Essay: What is carbonyl stress, what does it cause and why is it important in human biology?

Abstract
Reactive carbonyl species (RCS) are a common within living organisms, and are primarily recognized for their damaging properties. The main reason they are formed, are through the oxidation of lipids, amino acids and carbohydrates. RCS creates cytotoxicity and mutagenicity, by the chemical modification of aminophospholipids, proteins and nucleic acids. A large number of cross links and adducts are being drawn into a pathology of a vast range of human diseases due to biochemical alterations and toxicity of RCS. The continuous research of the relationship between the development of pathological disorders and metabolism of RCS may give us an insight on how to approach and prevent the growth of diseases and disorders.
Introduction
RCS are generally seen for their negative effect in human biology. They are produced in many various organisms, from microorganisms to humans; they come in forms of large biological compounds containing one or more carbonyl groups. Concentration of RCS is maintained at a steady state within a certain range and alters in the cell, just like other restrictions. Conversely, due to the changes of elimination and/ or production of RCS it may leave the range. If the steady state of reactive carbonyl species is increased, it can cause carbonyl stress which is a leading factor of chronic complications associated with diabetes, aging, and pathogenesis of metabolic syndrome, amongst others. However, if the steady-state is maintained within the correct range, it is seen to play an important role in cellular signalling messengers, immune response and regulators of gene expression.
Production of reactive carbonyl species
RCS can be found throughout different biological beings; over 20 reactive carbonyl species have been discovered through biological samples which can be derived either exogenously or endogenously. There are a few reactive carbonyls such as formaldehyde, glyoxal, crotonaldehyde, acrolein and acetone, which are present abundantly as pollutants – especially in industrial environments – which can penetrate into cells with ease. We also consume sources of RCS on a daily basis through food additives, browned foods and cigarette smoke. These are known as exogenous, due to the way they enter biological lives.
Fig 1: Most abundant RCS and their structures.
Over the years research has shown that RCS are endogenously produced through enzymatic, or nonenzymatic procedures (like glycation, lipid peroxidation and amino acid oxidation). During lipid peroxidation a key feature of the procedure is the breakdown of the free radical chain by polyunsaturated fatty acid residues found in phospholipids, triglycerides and cholesterolesters. These chemicals obtain a range of different reactive carbonyl species. Glycine and threonine are amino acids which have the ability to convert into their original forms of succinylacetone and aminoacetone, however it is also able to be converted into RCS; this all occurs during oxidative modification.
Carbohydrates such as fructose and glucose are involved in a biological process called glycation, which leads to the production of RCS. Humans today, consume excessive amounts of carbohydrates, and so there has been extensive research into glycation. The biological mechanism of reducing carbohydrates provides both positive and negative effects on living organisms. It has been suggested that reactive oxygen species (ROS) and reactive carbonyl species are involved in the defensive and cytotoxic effects when reducing carbohydrates.
There are enzymatic processes involving carbohydrates – such as glyoxal (GO), 3-deoxyglucosone (3-DG) and methylglyoxal (MGO), which are produced as by-products. The metabolic pathway called the polyol pathway is usually involved in the production of 3-DG, while the glycolysis metabolic pathway results in MGO produced as a by-product. During the triosophosphate isomerase reaction, enediol phosphate escapes from the enzymes active site and decomposes rapidly into inorganic phosphate and MGO.
Fig 2. Representation of methylglyoxal formation through glycolysis.
Generally speaking glyceraldehyde-3-phosphate, dioxyacetone phosphate and acetaldehyde are carbonyl metabolic intermediates, which are usually at low steady state concentration in cells, due to the rate at which they are utilised by the following pathway. On the other hand, in enzymatic reactions it is a different case. The regulation of reactive carbonyl by-products are not as efficiently regulated which changes the steady state concentration and can cause the by-products to become more intoxicating than the intermediates.
Negative impact of reactive carbonyl species
RCS are generally electrophilic, like the majority of by-products. In turn, intermediates of metabolism make them highly reactive to varied components of the cell, such as nucleophiles. Saturated RCS are usually less reactive than unsaturated RCS which is why they cause damage to biological pathology when dialdehydes, ketoaldehyde and α, β- unsaturated aldehydes are included. Biomolecules such as imidazole, hydroxyl groups and thiol have strong nucleophilic sites which attract electrophilic attacks. Highly reactive α- or β-dicarbonyl compunds like MGO, GO, 3-DG and Malondialdehyde (MDA) react with macromolecules that are nucleophilic (e.g. nucleic acids, aminophospholipids) and proteins, which cause irreversible changes to the formation of different cross links and adducts, which are all categorised as advanced lipoxidation end products (ALEs) or advanced glycation end product (AGEs).
AGEs and ALEs are generally insufficiently broken down compounds and can build up due to age. Adducts were discovered in peripheral blood as well as tissues and are known to have pathogenic properties. MGO and GO produce AGEs/ALEs through there interaction with phospholipids and nucleic acids which are represented by carboxymethylguanosine and carboxymethyl phosphatidylethanolamine. The modification of proteins results in creation of adducts: carboxymethyllysine, argpyrimidine, GO-lysine dimmer, carboxymethylcysteine and MGO-lysine dimmer – which are the most common types of ALEs and AGEs, because RCS have a high reactive rate with cysteine, arginine and lysine residues. RCS play a major part in pathogenesis, due to the high number of amino acid in the company of protein active sites. The first AGE isolated from glycated proteins was carboxymethyllysine, which joined with glucosepane and pentosidine as an important indicator in glycation within biological beings. Metabolic syndromes such as, elevated blood pressure, hyperglycemia, and glucose intolerance, for example, are all found that the features are induced by ALEs, AGEs and RCS.
ROS are seen to have a similar effect to RCS and should obtain similar physiochemical properties to each other. There are differences, however, such as the shorter lifespan, and lower stability of ROS. It is understood that H2O2 and HO2• as an uncharged ROS can cross membranes and diffuse into cells for long distances, and due to the high stability of RCS they are also able to leave the intracellular environment and interact with sites far from their origin.
Positive attributes and regulation of intracellular signalling
We can see that a high concentrate of RCS can be detrimental to biological life by causing accelerative aging, and pathological disorders. However, various RCS can also be generated by activated human phagocytes. There have been results showing phagocytic white blood cells can play an important role in in biological host defence mechanism, where they use RCS to attack against invading pathogens. RCS are highly toxic and reactive; during the 1960s an experimental study obtained results to show that MGO was a highly effective anticancer agent which was down to the compounds ability to preventing mitochondrial respiration and glycolysis of malignant cells. Not only does it contain anticancer properties but also shown to have antiviral, antifungal, antibacterial and antiviral effects.
The role of RCS has been debated for many years; though one topic that has been understood is its role in regulating signalling. RCS can be classified as signals due to their ability to cross and diffuse into biological membranes, inhibit enzymatic control, and activate specific receptors, as well as being involved in the reversible feature of signalling through degradation and resynthesis of proteins modified by RCS. 4-hydroxy-2-nonenal (4NHE), GO, MGO and MDA all have the ability to function as messengers that can inhibit and activate pathologic or physiologic signalling pathways by affecting the mechanism through a manner of time- and concentration-dependency. Research has shown that 4-HNE at lower concentrations promote proliferation, yet at a higher level can induce apoptosis and diversity. There are four main cell signalling pathways which are modulated by RCS, these pathways are involved in kinase/phosphate activities, nuclear transcription factor function, stress responses and proapoptic events, which are all present in living organisms.
Fig 3. RCS involved in the regulation of signalling.
Conclusion
There is evidence that suggests that RCS have the capability to adjust levels of homeostasis by having both deleterious and beneficial effects in the regulation of signalling and transcription. Various signalling networks participate in the damaging effects as well as being involved in the advantages of RCS. Experimental evidence implies the biological effects of RCS’ nature is both time- and dose-dependent and due to its ability to modulate biological processes, it has a direct effect on the development of various pathologies, immune response, proliferation, differentiation, and many more. Through further research, new tools could develop understanding around the link between the metabolism of RCS and its effect on the development of pathological disorders, as well as leading to the discovery of therapeutic methods to help cure or prevent more disorders and diseases.