higher eukaryotes, including humans, as well as in archaea and certain bacteria. This pathway serves as a primary source for a wide array of biomolecules indispensable for cellular function and survival.
What the MVA Pathway Builds
The MVA pathway is responsible for synthesizing a diverse array of molecules, with isoprenoids forming a large and varied class of these organic compounds. The pathway converts acetyl-CoA into isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are the foundational five-carbon building blocks for all isoprenoids.
Cholesterol, a well-known sterol, is a major product of this pathway. The MVA pathway also produces Coenzyme Q10 (CoQ10), an important compound for cellular energy. Dolichols, which are long-chain alcohols, are also synthesized through the MVA pathway.
It also generates farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), used for protein prenylation. This modification alters protein function and localization within the cell. The MVA pathway also contributes to the production of other molecules, such as precursors for heme A.
Vital Roles of MVA Pathway Products
The molecules produced by the MVA pathway play extensive roles in maintaining biological functions and overall health. Cholesterol, for example, is a primary component of animal cell membranes, influencing their structure and fluidity. It also serves as a precursor for the synthesis of all steroid hormones, including androgens, estrogens, progestagens, glucocorticoids, and mineralocorticoids.
Cholesterol is also converted into vitamin D, important for bone health, and into bile acids, essential for the digestion and absorption of dietary fats in the small intestine. Coenzyme Q10 (CoQ10), a fat-soluble molecule, is an important component of the mitochondrial electron transport chain, where it facilitates the production of adenosine triphosphate (ATP), the main energy currency of cells. Beyond energy generation, CoQ10 acts as a strong antioxidant, protecting cell membranes and lipoproteins from oxidative damage.
Dolichols are another important product, playing an important role in N-linked glycosylation, a process where sugars are transferred to proteins. This modification is important for proper protein folding, function, and stability.
Protein prenylation, involving FPP and GGPP, is important for the function of many signaling proteins, such as small GTPases like Ras, Rho, and Rab proteins. These prenylated proteins are involved in diverse cellular processes, including cell growth, differentiation, and vesicle trafficking, by enabling their proper membrane association and targeting.
Targeting the MVA Pathway in Medicine
The MVA pathway holds medical and pharmacological interest due to its involvement in numerous biological processes. Statins, a widely prescribed class of drugs, lower cholesterol levels by inhibiting a specific enzyme in the MVA pathway. These medications work by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, thereby reducing the liver’s production of cholesterol.
Beyond cholesterol management, the MVA pathway is being explored as a therapeutic target in other areas, including cancer. The pathway’s products, particularly isoprenoids, support cell proliferation and survival, making its disruption a potential anti-cancer strategy. Inhibiting protein prenylation, for instance, can promote apoptosis in cancer cells.
Research also indicates the MVA pathway’s relevance in some infectious diseases and its potential as a target for vaccine adjuvants. Interrupting the pathway has shown promise in stimulating immune responses and enhancing antigen presentation. While targeting the MVA pathway offers therapeutic benefits, it can also affect the production of other important MVA products like CoQ10. This reduction in CoQ10 has been associated with potential side effects such as myopathy.