Fumaric Acid Unveiled: From Nature's Palette to Therapeutic Potential

Fumaric acid, a naturally occurring compound found in various fruits and vegetables, transcends its role as a food additive. This article delves into the multifaceted nature of fumaric acid, exploring its chemical properties, biological pathways, and potential therapeutic applications in human diseases.

1. Fumaric Acid: Discovery, Structure, and Biosynthesis

2. Fumaric Acid Metabolism

3. Fumaric Acid in Human Diseases

3.1 Psoriasis Treatment

3.2 Neuroinflammatory Diseases

3.3 Renoprotective Effects

3.4 Cancer Therapy

Fumaric Acid: Discovery, Structure, and Biosynthesis

Fumaric acid, a dicarboxylic acid, is a naturally occurring compound found in various fruits and vegetables, particularly in high concentrations in the fumitory plant (Fumaria officinalis). With its sour taste and versatility, fumaric acid is commonly used as a food additive to enhance acidity and flavor in various products such as beverages, candies, and baked goods. Additionally, it has applications in the cosmetic industries, serving as an ingredient in skincare products. Beyond its daily uses, fumaric acid has garnered significant attention for its potential therapeutic effects, particularly in the treatment of certain diseases.

Fumaric acid was first discovered in the early 19th century by French chemist Jean-Baptiste Quéruel and German chemist Leopold Gmelin. Its chemical structure was elucidated by German chemist Adolph Strecker in 1860. Fumaric acid exists as a colorless solid at room temperature and forms white crystalline needles. Structurally, it is a trans-alkene dicarboxylic acid with the chemical formula C4H4O4, comprising a central carbon chain with two carboxyl groups at the terminal ends. The molecule exhibits geometric isomerism, existing predominantly in the trans form.

Fumaric acid biosynthesis

Fumaric acid biosynthesis is a complex metabolic process occurring in both plants and microorganisms. In plants, it primarily involves the tricarboxylic acid (TCA) cycle, also known as the citric acid cycle, and the malate-aspartate shuttle. Here's a step-by-step overview of the biosynthesis pathway:

1. Entry into the Tricarboxylic Acid (TCA) Cycle: Fumaric acid biosynthesis begins with the entry of pyruvate into the TCA cycle. Pyruvate is derived from glycolysis and enters the mitochondria where it is converted into acetyl-CoA by the pyruvate dehydrogenase complex.

2. Formation of Citrate: Acetyl-CoA combines with oxaloacetate to form citrate, a six-carbon molecule, in a reaction catalyzed by citrate synthase.

3. Conversion to Isocitrate: Citrate is then isomerized to isocitrate by the enzyme aconitase.

4. α-Ketoglutarate Formation: Isocitrate undergoes oxidative decarboxylation to form α-ketoglutarate in a reaction catalyzed by isocitrate dehydrogenase. This step releases a molecule of CO2 and generates NADH.

5. Succinyl-CoA Formation: α-Ketoglutarate is further oxidized to succinyl-CoA by the enzyme α-ketoglutarate dehydrogenase complex. This reaction also releases a molecule of CO2 and generates another molecule of NADH.

6. Fumarate Formation: Succinyl-CoA is converted to succinate through a series of enzymatic reactions, culminating in the formation of fumarate by the enzyme succinate dehydrogenase.

7. Final Step - Fumaric Acid Synthesis: Fumarate is hydrated to form fumaric acid. This reaction, catalyzed by fumarase, involves the addition of a water molecule across the double bond of fumarate, resulting in the formation of the final product, fumaric acid.

Figure 2. The biosyuthesis pathway (TCA cycle) of fumaric acid (image adapted from Wikimedia)

Fumaric acid metabolism

Fumaric acid metabolism involves its conversion into various intermediate metabolites through a series of enzymatic reactions. Here's a detailed overview of the fumaric acid metabolism pathway:

1. Entry into the Tricarboxylic Acid (TCA) Cycle: Fumaric acid can enter the TCA cycle at the point where fumarate is hydrated to form malate. This reaction is catalyzed by the enzyme fumarase. Once fumarate is converted to malate, it can proceed through the rest of the TCA cycle to generate energy in the form of ATP and reducing equivalents in the form of NADH and FADH2.

2. Conversion to Oxaloacetate: Fumarate can also be converted to oxaloacetate through the reverse reaction of malate synthesis. This reaction is catalyzed by the enzyme fumarate hydratase, also known as fumarase.

3. Involvement in the Urea Cycle: Fumarate can participate in the urea cycle by condensing with ammonia to form arginine. This reaction occurs in the cytoplasm and is catalyzed by the enzyme argininosuccinate synthase.

4. Involvement in the Purine Nucleotide Cycle: Fumarate is also involved in the purine nucleotide cycle, where it participates in the conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP) or guanosine monophosphate (GMP). This reaction is catalyzed by the enzyme IMP dehydrogenase.

5. Regulation of Iron Homeostasis: Fumarate has been shown to play a role in regulating iron homeostasis in cells. It acts as a signaling molecule to activate the expression of genes involved in iron uptake and storage. This process involves the inhibition of prolyl hydroxylases by fumarate, leading to the stabilization of hypoxia-inducible factor (HIF) and subsequent activation of iron-related genes.

Figure 3. The metabolism pathway of fumaric acid (Allegri G. et al., 2010)

Fumaric acid in Human diseases

Fumaric acid, also known as trans-butenedioic acid, plays multifaceted roles in various diseases, exhibiting both therapeutic and pathological effects. Here's an overview of its functions in diseases, along with some important findings and detailed explanations of their mechanisms:

1. Psoriasis Treatment

Fumaric acid esters (FAEs), particularly dimethyl fumarate (DMF), have been widely used in the treatment of psoriasis, a chronic inflammatory skin disorder. FAEs have shown efficacy in reducing psoriatic lesions and improving symptoms. Mechanistically, FAEs exert anti-inflammatory effects by inhibiting the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. NF-κB is a key transcription factor involved in the regulation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17), which play crucial roles in the pathogenesis of psoriasis.

2. Neuroinflammatory Diseases

 Fumaric acid esters have emerged as promising therapeutic agents for the treatment of neuroinflammatory diseases, including multiple sclerosis (MS). DMF, in particular, has been approved for the treatment of relapsing-remitting MS. The therapeutic effects of DMF in MS are attributed to its immunomodulatory properties, including the inhibition of inflammatory cytokine production and the promotion of anti-inflammatory responses. DMF activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, leading to the upregulation of antioxidant and cytoprotective genes, which mitigate oxidative stress and neuroinflammation in MS.

3. Renoprotective Effects

Studies have demonstrated the renoprotective effects of fumaric acid in various kidney diseases, such as diabetic nephropathy and ischemia-reperfusion injury. Fumaric acid attenuates renal injury by suppressing inflammatory responses, reducing oxidative stress, and inhibiting apoptotic pathways. Additionally, fumaric acid enhances mitochondrial function and promotes cellular energy metabolism, which contribute to the maintenance of renal homeostasis and function.

4. Cancer Therapy

Fumaric acid derivatives have shown promising anticancer activities against various types of cancer, including melanoma, colorectal cancer, and glioblastoma. Fumaric acid induces apoptosis and inhibits proliferation in cancer cells by modulating multiple signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway, the phosphoinositide 3-kinase (PI3K)/Akt pathway, and the Wnt/β-catenin pathway. Furthermore, fumaric acid alters the tumor microenvironment by regulating immune cell functions and inhibiting angiogenesis, thereby suppressing tumor growth and metastasis.

Reference

Allegri G, Fernandes MJ, Scalco FB, et al. Fumaric aciduria: an overview and the first Brazilian case report. J Inherit Metab Dis. 2010;33(4):411-419. doi:10.1007/s10545-010-9134-2

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