Introductory Chapter: General Aspects Regarding Cysteine and Homocysteine

Abstract

Cysteine and homocysteine are sulfur-containing amino acids that play significant roles in various biological processes. While cysteine is a building block of proteins and a precursor to important biomolecules, homocysteine is a metabolic intermediate that can impact health when present in elevated levels. The metabolism of cysteine and homocysteine is tightly regulated and interconnected. Adequate levels of vitamins B6, B12, and folate are essential for the proper functioning of the metabolic pathways involved in their synthesis and conversion. Elevated homocysteine levels are a biomarker for various diseases, and managing these levels is crucial for preventing associated health risks. Cysteine and homocysteine are vital sulfur-containing amino acids with significant roles in human health. Understanding their metabolism and regulation is crucial for maintaining health and preventing diseases. Therapeutic interventions focusing on dietary and lifestyle modifications can effectively manage abnormal levels of these amino acids, contributing to overall well-being.

1. Introduction

Amino acids are fundamental building blocks of life, playing pivotal roles in various metabolic processes. These two amino acids, cysteine and homocysteine, contain the sulfur atom and are particularly important because they play a crucial role in various physiological processes [1, 2]. Cysteine was first isolated by Eugen Baumann, a German chemist, in 1884. Baumann was investigating the components of animal horn material when he identified cystine, the oxidized dimer form of cysteine [3]. Cysteine is involved in the synthesis of proteins, antioxidants, and important molecules such as glutathione, which help protect cells against oxidative stress. Modern techniques in protein engineering utilize cysteine residues to create more stable and functional proteins for therapeutic and industrial applications [4].

Homocysteine was first discovered by Vincent du Vigneaud, an American biochemist, during his research on the metabolic pathways of sulfur-containing amino acids. Du Vigneaud was awarded the Nobel Prize in Chemistry for his work on the synthesis of essential biological substances, including his research on methionine and homocysteine [5]. Kilmer McCully, an American pathologist, proposed the “homocysteine hypothesis” of arteriosclerosis. McCully’s research showed that elevated levels of homocysteine could damage blood vessels, leading to cardiovascular diseases, such as heart attacks and strokes [6]. His work was initially controversial but later gained acceptance and led to a broader understanding of homocysteine’s role in vascular health.

Homocysteine is a metabolite of methionine and is involved in methylation reactions and the synthesis of important molecules, such as DNA and neurotransmitters. However, elevated levels of homocysteine have been associated with several pathological processes, such as cardiovascular disease, neurodegenerative disorders, and impaired cognitive function. Additionally, research has shown that elevated homocysteine levels can contribute to the development of insulin resistance and diabetes. Furthermore, it has been suggested that the imbalance between cysteine and homocysteine levels can disrupt the redox balance in cells, leading to increased oxidative stress and cellular damage [7]. Advances in genetic research have identified mutations in genes involved in homocysteine metabolism (such as MTHFR) that can affect homocysteine levels and influence disease risk [8]. Personalized medicine approaches are being explored to address these genetic variations and optimize treatment strategies. These new insights highlight the intricate roles of cysteine and homocysteine in various pathological processes, shedding light on potential therapeutic targets for diseases associated with the dysregulation of these amino acids. New insights into the roles of cysteine and homocysteine in pathological processes have revealed their importance in various physiological functions, as well as their potential contribution to the development and progression of several diseases [9, 10].

2. Cysteine metabolism

Cysteine metabolism is a biochemical process that involves both synthesis and degradation of cysteine. Cysteine is an important amino acid for protein synthesis, detoxification, and various metabolic functions.

Cysteine synthesis occurs through the methionine transsulfuration pathway.

Methionine, an essential amino acid, is first converted to S-adenosylmethionine (SAM) by an ATP-dependent reaction.

SAM subsequently donates a methyl group in various methylation reactions, becoming S-adenosylhomocysteine (SAH), which is then hydrolyzed to homocysteine by S-adenosylhomocysteine hydrolase.

Homocysteine is converted to cystathionine by a reaction catalyzed by cystathionine β-synthase (CBS) with the help of serine. Cystathionine is then cleaved by cystathionine γ-lyase (CGL) to produce cysteine, α-ketobutyrate, and ammonia.

The activity of key enzymes like CBS and CGL is regulated by feedback mechanisms and can be influenced by the cellular levels of substrates and products.

Degradation of cysteine involves several pathways (Figure 1):

1. Cysteine dioxygenase (CDO) pathway: CDO converts cysteine to cysteine sulfinic acid, which can be further metabolized to taurine or undergo desulfurization to form pyruvate and sulfate. Taurine, an important molecule derived from cysteine sulfinic acid, plays significant roles in bile salt formation and cellular osmoregulation.

2. Desulfhydration pathway: cysteine can be directly converted to pyruvate by desulfurization, with the release of ammonia and hydrogen sulfide (H₂S) [11].

3. Mercaptopyruvate pathway: cysteine aminotransferase catalyzes the transamination of cysteine with α-ketoglutarate to form 3-mercaptopyruvate which can be further converted by 3-mercaptopyruvate sulfurtransferase (MPST) to pyruvate and H₂S.

4. Glutathione pathway: cysteine is a precursor for glutathione (GSH), an important cellular antioxidant.

Figure 1.

Cysteine degradation.

Cysteine degradation is a multifaceted process that integrates various metabolic pathways to maintain amino acid balance, detoxify sulfur compounds, produce important signaling molecules like hydrogen sulfide and contribute to the synthesis of biomolecules, such as taurine and glutathione.

3. Physiological roles and clinical significance

Cysteine plays several crucial roles in the body (Figure 2) [12]:

• Cysteine is a key component of many proteins, contributing to their structural stability through disulfide bonds [13].

• It is a precursor of glutathione, a major intracellular antioxidant that protects cells from oxidative stress [14].

• Cysteine participates in the detoxification of harmful substances through conjugation reactions in the liver [15].

Figure 2.

The importance of cysteine in human health.

Clinical relevance of cysteine [16].

Homocystinuria: a disorder caused by deficiencies in cystathionine-β-synthase, leading to the accumulation of homocysteine and associated complications, such as cardiovascular disease.

Cystinosis: a condition characterized by the accumulation of cystine (the oxidized dimer form of cysteine) in lysosomes, leading to kidney damage and other systemic problems.

Glutathione deficiency: can result from impaired cysteine metabolism, leading to increased oxidative stress and susceptibility to various diseases.

Homocysteine has significant clinical relevance:

• Cardiovascular health: elevated levels of homocysteine, known as hyperhomocysteinemia, are associated with an increased risk of cardiovascular diseases, including atherosclerosis and thrombosis [17].

• Neurological function: homocysteine levels are linked to cognitive function and neurological disorders, with high levels potentially contributing to neurodegenerative diseases [18].

• Gastrointestinal disorders: the association between hyperhomocysteinemia and inflammatory bowel disease, along with other autoimmune diseases, is supported by the role of homocysteine in promoting inflammation, oxidative stress, endothelial dysfunction, and immune dysregulation [19].

• Chronic renal diseases: elevated homocysteine (Hcy) levels have been observed in patients with chronic renal failure (CRF), those on dialysis, and even after a kidney transplant [19].

Today, homocysteine is recognized as an important biomarker for several health conditions, and maintaining its levels within a normal range is considered beneficial for overall health. The ongoing research aims to better understand the complex interactions between genetics, nutrition, and lifestyle factors in the regulation of homocysteine levels and their impact on health. Further studies are also focused on the potential therapeutic benefits of lowering homocysteine levels in various diseases.

Conflict of interest

The authors declare no conflict of interest.