Mevalonate pathway
The mevalonate pathway is a key anabolic metabolic pathway in eukaryotes, archaea, and some bacteria that synthesizes isoprenoid precursors from acetyl-CoA, enabling the production of cholesterol, non-sterol isoprenoids, and other vital biomolecules essential for cellular function.[1][2] This pathway begins with the condensation of three molecules of acetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) via HMG-CoA synthase, followed by the rate-limiting reduction of HMG-CoA to mevalonate catalyzed by HMG-CoA reductase (HMGCR), an enzyme targeted by statins for cholesterol-lowering therapy.[3] Mevalonate is then sequentially phosphorylated and decarboxylated to yield isopentenyl pyrophosphate (IPP), the universal five-carbon building block of isoprenoids, through the actions of mevalonate kinase, phosphomevalonate kinase, and mevalonate diphosphate decarboxylase.[1] IPP isomerizes to dimethylallyl pyrophosphate (DMAPP), which condenses stepwise—first to geranyl pyrophosphate and then to farnesyl pyrophosphate (FPP)—via farnesyl pyrophosphate synthase, marking the entry into branched downstream routes.[3] FPP serves as a branch point: two molecules condense to form squalene via squalene synthase, initiating cholesterol biosynthesis through epoxidation and cyclization steps that produce lanosterol and ultimately cholesterol; alternatively, FPP extends to geranylgeranyl pyrophosphate (GGPP) for non-sterol isoprenoid synthesis.[1] Key products include cholesterol for membrane fluidity and precursor to steroid hormones, bile acids, and vitamin D; GGPP and FPP for prenylation of proteins like Ras and Rho GTPases, crucial for signal transduction; and other isoprenoids such as ubiquinone (for electron transport), dolichol (for glycosylation), and heme A.[4] The pathway's regulation is tightly controlled, primarily at the HMGCR step through sterol regulatory element-binding protein 2 (SREBP2) transcription and feedback inhibition by sterols and isoprenoids, ensuring homeostasis in lipid metabolism.[5] Dysregulation of the mevalonate pathway contributes to diseases like hypercholesterolemia and cancer, where upregulated activity supports tumor growth via enhanced prenylation and membrane synthesis, highlighting its therapeutic targeting potential beyond cardiovascular applications.[1] Evolutionarily, it contrasts with the non-mevalonate (MEP) pathway in plants and many bacteria, underscoring its essential role in eukaryotic and archaeal physiology.[3]Introduction
Definition and overview
The mevalonate pathway is an anabolic metabolic pathway that converts acetyl-CoA into isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP), utilizing mevalonate as a key intermediate.[6] These five-carbon isoprenoid units serve as building blocks for a diverse array of biomolecules, including sterols, dolichols, and prenyl groups essential for cellular functions.[7] The pathway was identified in the 1950s through pioneering work by Feodor Lynen and Konrad Bloch, who elucidated the mechanisms of cholesterol biosynthesis from acetate precursors, earning them the 1964 Nobel Prize in Physiology or Medicine for discoveries concerning the metabolism of cholesterol and fatty acids.[8] Lynen's group in particular demonstrated the role of mevalonate as a critical intermediate in this process using yeast extracts.[9] In outline, the pathway proceeds from the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA, followed by its reaction with another acetyl-CoA to yield 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), which is then reduced to mevalonate; subsequent phosphorylation and decarboxylation steps produce IPP and DMAPP.[7] This route serves as the primary means of isoprenoid biosynthesis in eukaryotes—including animals, fungi, and the cytosol of plants—archaea, and certain bacteria, while many bacteria and the plastids of plants employ an alternative non-mevalonate (MEP) pathway.[10]Biological significance
The mevalonate pathway serves as the primary biosynthetic route for isoprenoids in animals, fungi, the cytosol of plants, archaea, and some bacteria, generating over 30,000 distinct compounds that fulfill diverse cellular roles.[11] These include sterols such as cholesterol, which maintain membrane fluidity and integrity; prenyl groups like farnesyl and geranylgeranyl pyrophosphate that enable post-translational modification of proteins, including small GTPases involved in signaling; dolichols essential for N-linked glycosylation of proteins in the endoplasmic reticulum; ubiquinones (coenzyme Q) that function as electron carriers in the mitochondrial respiratory chain; and the polyprenyl component of heme A, a key prosthetic group in cytochrome c oxidase for oxidative phosphorylation.[12][13] This vast array of products underscores the pathway's centrality in supporting membrane structure, protein function, and energy production across cellular compartments. Evolutionarily, the mevalonate pathway represents an ancient metabolic innovation conserved across the three domains of life, likely originating in the last universal common ancestor and adapting to specialized roles in eukaryotes.[14] Its persistence highlights its indispensable contributions to fundamental processes: sterols and hopanoids ensure membrane adaptability in varying environments, prenylation of proteins like Ras facilitates intracellular signaling cascades critical for growth and differentiation, and isoprenoid-derived cofactors such as ubiquinone and heme A sustain aerobic respiration and energy homeostasis.[11][12] In modern organisms, particularly mammals, the pathway's flux intensifies during cell proliferation, as seen in rapidly dividing tissues and cancer cells, where heightened demand for isoprenoids supports biomass accumulation and survival signaling.[12] The pathway draws substantially from the cellular acetyl-CoA pool, integrating it into broader metabolism and consuming a notable fraction under basal conditions to fuel isoprenoid demands.[15] This interconnects the mevalonate route with fatty acid synthesis, as both compete for the same cytosolic acetyl-CoA substrate derived from mitochondrial export via citrate.[15] Furthermore, it ties into upstream catabolic networks, with acetyl-CoA originating from glycolysis and the tricarboxylic acid (Krebs) cycle, enabling coordinated responses to nutrient availability and energy status that balance biosynthesis with cellular growth needs.[12]Biosynthetic pathway
Upper mevalonate pathway
The upper mevalonate pathway comprises the initial three enzymatic steps that convert three molecules of acetyl-CoA into mevalonate, the committed precursor for downstream isoprenoid biosynthesis in eukaryotes.[7] This segment of the pathway is highly conserved across species and serves as the entry point for acetyl-CoA derived from carbohydrate or lipid metabolism into isoprenoid production.[16] The first step involves the reversible Claisen-type condensation catalyzed by acetoacetyl-CoA thiolase (EC 2.3.1.9), where two molecules of acetyl-CoA form acetoacetyl-CoA:$2 \text{ acetyl-CoA} \rightleftharpoons \text{acetoacetyl-CoA} + \text{CoA}
This reaction establishes the four-carbon β-ketoacyl intermediate essential for chain elongation.[7][16] In the second step, HMG-CoA synthase (EC 2.3.3.10) catalyzes the irreversible aldol addition of a third acetyl-CoA to acetoacetyl-CoA, incorporating water to yield 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), a six-carbon branched-chain thioester:
\text{acetoacetyl-CoA} + \text{acetyl-CoA} + \text{H}_2\text{O} \rightarrow \text{HMG-CoA} + \text{CoA} + \text{H}^+
This condensation introduces the hydroxyl and methyl groups characteristic of HMG-CoA.[7][16] The third and rate-limiting step is the reduction of HMG-CoA to (R)-mevalonate, mediated by HMG-CoA reductase (EC 1.1.1.34), which requires two equivalents of NADPH and proceeds via a sequential two-step reduction mechanism:
\text{HMG-CoA} + 2 \text{ NADPH} + 2 \text{ H}^+ \rightarrow \text{mevalonate} + \text{CoA} + 2 \text{ NADP}^+
This enzyme represents the primary regulatory point in the pathway.[7][16] Overall, the upper pathway stoichiometry balances as follows:
$3 \text{ acetyl-CoA} + 2 \text{ NADPH} + 2 \text{ H}^+ + \text{H}_2\text{O} \rightarrow \text{mevalonate} + 3 \text{ CoA} + 2 \text{ NADP}^+
In animal cells, the synthesis of acetoacetyl-CoA and HMG-CoA occurs in the cytosol, while the reduction to mevalonate takes place in the endoplasmic reticulum membrane.[17][16]