What does fumarate do in the body? Uncovering Its Metabolic and Pharmacological Roles

October 8, 2025 •

4 min read

Fumarate is a key intermediate in the citric acid cycle (Krebs cycle), a fundamental metabolic pathway that generates the majority of the energy for cells in the form of ATP [1.2.1, 1.6.1]. So, what does fumarate do in the body beyond basic energy production?

Quick Summary

Fumarate is a vital intermediate in the body's energy production pathway, the Krebs cycle. It also functions as a signaling molecule, plays a role in immunity, and is used as a salt in medications to improve stability and bioavailability.

Key Points

Core Metabolic Function: Fumarate is a critical intermediate in the Krebs (citric acid) cycle, essential for producing cellular energy (ATP) [1.2.1, 1.6.1].
Formation and Conversion: It is formed from succinate and is then converted to malate within the mitochondria, a key step in cellular respiration [1.3.3].
Pharmaceutical Excipient: As a salt, fumarate is used in drug formulations to increase the stability, control pH, and improve the bioavailability of active ingredients [1.4.1, 1.4.3].
Active Therapeutic Agent: Fumaric acid esters, like dimethyl fumarate (DMF), are medications used to treat multiple sclerosis (MS) and psoriasis due to their immunomodulatory properties [1.4.5, 1.4.7].
Immune System Modulation: Fumarate acts as a signaling molecule that can regulate innate and adaptive immune responses, influencing both autoimmune conditions and cancer immunity [1.2.3, 1.6.4].
Tumor Suppression: Beyond metabolism, fumarate is involved in the DNA damage response pathway, contributing to its function as a tumor suppressor by helping maintain genomic stability [1.3.5, 1.6.6].
Dual Roles: The molecule plays a dual role as both a fundamental metabolite for energy and a sophisticated signaling agent with therapeutic applications [1.6.4].

Introduction to Fumarate

Fumarate is a naturally occurring organic compound essential to life [1.4.1]. It is the ionized form of fumaric acid and exists as a critical intermediate in one of the most important biochemical pathways: the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle [1.2.1, 1.6.4]. This cycle is the central hub for cellular respiration, responsible for generating energy from carbohydrates, fats, and proteins [1.6.1]. Beyond this core metabolic function, fumarate has emerged as a multifaceted molecule, acting as a cellular signal, an immune system modulator, and a key component in modern pharmaceuticals [1.2.3, 1.6.4]. Its unique properties allow it to bridge the gap between basic metabolism and complex processes like disease treatment and DNA repair [1.6.6].

The Central Role of Fumarate in Energy Metabolism

The primary and most well-known function of fumarate is its participation in the Krebs cycle, which occurs within the mitochondria of cells [1.3.6, 1.6.5]. This eight-step process is fundamental for converting nutrients into usable energy.

Formation from Succinate: Fumarate is formed in the seventh step of the Krebs cycle through the oxidation of another intermediate called succinate. This reaction is catalyzed by the enzyme succinate dehydrogenase [1.2.1, 1.3.3].
Conversion to Malate: Once formed, fumarate is quickly converted into L-malate by the enzyme fumarase (or fumarate hydratase) [1.3.1, 1.3.2].
Fueling ATP Production: The conversion of succinate to fumarate is coupled with the reduction of flavin adenine dinucleotide (FAD) to FADH2. This FADH2 molecule then donates its electrons to the electron transport chain, a process which directly leads to the production of adenosine triphosphate (ATP), the cell's main energy currency [1.2.1, 1.6.1].

Disruptions in this part of the cycle, such as a deficiency in the fumarase enzyme, can impair energy production and lead to serious metabolic disorders [1.3.2, 1.3.7].

Fumarate in Pharmacology: More Than a Metabolite

Beyond its natural role, fumarate (as fumaric acid) is widely used in the pharmaceutical industry. It is often combined with an active pharmaceutical ingredient (API) to form a 'fumarate salt' [1.4.3]. This formulation strategy offers several significant advantages.

Enhancing Drug Stability and Bioavailability

Many drug molecules are unstable in their base form. Converting them into a fumarate salt significantly enhances their chemical stability, reduces their susceptibility to degradation from heat and moisture, and can prolong shelf life [1.4.3]. Fumaric acid acts as a pH stabilizer and can create a slightly acidic microenvironment within a tablet, protecting the API from degradation [1.4.1, 1.4.3]. This increased stability ensures the drug remains potent and effective. Furthermore, some fumarate salts, like sodium stearyl fumarate, are more hydrophilic (water-loving) than other common excipients, which can lead to faster tablet disintegration and improved drug dissolution and absorption (bioavailability) [1.4.2].

Fumaric Acid Esters (FAEs) in Therapeutics

Derivatives of fumaric acid, known as fumaric acid esters (FAEs), are active therapeutic agents themselves. The most prominent example is dimethyl fumarate (DMF).

Psoriasis: DMF is approved for treating moderate-to-severe plaque psoriasis [1.4.5, 1.5.4]. Its mechanism is immunomodulatory; it is thought to shift the immune response from a pro-inflammatory T-helper 1 (Th1) and Th17 profile towards an anti-inflammatory Th2 phenotype [1.7.1, 1.7.2]. This helps reduce the skin inflammation and keratinocyte proliferation characteristic of psoriasis plaques [1.7.2].
Multiple Sclerosis (MS): DMF is also a first-line oral therapy for relapsing forms of multiple sclerosis [1.4.7]. While its exact mechanism in MS is not fully understood, it is believed to activate the Nrf2 antioxidant pathway, which helps protect central nervous system cells from oxidative stress [1.7.4]. It also exhibits anti-inflammatory and immunomodulatory effects [1.4.4, 1.7.1].


Feature	Fumarate (as an Excipient)	Fumaric Acid Esters (e.g., DMF)
Primary Function	Enhances stability, solubility, and bioavailability of another drug [1.4.1, 1.4.3]	Acts as the primary active therapeutic agent [1.4.5]
Mechanism	Forms a stable salt, controls microenvironment pH [1.4.3]	Immunomodulatory and antioxidant effects via Nrf2 and other pathways [1.7.1, 1.7.4]
Common Use	Tablet and capsule formulations of various drugs (e.g., antivirals, antifungals) [1.4.1]	Treatment of Multiple Sclerosis and Psoriasis [1.4.7, 1.5.4]
Example	Vonoprazan Fumarate, Quetiapine Fumarate [1.4.3, 1.5.6]	Dimethyl fumarate (Tecfidera®, Skilarence®), Diroximel fumarate (Vumerity™) [1.5.1]

Broader Biological Significance

Recent research has uncovered even more roles for fumarate. It is not just a passive intermediate but an active signaling molecule that can influence cellular processes.

Immune Regulation: Fumarate integrates metabolism with both innate and adaptive immunity. Its accumulation can modulate immune cell differentiation and cytokine production, which has implications for both autoimmune diseases and cancer immunotherapy [1.2.3, 1.6.4].
DNA Damage Response: Studies have shown that a cytosolic (non-mitochondrial) form of the fumarase enzyme, and by extension fumarate itself, plays a role in the cellular response to DNA damage, particularly double-strand breaks [1.6.6]. This function as a tumor suppressor links cellular metabolism directly to genome stability [1.3.5].

Conclusion

Fumarate is far more than a simple cog in the metabolic machine. Its fundamental role in the Krebs cycle is the cornerstone of cellular energy production, making life as we know it possible [1.2.1]. In pharmacology, its salt form is a workhorse, enhancing the stability and effectiveness of numerous medications, while its ester derivatives have become powerful therapies for debilitating autoimmune diseases like MS and psoriasis [1.4.3, 1.4.5]. As research continues to peel back the layers of its function, fumarate is revealing itself to be a critical signaling molecule that sits at the crossroads of metabolism, immunity, and even DNA repair [1.2.3, 1.6.6].

For more information on the use of fumaric acid esters for skin conditions, you can visit DermNet [1.5.4].

Frequently Asked Questions

Fumarate's primary role is as a key intermediate in the citric acid cycle (Krebs cycle), a central metabolic pathway inside our cells' mitochondria that is responsible for generating energy in the form of ATP [1.2.1, 1.6.1].

In the Krebs cycle, fumarate is produced from the oxidation of succinate and is then hydrated to form malate. This step is crucial for continuing the cycle and producing FADH2, a molecule that directly contributes to cellular energy production [1.2.5, 1.3.3].

Fumaric acid is used to form stable salts with active drug ingredients. This process enhances the drug's chemical stability, protects it from degradation, improves dissolution, and can increase its absorption and bioavailability in the body [1.4.1, 1.4.3].

Dimethyl fumarate is a medication derived from fumaric acid used to treat relapsing forms of multiple sclerosis (MS) and moderate-to-severe plaque psoriasis [1.4.5, 1.4.7].

Yes, recent research shows that fumarate acts as a signaling molecule that links cellular metabolism with the immune system. It can modulate the activity of both innate and adaptive immune cells, which is relevant in autoimmune diseases and cancer [1.2.3, 1.6.4].

Yes, the body produces fumarate continuously as part of the Krebs cycle and the urea cycle [1.2.2, 1.2.3]. It is also formed in the skin during exposure to sunlight [1.2.2].

Genetic defects in the enzyme that processes fumarate (fumarase) can lead to a rare metabolic disorder called fumarase deficiency, which impairs cellular energy production and can cause severe neurological problems [1.2.4, 1.3.2]. Accumulation of fumarate is also linked to certain types of cancer [1.3.4, 1.6.3].