Aldehydes: Structures, Formation, Biological Effects and Analytical Methods

Structures and Formation of Bioactive Aldehydes

Aldehydes are organic compounds characterized by the presence of a carbonyl group (-C=O) at the terminal carbon, which is also bonded to a hydrogen atom. This unique structural feature distinguishes aldehydes from other functional groups, such as ketones, carboxylic acids, and esters.

The general chemical formula of an aldehyde is R-CHO, where R represents an organic substituent or a hydrogen atom. The presence of different R groups gives rise to a wide variety of aldehydes with distinct chemical properties and biological functions.

Chemical structures of several reactive aldehydes (Baker et al., 2019).

Formation of Aldehydes

Bioactive aldehydes can be produced by a variety of mechanisms, including enzymatic and non-enzymatic processes. Aldehyde production in living beings is predominantly mediated by enzymes such as alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs).

ADHs catalyze the oxidation of primary alcohols to aldehydes in the case of alcohol metabolism. ADH, for example, oxidizes ethanol (CH3CH2OH) to acetaldehyde (CH3CHO), a bioactive aldehyde. In a following enzymatic step, ALDH converts acetaldehyde to acetic acid (CH3COOH).

Bioactive aldehydes can also be formed by non-enzymatic mechanisms. Lipid peroxidation is a well-known non-enzymatic process that happens when polyunsaturated fatty acids (PUFAs) experience oxidative destruction. PUFAs are oxidized to reactive aldehydes such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) during lipid peroxidation.

Oxidation of Alcohols to Aldehydes

The oxidation of primary alcohols can result in the formation of aldehydes. Two hydrogen atoms are removed from the alcohol molecule, leading in the creation of a carbonyl group (-C=O) at the terminal carbon. Various oxidizing agents, such as chromium trioxide (CrO3) or pyridinium chlorochromate (PCC), can be used to convert primary alcohols to aldehydes. These reagents oxidize the alcohol functional group while leaving the other functional groups alone. For example, utilizing PCC to oxidize ethanol (CH3CH2OH) produces acetaldehyde (CH3CHO), an essential bioactive aldehyde implicated in a variety of physiological activities.

Oxidative Stress and Aldehyde Formation

Aldehydes can develop as a result of oxidative stress in biological systems. Reactive oxygen species (ROS) generation and cellular antioxidant defense mechanisms must balance each other out for oxidative stress to occur. Oxidative damage can result from ROS, such as superoxide radicals and hydrogen peroxide (H2O2), reacting with lipids, proteins, and DNA. Reactive aldehydes like MDA and 4-HNE are created specifically when polyunsaturated fatty acids (PUFAs) are oxidized by ROS. Further interactions between these reactive aldehydes and biomolecules might result in adducts that change the structure and functionality of the biomolecules. For instance, 4-HNE can create covalent adducts with proteins that degrade cellular function and cause proteins to malfunction.

Enzymatic Metabolism of Aldehydes

In living organisms, aldehydes produced as metabolic intermediates or byproducts are efficiently metabolized by enzymatic processes to prevent their accumulation and potential toxicity.

The conversion of aldehydes to less reactive and more soluble compounds is primarily mediated by aldehyde dehydrogenases (ALDHs). ALDHs catalyze the oxidation of aldehydes to their corresponding carboxylic acids, which are further metabolized or excreted from the body.

For example, acetaldehyde, a bioactive aldehyde formed during alcohol metabolism, is rapidly metabolized to acetic acid by ALDH. Acetic acid can then enter the tricarboxylic acid (TCA) cycle and be further metabolized for energy production.

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Biological Effects of Aldehydes

Aldehydes exhibit a wide range of biological effects, playing both beneficial and detrimental roles in various biological processes. Their effects can be attributed to their chemical reactivity and ability to interact with biomolecules, leading to physiological and pathological consequences.

Cellular Signaling

Aldehydes, at low concentrations, can act as signaling molecules in cellular communication and regulation of physiological processes. They can modulate signaling pathways and gene expression, influencing cell proliferation, differentiation, and apoptosis. One example of a bioactive aldehyde involved in cellular signaling is retinaldehyde. Retinaldehyde plays a crucial role in vision by serving as the chromophore for opsins in the visual pigments of photoreceptor cells. The absorption of light by retinaldehyde triggers a cascade of events leading to the generation of electrical signals and visual perception.

Oxidative Stress and Cellular Damage

Overproduction of reactive aldehydes, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), can lead to oxidative stress and cellular damage. Reactive aldehydes can react with proteins, lipids and DNA, leading to changes in their structure and function. For example, the reaction of reactive aldehydes with proteins can lead to the formation of protein adducts and cross-links that impair protein function and cellular processes. In addition, aldehydes can induce DNA damage through the formation of DNA adducts, leading to gene mutations and potential carcinogenic effects. These effects highlight the importance of cellular defense mechanisms, such as antioxidant systems and DNA repair pathways, to minimize the deleterious effects of aldehydes.

Inflammation and immune response

Aldehydes can modulate inflammatory processes and immune responses. They can activate immune cells, such as macrophages and neutrophils, leading to the release of pro-inflammatory cytokines and chemokines. One biologically active aldehyde involved in the immune response is acrolein. Acrolein is produced during the metabolism of certain drugs and chemicals, as well as under conditions of oxidative stress. It can trigger inflammation by activating the nuclear factor kappa B (NF-κB) signaling pathway, which regulates the expression of inflammatory mediators. Aldehydes, including acetaldehyde, can alter proteins and produce new antigens, which can cause an immune response and lead to the development of autoimmune diseases.

Cellular Toxicity and Disease

Excessive accumulation of aldehydes can lead to cytotoxicity and contribute to the pathogenesis of various diseases. For example, aldehydes from lipid peroxidation have been implicated in the development and progression of cardiovascular diseases, neurodegenerative diseases, and cancer.

In cardiovascular diseases, aldehydes can induce endothelial dysfunction, promote the formation of atherosclerotic plaques, and contribute to the development of hypertension. They can also impair heart function and contribute to the development of heart failure.

In neurodegenerative diseases, aldehydes, especially 4-hydroxynonenal (4-HNE), can exert cytotoxic effects on neurons, leading to oxidative stress, mitochondrial dysfunction and neuronal death. Aldehydes-mediated damage can be observed in diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

Aldehydes are also thought to be associated with the development and progression of cancer. Their ability to modify DNA and proteins can promote genomic instability, abnormal cell signaling, and tumor growth. Aldehyde detoxifying enzymes, such as aldehyde dehydrogenases (ALDHs), play a key role in protecting cells from the deleterious effects of aldehydes and maintaining cellular homeostasis.

Bioactive Aldehydes in Plants

Aldehydes are important in plant biology because they participate in different physiological processes and contribute to plant adaptability and defense systems. Plants, for example, can create aldehydes as secondary metabolites in response to environmental stresses such as drought or pathogen assault, which operate as signaling molecules and trigger defensive responses.

Plants include bioactive aldehydes such as jasmonic acid, salicylaldehyde, and hexenal. Jasmonic acid, a linolenic acid derivative, is an important regulator of plant defensive responses against herbivores and pathogens. Salicylaldehyde, a plant hormone produced from salicylic acid, is implicated in plant immunological responses. Hexenal, which is produced by the oxidation of polyunsaturated fatty acids, is responsible for the distinctive scent of newly cut grass and functions as a signaling molecule in plant defense against insects.

The role of lipid-peroxide-derived aldehydes in plants (Liang et al., 2022).

Aldehyde Analytical Methods: GC-MS and LC-MS

For the identification and quantification of aldehydes in diverse samples, accurate and sensitive analytical procedures are required. For aldehyde analysis, two widely used methods are gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). Each approach has benefits and is appropriate for various types of aldehydes and sample matrices.

Gas Chromatography-Mass Spectrometry (GC-MS

GC-MS is an effective technology for analyzing volatile and semi-volatile aldehydes. The use of gas chromatography and mass spectrometry in conjunction allows for the separation, identification, and quantification of aldehydes in complicated mixtures. GC-MS analysis begins with the injection of an aldehyde sample into a gas chromatograph, where it is vaporized and separated depending on its volatility and affinity for the stationary phase. The separated aldehydes are then ionized, broken, and identified in the mass spectrometer based on their mass-to-charge ratio. High sensitivity, good separation capabilities, and the capacity to detect aldehydes based on their mass spectra are all advantages of GC-MS. It is especially effective for detecting volatile aldehydes in environmental, culinary, and fragrance samples.

Liquid Chromatography-Mass Spectrometry (LC-MS

LC-MS is a flexible technology that may be used to analyze both polar and non-volatile aldehydes. In LC-MS analysis, the aldehyde sample is initially separated by liquid chromatography based on its interactions with the stationary phase. The separated aldehydes are then introduced into the mass spectrometer, where they are ionized, fragmented, and identified. LC-MS can analyze a wide spectrum of aldehydes in complex matrices such as biological fluids, environmental materials, and food extracts. It has high sensitivity, selectivity, and the capacity to detect and quantify aldehydes based on their mass spectra and retention durations. For aldehyde analysis, many LC-MS technologies can be used, including reversed-phase LC-MS, hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS), and ion mobility spectrometry-mass spectrometry (IMS-MS).

In some cases, a combination of GC-MS and LC-MS techniques, known as comprehensive two-dimensional gas chromatography-mass spectrometry (GC×GC-MS) or online LC-GC-MS, can be employed to achieve comprehensive aldehyde analysis.

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References

Baker, G., Matveychuk, D., MacKenzie, E. M., Holt, A., Wang, Y., & Kar, S. (2019). Attenuation of the effects of oxidative stress by the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine. Chemico-Biological Interactions, 304, 139-147.
Liang, X., Qian, R., Wang, D., Liu, L., Sun, C., & Lin, X. (2022). Lipid-Derived Aldehydes: New Key Mediators of Plant Growth and Stress Responses. Biology, 11(11), 1590.

* For Research Use Only. Not for use in diagnostic procedures.

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