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Farnesyl pyrophosphate

Farnesyl pyrophosphate (FPP), also known as farnesyl diphosphate, is an essential isoprenoid intermediate in the mevalonate pathway, serving as a precursor for the biosynthesis of sesquiterpenes, sterols, and other vital cellular lipids.^[1] With the molecular formula C₁₅H₂₈O₇P₂, FPP features a linear chain of three isoprene units (15 carbons) linked head-to-tail, typically in the all-trans configuration, and esterified to a pyrophosphate group that facilitates its enzymatic transfer in metabolic reactions.^[2] It is synthesized by the enzyme farnesyl pyrophosphate synthase (FPPS), which catalyzes the sequential condensation of dimethylallyl pyrophosphate (DMAPP) with two molecules of isopentenyl pyrophosphate (IPP), first forming geranyl pyrophosphate (GPP, C₁₀) and then extending it to FPP (C₁₅).^[3]^[1] As a central branch point in isoprenoid metabolism, FPP is converted to squalene by squalene synthase for cholesterol and steroid hormone production, or to geranylgeranyl pyrophosphate (GGPP) for longer-chain prenyl groups; it also acts as a lipid donor in the farnesylation of proteins, including small GTPases like Ras and Rho, enabling their anchoring to cell membranes and regulation of signaling pathways such as proliferation and cytoskeletal dynamics.^[1]^[3] Beyond biosynthesis, FPP functions as an endogenous signaling molecule, activating transient receptor potential vanilloid 3 (TRPV3) ion channels to mediate pain responses in sensory neurons and keratinocytes, and serving as an antagonist to P2Y₁₂ receptors in platelets to inhibit aggregation.^[3]^[4] In pathology, elevated FPP levels contribute to oncogenesis by promoting prenylation-dependent activation of oncogenic proteins, making the mevalonate pathway—and FPP production—a therapeutic target; statins, which inhibit upstream HMG-CoA reductase, deplete FPP to induce apoptosis and suppress tumor growth in cancers like breast and medulloblastoma.^[1]

Chemical properties

Molecular structure

Farnesyl pyrophosphate has the molecular formula C_{15}H_{28}O_7P_2.^[2] Its systematic IUPAC name is (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl trihydrogen diphosphate.^[5] Common synonyms include farnesyl diphosphate (FDP) and farnesyl pyrophosphate (FPP), with the latter reflecting its historical designation as an ester of farnesol and pyrophosphoric acid.^[2] The molecule consists of a linear 15-carbon farnesyl chain assembled from three consecutive isoprene units, featuring methyl branches at positions 3, 7, and 11, and double bonds at positions 2-3, 6-7, and 10-11.^[6] This hydrocarbon chain is attached at its terminal (position 1) primary alcohol carbon via a phosphate ester linkage to a pyrophosphate moiety, -OP(O)(OH)O-P(O)(OH)_2, which imparts polarity and reactivity to the otherwise hydrophobic tail.^[2] In biological contexts, farnesyl pyrophosphate occurs predominantly in the all-trans (2E,6E) stereochemical configuration, with the double bonds adopting extended conformations that facilitate its interactions in enzymatic processes.^[7] This stereoisomer is the naturally occurring form produced by farnesyl pyrophosphate synthase.^[7]

Physical characteristics

Farnesyl pyrophosphate possesses a molecular weight of 382.33 g/mol.^[8] The compound typically appears as a white to brown material, often provided in the form of a methanol:ammonia solution for stability.^[8] It exhibits slight solubility in water and in methanol upon sonication, reflecting its amphiphilic nature with a hydrophobic farnesyl chain and polar pyrophosphate moiety; it is generally insoluble in non-polar solvents such as hydrocarbons.^[8]^[9] Farnesyl pyrophosphate decomposes at temperatures above 107°C without a distinct melting point, and it is unstable at room temperature, necessitating low-temperature storage or stabilization.^[8] A predicted boiling point of 533.8 ± 60.0 °C exists, though the compound decomposes prior to reaching this temperature.^[8] Spectroscopic analysis reveals characteristic features attributable to its isoprenoid structure, including UV absorption near 210 nm from the alkene double bonds and proton NMR signals for the methylene and methyl groups in the farnesyl units, typically appearing in the 1.0–5.5 ppm range.^[10]

Stability and reactivity

Farnesyl pyrophosphate exhibits significant sensitivity to hydrolysis due to its labile pyrophosphate bond, which undergoes cleavage under both acidic and neutral to alkaline conditions. In acidic environments, the compound is notably unstable, necessitating extraction procedures under neutral or slightly basic pH to prevent degradation.^[11] At neutral or alkaline pH, non-enzymatic hydrolysis is facilitated by bivalent cations such as Mg²⁺ or Mn²⁺, leading to the formation of alcohols like nerolidol and farnesols, along with inorganic pyrophosphate that further hydrolyzes to phosphate.^[12] This process typically yields farnesol and inorganic phosphate as primary products, highlighting the compound's vulnerability outside controlled biological settings. The pyrophosphate moiety also imparts thermal instability to farnesyl pyrophosphate, with degradation accelerating at elevated temperatures and necessitating low-temperature storage to preserve integrity. Commercial preparations recommend storage in dry form or frozen stock solutions at -20°C or below to minimize hydrolysis and maintain stability.^[13] Under frozen conditions at -20°C, the compound demonstrates high stability, exhibiting less than 2% hydrolysis over three months, whereas exposure to room temperature or higher promotes rapid decomposition.^[14] In terms of reactivity, the pyrophosphate group functions as an efficient leaving group in nucleophilic substitution reactions, enabling the transfer of the farnesyl moiety in non-biological model systems mimicking prenylation. This reactivity is evident in condensation assays where nucleophiles, such as thiolates, displace the pyrophosphate, underscoring its role in synthetic and analytical applications.^[15] In aqueous media, farnesyl pyrophosphate displays limited stability, with half-life influenced by pH, temperature, and ionic conditions; buffered solutions at -20°C extend usability, but room-temperature exposure in buffers leads to noticeable degradation within hours to days, as supported by data on stability under optimized cold extraction conditions.^[11]

Biosynthesis

Pathway origins

Farnesyl pyrophosphate (FPP) is synthesized de novo through two primary metabolic pathways that converge on the production of its universal five-carbon precursors, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP).^[16] The mevalonate pathway predominates in animals, fungi, and archaea, initiating from acetyl-CoA derived from central carbon metabolism.^[17] In this route, three molecules of acetyl-CoA condense to form acetoacetyl-CoA, which then reacts with another acetyl-CoA to produce 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA); the subsequent reduction of HMG-CoA by HMG-CoA reductase yields mevalonate, marking a key regulatory step in the pathway.^[18] Mevalonate is then phosphorylated and decarboxylated through a series of reactions involving mevalonate kinase, phosphomevalonate kinase, and diphosphomevalonate decarboxylase to generate IPP, which isomerizes to DMAPP via IPP isomerase.^[16] These C5 units (IPP and DMAPP) serve as building blocks for longer isoprenoid chains, with dimethylallyl pyrophosphate (DMAPP) first condensing with one IPP molecule to form the C10 intermediate geranyl pyrophosphate (GPP), the immediate precursor to FPP.^[19] GPP acts as an allylic electrophile in subsequent prenyltransferase reactions, enabling chain elongation.^[20] An alternative route, the 2-C-methyl-D-erythritol 4-phosphate (MEP) or non-mevalonate pathway, operates in most bacteria, plant plastids, algae, and certain protozoa, bypassing mevalonate entirely.^[21] This pathway begins with the condensation of glyceraldehyde-3-phosphate and pyruvate, catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (DXS) to produce 1-deoxy-D-xylulose 5-phosphate (DXP), followed by a series of reductions, cyclizations, and phosphorylations involving enzymes such as DXP reductoisomerase (DXR), 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase, and others, ultimately yielding IPP and DMAPP.^[22] Like the mevalonate pathway, the MEP route produces IPP and DMAPP, which condense stepwise to GPP and then to FPP.^[23] Organism-specific variations reflect evolutionary adaptations: animals and fungi rely exclusively on the mevalonate pathway for isoprenoid synthesis, including FPP production, whereas plants utilize both pathways in parallel, with the MEP pathway localized to plastids for primary metabolism and the mevalonate pathway in the cytosol for other isoprenoids.^[24] Bacteria predominantly employ the MEP pathway, though some incorporate mevalonate elements under specific conditions.^[25] The final assembly of FPP from GPP and IPP is mediated by farnesyl pyrophosphate synthase, as detailed in enzymatic synthesis sections.^[26]

Enzymatic synthesis

Farnesyl pyrophosphate (FPP), also known as farnesyl diphosphate, is produced via the head-to-tail condensation of one molecule of geranyl pyrophosphate (GPP) with one molecule of isopentenyl pyrophosphate (IPP), a key step in the mevalonate pathway of isoprenoid biosynthesis. This reaction is catalyzed by the enzyme farnesyl pyrophosphate synthase (FPPS; EC 2.5.1.10), which sequentially performs two similar condensations: first combining dimethylallyl pyrophosphate (DMAPP) and IPP to form GPP, followed by the addition of another IPP to yield FPP.^[27] FPPS functions as a homodimeric enzyme, with each subunit adopting an all-α-helical fold that creates a binding pocket for the allylic substrate and IPP. The catalytic mechanism initiates with the Mg²⁺-assisted ionization of the allylic pyrophosphate (GPP), generating an allylic carbocation that undergoes nucleophilic attack by the C4 carbon of IPP, forming a new carbon-carbon bond. This is followed by stereospecific elimination of a proton from the C2 position of IPP, releasing inorganic pyrophosphate (PPᵢ) and producing the trans-configured double bond.^[27] The balanced equation for the terminal condensation is:

\text{GPP} + \text{IPP} \rightarrow (2E,6E)\text{-FPP} + \text{PP}_\text{i}

The reaction demonstrates high stereospecificity, yielding predominantly the all-E isomer of FPP (typically >95% in eukaryotic systems), essential for its downstream roles in prenylation and terpenoid synthesis.^[27] FPPS activity is regulated through allosteric inhibition by its product FPP, which binds to a regulatory pocket and locks the enzyme in an inactive conformation, providing negative feedback to prevent overaccumulation. Gene expression of FPPS is elevated in cholesterol-synthesizing tissues such as the liver, where it is transcriptionally controlled by sterol regulatory elements responsive to pathway intermediates.^[28]^[29] Indirect inhibition of FPP synthesis occurs via statins, which block HMG-CoA reductase upstream in the mevalonate pathway, thereby depleting the pool of IPP and DMAPP/GPP available as substrates for FPPS.^[30]

Biological functions

Role in prenylation

Farnesyl pyrophosphate (FPP) acts as the lipid donor in protein prenylation, a post-translational modification that attaches a 15-carbon farnesyl group to the thiol of a cysteine residue near the C-terminus of target proteins. This process is catalyzed by the heterodimeric enzyme protein farnesyltransferase (FTase), which recognizes the CaaX motif in substrate proteins, where C denotes cysteine, aa represents one or two aliphatic amino acids (typically valine, leucine, isoleucine, or methionine), and X is a variable residue such as serine, alanine, methionine, or glutamine.^[31] The main targets of farnesylation are small GTPases from the Ras superfamily, including H-Ras, N-Ras, and K-Ras, as well as Rho family GTPases like RhoA and Cdc42. Prenylation anchors these proteins to lipid membranes, such as the plasma membrane or endomembranes, which is essential for their activation, subcellular localization, and ability to interact with regulators and effectors in signal transduction cascades.^[32]^[33] Mechanistically, FTase first binds FPP in its active site, followed by the protein substrate; the enzyme's zinc ion coordinates and deprotonates the cysteine thiolate, promoting a direct nucleophilic SN1-like attack on the electrophilic C1 carbon of the farnesyl moiety. This displaces the pyrophosphate leaving group, forming a stable thioether linkage between the protein and farnesyl group while releasing inorganic pyrophosphate (PPi). The overall reaction is:

\text{Protein-Cys-SH} + \text{FPP} \xrightarrow{\text{FTase, Zn}^{2+}} \text{Protein-Cys-S-Farnesyl} + \text{PP}_\text{i}

^[34]^[31] This modification plays a critical role in cellular processes, including signal-mediated cell proliferation via Ras-ERK pathways and vesicular trafficking through Rho-mediated cytoskeletal dynamics and membrane association. Dysregulation of farnesylation, such as excessive prenylation of oncogenic Ras mutants, promotes uncontrolled proliferation and is a hallmark of various cancers, including pancreatic and colorectal carcinomas.^[32]^[35]^[31]

Involvement in terpenoid production

Farnesyl pyrophosphate (FPP) serves as a critical branch point intermediate in the biosynthesis of sesquiterpenes and higher terpenoids, channeling isoprenoid precursors into diverse metabolic pathways across eukaryotes.^[36] In this capacity, FPP acts as a direct substrate for terpenoid synthases and condensing enzymes, enabling the production of compounds essential for cellular functions, signaling, and secondary metabolism.^[19] As the C15 isoprenoid product of farnesyl pyrophosphate synthase, FPP is utilized by sesquiterpene synthases to generate a wide array of C15 terpenoids, which play roles in plant defense, aroma, and pigmentation. For instance, (E)-β-farnesene, a volatile compound involved in aphid repellence in plants, is formed through the cyclization of FPP by dedicated sesquiterpene synthases such as those identified in Arabidopsis thaliana.^[37] These enzymes catalyze the ionization and subsequent rearrangement of FPP, yielding linear or cyclic sesquiterpenes like farnesene and amorpha-4,11-diene, the latter a precursor to antimalarial artemisinin in Artemisia annua.^[36] In the sterol biosynthesis pathway, two molecules of FPP are head-to-head condensed by squalene synthase (SQS), a rate-limiting enzyme localized to the endoplasmic reticulum, to form the C30 intermediate presqualene diphosphate, which is then reduced to squalene.^[38] Squalene subsequently undergoes cyclization to lanosterol and further modifications to yield sterols such as cholesterol in animals and phytosterols in plants, which are vital for membrane integrity and hormone precursors.^[19] This SQS-mediated step represents a key commitment to triterpenoid production, diverting FPP from other fates.^[36] Beyond sesquiterpenes and sterols, FPP contributes to the synthesis of non-terpenoid isoprenoids, including ubiquinone (coenzyme Q) in the mitochondrial electron transport chain and dolichol, a polyisoprenoid required for N-linked glycosylation in the endoplasmic reticulum.^[19] These pathways highlight FPP's versatility as a precursor for essential cellular components.^[39] The localization of FPP-dependent terpenoid production exhibits compartmentalization that varies by organism and pathway. In animals, FPP biosynthesis and utilization occur primarily in the cytosol and endoplasmic reticulum via the mevalonate pathway.^[40] In plants, FPP pools are generated in the cytosol through the mevalonate route for sesquiterpenes and sterols, while plastidial FPP from the methylerythritol phosphate pathway supports additional terpenoid branches, with potential cross-talk via metabolite export.^[40] Mitochondrial involvement is noted for ubiquinone assembly in both kingdoms.^[19]

Signaling roles

Beyond its roles in prenylation and terpenoid production, FPP functions as an endogenous signaling molecule. It activates transient receptor potential vanilloid 3 (TRPV3) ion channels in sensory neurons and keratinocytes, contributing to pain responses and thermosensation.^[41] FPP also acts as an antagonist to P2Y₁₂ receptors in platelets, inhibiting ADP-induced platelet aggregation and thereby exerting antithrombotic effects. This inhibition occurs at micromolar concentrations (IC₅₀ ≈ 45–66 μM) and involves blockade of downstream signaling like GTPγS binding.^[4] As of 2024, FPP has been shown to potentiate dendritic cell migration and survival in models of autoimmunity, such as lupus, by coordinating protein geranylgeranylation with mitochondrial remodeling to enhance germinal center responses.^[42]

Pharmacology and applications

Inhibitors and antagonists

Farnesyl pyrophosphate (FPP) serves as a key intermediate in prenylation pathways, making enzymes involved in its synthesis and utilization prime targets for inhibitors that disrupt these processes. Inhibitors primarily target farnesyl pyrophosphate synthase (FPPS), which produces FPP, or farnesyltransferase (FTase), which transfers the farnesyl group from FPP to proteins. Additionally, inhibitors of geranylgeranyltransferase (GGTase) affect related prenylation events downstream of FPP metabolism. These compounds generally act as substrate analogs or competitive binders, with development accelerating in the 1990s amid interest in blocking oncogenic signaling.^[43] FTase inhibitors (FTIs) were pioneered in the mid-1990s as potential anticancer agents by targeting the farnesylation of Ras proteins, which require FPP-derived modification for membrane localization and function. Tipifarnib and lonafarnib, both non-peptidic CAAX tetrapeptide mimetics, exemplify this class; they competitively bind to the farnesyl-binding pocket of FTase, preventing FPP substrate access and inhibiting protein prenylation with high potency. Tipifarnib exhibits an IC₅₀ of approximately 0.6 nM against FTase, while lonafarnib shows an IC₅₀ of 1.9 nM, demonstrating selectivity over GGTase at low concentrations. These inhibitors advanced to clinical trials by the early 2000s, building on preclinical screens of chemical libraries that identified non-thiol containing structures to improve pharmacokinetics.^[44]^[45]^[46]^[47] FPPS inhibitors, particularly nitrogen-containing bisphosphonates (N-BPs), act upstream by blocking FPP production through mimicry of the enzyme's substrates, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). Zoledronate, a potent N-BP, binds to the allylic substrate site of FPPS, forming a time-dependent, non-competitive complex that isomerizes and depletes downstream prenyl pyrophosphates like FPP and geranylgeranyl pyrophosphate (GGPP); its IC₅₀ against human FPPS is around 20 nM. This mechanism disrupts mevalonate pathway flux, originally exploited in the 1990s for bone disorders but later recognized for broader prenylation inhibition. Other bisphosphonates like risedronate follow similar binding but with lower affinity, highlighting the role of the imidazole ring in zoledronate for enhanced inhibition.^[48]^[49]^[50]^[51] GGTase inhibitors target geranylgeranylation, a parallel prenylation process influenced by FPP-derived intermediates, and include peptidomimetic compounds like GGTI-298, developed in the late 1990s to selectively block GGTase I over FTase. GGTI-298 acts as a competitive inhibitor by mimicking the CAAX motif and binding the geranylgeranyl pocket, preventing substrate transfer with an IC₅₀ of about 3 μM for Rap1A processing, while sparing farnesylated proteins at lower doses. This selectivity arises from structural differences in the enzyme active sites, enabling dual FTI/GGTI strategies in research. Early GGTIs emerged from rational design efforts in the 1990s, complementing FTI development to address compensatory geranylgeranylation observed in cancer models.^[52]^[53]^[54]^[55] Overall, the evolution of these inhibitors from 1990s academic screens to 2000s pharmaceutical candidates reflects a shift toward substrate-competitive and allosteric mechanisms, with IC₅₀ values in the nanomolar range underscoring their biochemical efficacy against FPP-related targets.^[43]^[45]

Clinical relevance

Farnesyl pyrophosphate (FPP) plays a critical role in cancer therapy through its involvement in protein prenylation, particularly targeting Ras-driven tumors via farnesyltransferase (FTase) inhibitors (FTIs). These inhibitors prevent the farnesylation of Ras proteins, which are frequently mutated in cancers such as pancreatic cancer, aiming to disrupt oncogenic signaling. Clinical trials of FTIs like tipifarnib and lonafarnib in pancreatic cancer patients have shown limited efficacy, primarily due to compensatory geranylgeranylation of Ras by geranylgeranyltransferase, allowing alternative membrane localization and persistent tumor growth.^[56]^[57] Despite these challenges, FTIs continue to be explored in combination therapies for HRAS-mutant solid tumors, demonstrating partial responses in select cohorts.^[58] In bone disorders, inhibitors of farnesyl pyrophosphate synthase (FPPS), such as nitrogen-containing bisphosphonates (e.g., zoledronic acid and alendronate), are widely used to treat conditions like Paget's disease and hypercalcemia of malignancy. These drugs competitively bind to FPPS, blocking the synthesis of FPP and downstream isoprenoids, which disrupts osteoclast function and reduces excessive bone resorption. Clinical evidence supports their efficacy in normalizing bone turnover markers and alleviating symptoms in Paget's disease patients, with zoledronic acid showing rapid and sustained responses in hypercalcemia cases.^[59]^[60] FPP synthesis via the methylerythritol phosphate (MEP) pathway in bacteria and apicoplasts of parasites presents a target for infectious disease treatments, exemplified by fosmidomycin, an antibiotic that inhibits 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), upstream of FPP production. This disruption halts isoprenoid biosynthesis essential for bacterial cell wall integrity and parasite survival, showing promise against malaria (Plasmodium falciparum) and bacterial pathogens like Escherichia coli and Pseudomonas aeruginosa. Phase II trials of fosmidomycin for acute falciparum malaria demonstrated antimalarial efficacy, though bioavailability issues limit standalone use, prompting combination strategies. As of 2025, ongoing research includes reengineering fosmidomycin derivatives to enhance potency against tuberculosis and malaria, modified dosing schedules in animal models to reduce recrudescence, and development of triple therapies combining fosmidomycin with clindamycin and additional agents.^[61]^[62]^[63]^[64]^[65] Dysregulation of FPP-related pathways contributes to adverse effects and disease links, including statin-induced myalgia from depletion of FPP and downstream geranylgeranyl pyrophosphate, which impairs mitochondrial function and CoQ10 synthesis in muscle cells. Statins like simvastatin exacerbate this by inhibiting HMG-CoA reductase, leading to reduced prenylation of small GTPases and ATP availability, with myalgia affecting up to 10-15% of users. In progeria, such as Hutchinson-Gilford progeria syndrome (HGPS), defective lamin A prenylation via persistent farnesylated progerin causes nuclear envelope abnormalities; FTIs like lonafarnib mitigate this by blocking farnesylation, improving nuclear morphology and extending survival in clinical studies.^[66]^[67] As of 2025, ongoing research advances FTI applications, with preliminary data from Kura Oncology's programs showing enhanced antitumor activity in preclinical models of RAS-mutant cancers, and expanded clinical trials evaluating next-generation FTIs for solid tumors. In HGPS, lonafarnib remains the only FDA-approved therapy, with recent reviews confirming its role in slowing disease progression through reduced progerin farnesylation.^[68]^[69]^[70]

Structural analogs

Structural analogs of farnesyl pyrophosphate (FPP) share a similar allylic pyrophosphate moiety and isoprenoid carbon backbone but differ in chain length or stereochemistry, influencing their reactivity in enzymatic reactions. These compounds often serve as precursors or mimics in the mevalonate pathway, where FPP itself is synthesized from geranyl pyrophosphate (GPP) and isopentenyl pyrophosphate (IPP). Geranyl pyrophosphate (GPP), a 10-carbon analog, acts as the immediate precursor to FPP in the biosynthetic pathway. It consists of two isoprene units linked by a trans double bond, forming a shorter chain compared to FPP's three units, which limits its substrate specificity for certain prenyltransferases. The reduced chain length of GPP decreases its hydrophobicity and alters binding affinity to enzymes like farnesyl pyrophosphate synthase.^[19] Geranylgeranyl pyrophosphate (GGPP), an extended 20-carbon analog, results from the addition of another IPP unit to FPP, featuring four isoprene units with predominantly trans configurations. This elongation increases the molecule's flexibility and lipophilicity, enabling its use in geranylgeranylation processes distinct from farnesylation. The longer chain in GGPP enhances interactions with larger protein pockets in geranylgeranyltransferases compared to FPP.^[71]^[72] Farnesol represents the dephosphorylated alcohol derivative of FPP, retaining the 15-carbon sesquiterpene skeleton but lacking the pyrophosphate group, which makes it a neutral, volatile compound. This removal converts the charged, reactive allylic pyrophosphate into a more stable alcohol, often utilized in plant and microbial signaling or as a fragrance component. The absence of the phosphate in farnesol significantly reduces its enzymatic reactivity toward prenyltransferases.^[73]^[74] Nerolidyl pyrophosphate serves as the cis isomer of FPP, featuring a cis double bond in the central isoprene linkage instead of trans, which alters the conformational flexibility and cyclization propensity in terpene synthases. This stereochemical difference positions nerolidyl pyrophosphate as an intermediate in certain sesquiterpene biosyntheses, where it facilitates folding for ring formation not favored by the all-trans FPP.^[75]^[76] Synthetic analogs, such as 8-anilinogeranyl pyrophosphate (AGPP) and frame-shifted FPP variants, are designed to mimic FPP's structure for research into prenylation mechanisms. AGPP incorporates an aniline group at the terminal position, enhancing transferability to protein substrates by farnesyltransferase while maintaining the pyrophosphate and isoprenoid features. Frame-shifted analogs shift the isoprene units by one carbon, probing enzyme active site tolerances and yielding modified chain geometries that affect binding kinetics. These differences in substitution or positioning highlight how alterations in double bond geometry or peripheral groups can modulate specificity and inhibitory potential.^[77]^[78]

Metabolic derivatives

Farnesyl pyrophosphate (FPP) serves as a key precursor in the biosynthesis of squalene through the action of squalene synthase, also known as farnesyl-diphosphate farnesyltransferase (FDFT1), which catalyzes the head-to-head condensation of two FPP molecules to form the linear triterpene squalene, releasing pyrophosphate as a byproduct.^[6] This reaction represents the committed step in the cholesterol biosynthetic pathway and occurs primarily in the endoplasmic reticulum (ER) of eukaryotic cells.^[79] In plants, FPP is converted to farnesene isomers, such as α-farnesene and β-farnesene, via farnesene synthases that facilitate the ionization and subsequent cyclization or rearrangement of the FPP substrate, often yielding sesquiterpenes involved in aroma compounds and defense mechanisms.^[80] For instance, α-farnesene biosynthesis in apple fruit proceeds through the mevalonate pathway, where FPP is directly transformed by α-farnesene synthase, contributing to the characteristic apple scent and playing a role in post-harvest scald development.^[81] FPP contributes to the polyprenyl tail of ubiquinone (coenzyme Q) by serving as an initial building block in the synthesis of the isoprenoid side chain, where polyprenyl diphosphate synthase extends FPP with multiple isopentenyl pyrophosphate (IPP) units to form the appropriate-length polyprenyl diphosphate, which is then attached to the quinone ring by polyprenyltransferase (COQ2).^[82] This tail, comprising 10 isoprene units in humans, is essential for the lipid-soluble properties and electron transport function of ubiquinone in the mitochondrial respiratory chain.^[83] Dolichol, a long-chain α-saturated polyisoprenoid alcohol, is biosynthesized from FPP through successive cis-addition of IPP units catalyzed by cis-prenyltransferases, resulting in chains of 17–21 isoprene units that function as lipid carriers in N-linked glycosylation of proteins.^[84] This process occurs predominantly in the ER, with contributions from peroxisomes, reflecting compartmental shifts in isoprenoid metabolism where FPP translocates from cytosolic or mitochondrial origins to these organelles for elongation and subsequent reduction to dolichol.^[85] The ER localization ensures dolichol's role in the secretory pathway, where it anchors oligosaccharides for transfer to nascent polypeptides.^[84]

References

[1]
Targeting the Mevalonate Pathway in Cancer - PMC
This review focuses on recent advances in understanding of mevalonate pathway ... farnesyl pyrophosphate (FPP) is a major branch point in the mevalonate pathway.
[2]
Farnesyl pyrophosphate | C15H28O7P2 | CID 445713 - PubChem
2-trans,6-trans-farnesyl diphosphate is the trans,trans-stereoisomer of farnesyl diphosphate. It has a role as an Escherichia coli metabolite and a mouse ...Missing: function | Show results with:function
[3]
Farnesyl Pyrophosphate - an overview | ScienceDirect Topics
Farnesyl pyrophosphate (FPP) is defined as an endogenous bioactive lipid characterized by an acyl chain with multiple double bonds conjugated to a more polar ...
[4]
Farnesyl pyrophosphate is an endogenous antagonist to ADP ... - NIH
Jul 1, 2013 · FPP is an insurmountable antagonist of ADP-induced platelet aggregation mediated by the P2Y 12 receptor. It could be an endogenous antithrombotic factor.<|control11|><|separator|>
[5]
Farnesyl pyrophosphate | C15H28O7P2 - ChemSpider
Molecular formula: C15H28O7P2 ... Verified. (2E,6E)-3,7,11-Trimethyl-2,6,10-dodecatrien-1-yl trihydrogen diphosphate. [IUPAC name – generated by ACD/Name].
[6]
Showing metabocard for Farnesyl pyrophosphate (HMDB0000961)
Farnesyl pyrophosphate is a very hydrophobic molecule, practically insoluble (in water), and relatively neutral. Structure. Data?1589397769. MOL3D MOLSDF3D SDF ...
[7]
Stereospecific Synthesis and Biological Evaluation of Farnesyl ...
A unified, stereospecific synthetic route to the three geometric isomers of (E,E)-farnesyl diphosphate (E,E-FPP) (1, 2, and 3) has been developed.
[8]
FARNESYLPYROPHOSPHATE | 13058-04-3 - ChemicalBook
Jan 27, 2025 · Melting point, >107°C (dec.) Boiling point, 533.8±60.0 °C(Predicted). Density, 1.233±0.06 g/cm3(Predicted). Flash point, 11 °C. storage temp. - ...
[9]
Farnesyl pyrophosphate (PAMDB000210)
Structure for Farnesyl pyrophosphate (PAMDB000210) ; Chemical Formula: C15H28O7P ; Average Molecular Weight: 382.3261 ; Monoisotopic Molecular Weight: ...Missing: stereochemistry | Show results with:stereochemistry
[10]
Synthesis, Properties and Applications of Diazotrifluropropanoyl ...
Photoactive analogues of farnesyl diphosphate (FPP) are useful probes in studies of enzymes that employ this molecule as a substrate.Missing: absorption | Show results with:absorption
[11]
Current Development in Isoprenoid Precursor Biosynthesis and ...
This review summarizes the newly discovered IPP and DMAPP production pathways ... The pathway starts with the acetyl-CoA acetyltransferase (AACT) catalyzed ...
[12]
Two-step pathway for isoprenoid synthesis - PNAS
Dec 24, 2018 · The mevalonate (MVA) pathway involves seven reactions to produce IPP from acetyl-CoA. DMAPP is then produced through the isomerization of IPP ...
[13]
Mevalonate and Nonmevalonate Pathways for the Biosynthesis of ...
Mevalonate Pathway for the Biosynthesis of IPP and. DMAPP. In this pathway, three molecules of acetyl-CoA condense suc- cessively to form HMG-CoA. This CoA ...<|separator|>
[14]
Farnesyl Diphosphate - an overview | ScienceDirect Topics
Farnesyl-diphosphate (FPP) and geranylgeranyl-diphosphate (GGPP) are produced by sequential condensation reactions of dimethylallyl-diphosphate with two or ...
[15]
A cytosolic bifunctional geranyl/farnesyl diphosphate synthase ...
We show that geraniol is synthesized through the cytosolic mevalonate (MVA) pathway by a bifunctional geranyl/farnesyl diphosphate synthase, RcG/FPPS1, ...
[16]
Five Questions about Non-Mevalonate Isoprenoid Biosynthesis - PMC
Dec 22, 2011 · The basic isoprenoid building blocks (IPP and DMAPP) are generated in cells by one of two distinct biosynthetic routes. The classical ...
[17]
The Non-mevalonate Pathway of Isoprenoid Precursor Biosynthesis
Two biosynthetic routes to IPP and DMAPP have evolved. For many years it was assumed that the mevalonate (MVA) pathway was the sole route to IPP and DMAPP.
[18]
The non-mevalonate pathway requires a delicate balance of ...
Feb 29, 2024 · This work shows that an intricate balance of the MEP pathway intermediates determines the terpene yield in engineered E. coli.
[19]
(PDF) An overview of the non-mevalonate pathway for terpenoid ...
Aug 9, 2025 · Two independent pathways for biosynthesis of IPP and DMAPP in plants. The terminal steps [from MECP to IPP/DMAPP (marked by '?')] are not ...
[20]
Metabolic plasticity for isoprenoid biosynthesis in bacteria
As described above, the universal precursors of all isoprenoids, IPP and DMAPP, can be synthesized by two major pathways [1]: the MVA pathway and the MEP ...
[21]
Evidence of a Novel Mevalonate Pathway in Archaea | Biochemistry
Jun 10, 2014 · The system involves 12 enzymes to perform the complex transformation, while providing and balancing the ATP, NADPH, and acetyl-CoA cofactors.
[22]
Farnesyl Diphosphate Synthase: The Art of Compromise between ...
FPP synthase catalyzes two reactions – the sequential addition of the hydrocarbon moieties of dimethylallyl diphosphate (C5) and geranyl diphosphate (C10) to ...
[23]
Human farnesyl pyrophosphate synthase is allosterically inhibited ...
Jan 18, 2017 · Farnesyl pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target.
[24]
Identification and regulation of a rat liver cDNA encoding farnesyl ...
Jan 5, 1989 · We conclude that CR39 encodes the prenyltransferase of cholesterol biosynthesis, farnesyl pyrophosphate synthetase.
[25]
Farnesyl transferase inhibitors and statins block protein prenylation
Two major classes of drugs have been developed that block protein farnesylation. The first class, which includes lovastatin and various synthetic HMG-CoA ...
[26]
Farnesyltransferase—New Insights into the Zinc-Coordination ...
This could imply an effective mechanism by which the enzyme would facilitate the nucleophilic addition during the prenylation reaction (Tobin et al., 2003).
[27]
Inhibition of farnesyl pyrophosphate synthase improves pressure ...
Dec 23, 2016 · Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. FPPS catalyzes the formation of geranyl pyrophosphate (GPP) ...
[28]
Farnesyltransferase Inhibitors Alter the Prenylation and Growth ...
Two enzymes are involved in the isoprenylation of Ras and Rho proteins, protein farnesyltransferase (FTase)1 and protein geranylgeranyltransferase I (GGTase-I), ...
[29]
https://pubmed.ncbi.nlm.nih.gov/2909544/
[30]
Prenylated Proteins: Structural Diversity and Functions - IntechOpen
The FPP is bound by the FTase first, which is then followed by the binding of the protein.
[31]
Metabolic Engineering of Terpenoid Biosynthesis in Medicinal Plants
In the context of terpenoid biosynthesis, branch-point metabolites such as farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP) function as ...
[32]
Molecular characterization of two isoforms of a farnesyl ...
Jan 30, 2015 · For analysis of the catalytic product of TaFPS1 and TaFPS2, the GC oven temperature was maintained at 40°C for 1 min and then increased to 250°C ...Missing: thermal decomposition
[33]
Farnesyl pyrophosphate – Knowledge and References
It is a precursor of sesquiterpenes, triterpenes, sterols, and other secondary metabolites such as ubiquinones and dolichols. Farnesyl pyrophosphate is a ...
[34]
Farnesyltransferase Inhibitors | Cancer Research - AACR Journals
This article presents an overview of preclinical studies and clinical trials of a number of independently derived farnesyltransferase inhibitors (FTIs).
[35]
Development of Farnesyl Transferase Inhibitors: A Review
Jun 23, 2005 · Examples of the latter compounds are tipifarnib and lonafarnib, both identified by screening large libraries of chemical entities and not ...
[36]
Development of farnesyl transferase inhibitors: a review - PubMed
The exact mechanism of action of this class of agents is, however, currently unknown. The drugs inhibit farnesylation of a wide range of target proteins, ...
[37]
Lonafarnib: Uses, Interactions, Mechanism of Action - DrugBank
Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), with a reported IC50 value of 1.9 nM; lonafarnib is specific for FTase, as it does not appreciably ...
[38]
https://pmc.ncbi.nlm.nih.gov/articles/PMC166504/
[39]
Molecular Mechanisms of Action of Bisphosphonates: Current Status
Oct 24, 2006 · Results: Nitrogen-containing bisphosphonates act intracellularly by inhibiting farnesyl diphosphate synthase, an enzyme of the mevalonate ...
[40]
Zoledronic Acid | Ras GTPase Inhibitors - R&D Systems
Zoledronic Acid is a potent bisphophonate farnesyl diphosphate (FPP) synthase inhibitor (IC 50 = 20 nM). Inhibits osteoclast-mediated bone resorption.Missing: IC50 pyrophosphate
[41]
Phosphonate and Bisphosphonate Inhibitors of Farnesyl ... - Frontiers
Widely used to treat bone-resorption disorders, these drugs work by inhibiting the enzyme farnesyl pyrophosphate synthase. Playing a key role in the isoprenoid ...
[42]
Phosphonate and Bisphosphonate Inhibitors of Farnesyl ...
Jan 6, 2021 · Widely used to treat bone-resorption disorders, these drugs work by inhibiting the enzyme farnesyl pyrophosphate synthase. ... The NMR ...
[43]
The Geranylgeranyltransferase-I Inhibitor GGTI-298 Arrests Human ...
The Geranylgeranyltransferase-I Inhibitor GGTI-298 Arrests Human Tumor Cells in G0/G1 and Induces p21WAF1/CIP1/SDI1 in a p53-independent Manner*. Andreas Vogt.
[44]
The geranylgeranyltransferase I inhibitor GGTI-298 induces ...
GGTI-298 has recently been shown to arrest human tumor cells in the G1 phase of the cell cycle, induce apoptosis, and inhibit tumor growth in nude mice.
[45]
Molecular and Pharmacological Characterization of the Interaction ...
Thus, we conclude that the observed GGTI-298 inhibitor effect was specific and blocked the interaction between GGTase-I and its substrate Rap1B. 2.3.<|control11|><|separator|>
[46]
Geranylgeranyltransferase I as a target for anti-cancer drugs - JCI
May 1, 2007 · The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent ...
[47]
Farnesyl Protein Transferase Inhibitors in Pancreatic Cancer
Subsequent pre-clinical research has revealed that other intracellular proteins than Ras are involved in the antiproliferative effects of farnesyl protein ...<|separator|>
[48]
New tricks for human farnesyltransferase inhibitor: cancer and beyond
Over the last several decades, FTase inhibitors (FTIs) were developed to disrupt the farnesylation of oncogenic Ras as anti-cancer agents, and some of them ...
[49]
Potential of Farnesyl Transferase Inhibitors in Combination ... - MDPI
Oct 22, 2021 · Tipifarnib, a farnesyl transferase inhibitor, is a small molecule drug candidate that has demonstrated promising clinical activity in HRAS-mutant head and neck ...
[50]
The molecular mechanism of nitrogen-containing bisphosphonates ...
These agents are currently used to treat postmenopausal and steroid-induced osteoporosis, Paget's disease, hypercalcemia, and osteolysis associated with ...
[51]
Bisphosphonates: an overview with special reference to alendronate
They are used in the treatment of Paget's disease of bone, hypercalcaemia and osteolytic bone disease of malignancy, primary and secondary hyperparathyroidism, ...Missing: FPPS | Show results with:FPPS
[52]
Isoprenoid Biosynthesis in Plasmodium falciparum - PMC
FOSMIDOMYCIN. An important reagent in the study of the MEP pathway has been the selective MEP pathway inhibitor, fosmidomycin. Fosmidomycin is a small, three ...
[53]
Fosmidomycin, an inhibitor of isoprenoid synthesis, induces ...
Oct 17, 2019 · The antibiotic, fosmidomycin (FSM) targets the methylerythritol phosphate (MEP) pathway of isoprenoid synthesis by inhibiting the essential ...Missing: FPP | Show results with:FPP
[54]
The Role of Coenzyme Q10 in Statin-Associated Myopathy - JACC
Statins block production of farnesyl pyrophosphate, an intermediate in the synthesis of ubiquinone or coenzyme Q10 (CoQ10). This fact, plus the role of CoQ10 ...
[55]
https://www.jci.org/articles/view/32108
[56]
Kura Oncology Announces Preliminary Data from Its Farnesyl ...
Oct 18, 2025 · Kura Oncology Announces Preliminary Data from Its Farnesyl Transferase Inhibitor (FTI) Programs at the 2025 European Society for Medical ...
[57]
https://pmc.ncbi.nlm.nih.gov/articles/PMC6072492/
[58]
(PDF) Assessing the Efficacy of Small Molecule Drugs in Hutchinson ...
Jun 30, 2025 · Farnesyltransferase inhibitors (FTIs) have shown potential in mitigating disease phenotypes in preclinical models, with lonafarnib achieving FDA ...
[59]
Crystal structure of type-III geranylgeranyl pyrophosphate synthase ...
Geranylgeranyl pyrophosphate synthase (GGPPs) catalyzes a condensation reaction of farnesyl pyrophosphate with isopentenyl pyrophosphate to generate C(20) ...
[60]
Crystal Structure of Geranylgeranyl Pyrophosphate Synthase (CrtE ...
May 24, 2020 · The crystal structure of CrtE solved to a resolution of 2.7 Å revealed a strong structural similarity to the large subunit of the heterodimeric ...
[61]
Farnesol is utilized for isoprenoid biosynthesis in plant cells ... - PNAS
Farnesyl pyrophosphate (F-P-P) is a key intermediate in the isoprenoid biosynthetic pathway positioned at a putative regulatory point capable of diverting ...Missing: decomposition | Show results with:decomposition<|separator|>
[62]
Cwh8 moonlights as a farnesyl pyrophosphate phosphatase and is ...
Sep 8, 2025 · Farnesol is a secreted autoregulatory molecule that represses filamentation. It is derived from farnesyl pyrophosphate (FPP), an ergosterol ...
[63]
Cyclonerodiol biosynthesis and the enzymic conversion of farnesyl ...
Cyclonerodiol biosynthesis and the enzymic conversion of farnesyl to nerolidyl pyrophosphate ... Incorporation of deuterium-labelled analogs of isopentenyl ...
[64]
Studies of the cryptic allylic pyrophosphate isomerase activity of ...
Two enantiomeric analogues of farnesyl pyrophosphate (1) were tested as inhibitors and anomalous substrates of trichodiene synthase.
[65]
"Farnesyl Pyrophosphate Analogs" by Hans Peter Spielmann ...
Sep 4, 2001 · The present invention describes design and synthesis of a farnesylpyrophosphate (FPP) analog, 8-anilinogeranyl pyrophosphate (AGPP) that is ...
[66]
Synthesis of Frame-Shifted Farnesyl Diphosphate Analogs - PMC
A set of synthetic approaches was developed and applied to the synthesis of eight frame-shifted farnesyl diphosphate (FPP) analogs.Missing: faranalogues | Show results with:faranalogues
[67]
Farnesyl-Diphosphate Farnesyltransferase - an overview
The substrate for squalene synthase is FPP, which also serves as a metabolic intermediate in the formation of sterols, dolichols, ubiquinones, and farnesylated ...
[68]
Fine-Tuning the Function of Farnesene Synthases for Selective ...
Nov 26, 2024 · Farnesene synthase from Artemisia annua (AaFS) catalyzes the reaction from farnesyl pyrophosphate (FPP) to give the sesquiterpene β-farnesene.
[69]
Biosynthesis of ??-Farnesene and its Relation to Superficial Scald ...
Aug 7, 2025 · Our results indicate that biosynthesis of α-farnesene in apple tissue occurs through the isoprenoid pathway, and the conversion of FPP to α- ...
[70]
Biochemistry of Mitochondrial Coenzyme Q Biosynthesis - PMC - NIH
Polyprenyl diphosphate synthase essentially defines the length of the side chain of ubiquinone. Biochim Biophys Acta. 1996;1302:217–223. doi: 10.1016/0005 ...
[71]
Coenzyme Q biochemistry and biosynthesis - PMC - NIH
Coq2p/COQ2 then attaches the tail to 4-HB to yield polyprenyl-hydroxybenzoate (PPHB) [3]. The final stage of CoQ biosynthesis involves a series of modifications ...
[72]
Biosynthesis of dolichol and cholesterol in rat liver peroxisomes
Isolated rat liver peroxisomes contain the complete enzymatic machinery required for the synthesis of both cholesterol and dolichol from farnesyl ...
[73]
Dolichol Biosynthesis and Its Effects on the Unfolded Protein ... - NIH
The biosynthesis of dolichols takes place mainly in the endoplasmic reticulum (ER) and to a lesser extent in peroxisomes (Chojnacki and Dallner, 1988). This ...