Methionine Sulfone
Introduction
Section titled “Introduction”Background
Section titled “Background”Methionine sulfone is an oxidized derivative of the essential amino acid methionine. It represents a further oxidation product of methionine sulfoxide, which is itself formed from methionine through various oxidative processes. The formation of methionine sulfone is generally considered an irreversible step in the oxidation pathway of methionine residues in proteins and free methionine. Its presence often serves as an indicator of significant oxidative stress within biological systems.
Biological Basis
Section titled “Biological Basis”Methionine is unique among amino acids due to its sulfur atom, which makes it highly susceptible to oxidation. This oxidation can occur non-enzymatically through reactive oxygen species (ROS) or enzymatically. The initial oxidation product is methionine sulfoxide, which can be reversibly reduced back to methionine by enzymes like methionine sulfoxide reductases (MSR). However, further oxidation of methionine sulfoxide leads to the formation of methionine sulfone. Once formed, methionine sulfone is largely resistant to cellular repair mechanisms, making its accumulation a marker of irreversible oxidative damage. When methionine residues within proteins are oxidized to methionine sulfone, it can alter protein structure, function, and stability, potentially leading to protein unfolding, aggregation, and loss of enzymatic activity.
Clinical Relevance
Section titled “Clinical Relevance”The presence of methionine sulfone in tissues and biological fluids is clinically relevant as a biomarker for oxidative stress. Elevated levels have been associated with various pathological conditions characterized by increased oxidative damage. These include neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, cardiovascular disorders, inflammatory conditions, and the general aging process. The accumulation of oxidized proteins, particularly those containing methionine sulfone, is thought to contribute to cellular dysfunction and disease progression by impairing critical cellular processes and overwhelming cellular repair systems.
Social Importance
Section titled “Social Importance”Understanding the formation and impact of methionine sulfone holds significant social importance, particularly in the context of public health and disease prevention. Research into methionine sulfone’s role could lead to the development of novel diagnostic tools for early detection of oxidative stress-related diseases or provide insights into potential therapeutic targets. Strategies aimed at mitigating oxidative stress, whether through antioxidant interventions or lifestyle modifications, could potentially influence the levels of methionine sulfone and thereby impact the progression of associated diseases. Further research is crucial to fully elucidate its precise role in disease pathogenesis and its potential as a therapeutic or preventative marker.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Initial genetic association studies, particularly those exploring novel biomarkers like methionine sulfone, frequently encounter methodological and statistical constraints that can influence the robustness and interpretability of findings. Small sample sizes in discovery cohorts can lead to an overestimation of effect sizes, a phenomenon known as effect-size inflation, where initial associations appear stronger than they are in larger, more representative populations. This challenge is compounded by the potential for cohort-specific biases, where the selection criteria or demographic characteristics of the studied groups may not accurately reflect the broader population, limiting the immediate applicability of the results.
Furthermore, the lack of independent replication across diverse cohorts remains a significant hurdle in validating initial associations with methionine sulfone levels. Findings from single studies, even those with statistical significance, require confirmation in separate populations to ensure their generalizability and to distinguish true genetic signals from spurious correlations. Without robust replication, there is a risk that reported associations might not be consistently observed or may represent false positives, making it difficult to confidently establish the genetic architecture underlying methionine sulfone variation.
Generalizability and Phenotypic Characterization
Section titled “Generalizability and Phenotypic Characterization”A critical limitation in understanding the genetic influences on methionine sulfone involves issues of generalizability and the precise characterization of the phenotype itself. Genetic studies are often conducted in populations of predominantly European ancestry, which can restrict the transferability of findings to other ancestral groups. Genetic variants influencing methionine sulfone levels may exhibit different frequencies or have varying effects across diverse ancestries, meaning that associations identified in one group might not hold true or be as strong in others, thereby limiting the global utility of the research.
Moreover, the measurement of methionine sulfone, while potentially robust, must contend with inherent variability and potential measurement error that could obscure true genetic signals. Factors such as diurnal rhythms, dietary intake, or sample handling procedures could introduce noise into the phenotypic data, making it harder to detect subtle genetic associations. A lack of standardized measurement protocols across different research settings could also hinder cross-study comparisons and meta-analyses, complicating efforts to build a comprehensive understanding of methionine sulfone’s genetic determinants.
Environmental Influences and Unexplained Variation
Section titled “Environmental Influences and Unexplained Variation”The intricate interplay between genetics and environmental factors represents another significant limitation in fully elucidating the factors influencing methionine sulfone levels. Environmental confounders, such as dietary patterns, lifestyle choices, or exposure to specific xenobiotics, can profoundly impact methionine sulfone concentrations independently or in conjunction with genetic predispositions. Without comprehensive data on these environmental variables, it becomes challenging to disentangle their effects from purely genetic ones, potentially masking true genetic associations or creating artefactual ones.
Furthermore, a substantial portion of the variation in complex traits, including potentially methionine sulfone, often remains unexplained by identified genetic variants, a phenomenon referred to as “missing heritability.” This gap suggests that many genetic factors, individually having small effects, or complex gene-gene and gene-environment interactions, are yet to be discovered or fully understood. Consequently, current knowledge provides only a partial picture of the biological pathways and regulatory mechanisms that govern methionine sulfone levels, indicating the need for more sophisticated analytical approaches and broader data collection to fill these remaining knowledge gaps.
Variants
Section titled “Variants”Genetic variations across several genes contribute to individual differences in metabolism and cellular function, potentially influencing levels of methionine sulfone, an oxidized form of the essential amino acid methionine. Methionine sulfone can serve as a biomarker for oxidative stress and is implicated in various metabolic pathways. The interplay of these variants can affect amino acid transport, enzyme activity, and cellular maintenance, thereby impacting the body’s redox balance and methionine processing.
Variants associated with amino acid transport and general metabolism include those in or nearSLC6A19, NAT8, and CYP3A5. The gene SLC6A19encodes a key sodium-dependent neutral amino acid transporter, primarily responsible for reabsorbing amino acids like methionine in the kidney and intestine . Variants such asrs121434346 within SLC6A19 and rs11133665 in the intergenic region between TERLR1 and SLC6A19may alter the efficiency of methionine transport. Such changes could affect systemic methionine availability, thereby influencing its susceptibility to oxidation into methionine sulfone.NAT8 (N-acetyltransferase 8) is involved in the metabolism of N-acetylated compounds, and variants like rs10201159 (intergenic ALMS1 - NAT8) and intronic variants rs13538 , rs4547554 (near ALMS1P1) could impact NAT8expression or function, indirectly affecting methionine metabolism or oxidative stress pathways . Furthermore,CYP3A5, a member of the cytochrome P450 family, plays a role in drug and xenobiotic metabolism, and variant rs62471929 might influence its activity, potentially affecting cellular redox states or the metabolism of related compounds, thereby indirectly contributing to methionine sulfone levels.
Ciliary function and broader cellular maintenance are influenced by variants in genes like ALMS1 and CEP89. ALMS1 (Alström Syndrome 1) is critical for primary cilium function and intracellular transport, with mutations causing Alström syndrome, a condition characterized by metabolic disturbances . Variants rs6546844 and rs6711001 in ALMS1may subtly modulate its function, potentially affecting cellular signaling and metabolic regulation. Disruption in these processes could lead to altered methionine handling or increased oxidative stress, influencing methionine sulfone concentrations. Similarly,CEP89 (Centrosomal Protein 89) is essential for the organization of centrosomes and cilia, structures vital for cell division and signal transduction . Variants such as rs2897034 and rs8101667 in CEP89might affect its expression or the integrity of ciliary structures, indirectly impacting metabolic pathways, including those involved in methionine oxidation.
Transcriptional regulation and DNA repair mechanisms, mediated by genes such as CDK12 and FBXL20, also have potential implications for methionine sulfone levels.CDK12 (Cyclin Dependent Kinase 12) is a kinase that regulates RNA polymerase II during transcription elongation and is involved in DNA damage response pathways . Variants like rs12942352 and rs71147354 in CDK12could alter its activity, affecting the expression of genes involved in metabolic regulation or oxidative stress response. Changes in the cellular transcriptional landscape could lead to imbalances in the processes that manage methionine oxidation.FBXL20(F-box and Leucine Rich Repeat Protein 20) is a component of E3 ubiquitin ligase complexes, crucial for targeted protein degradation and various cellular processes, including DNA repair and cell cycle control . The variantrs11078896 in FBXL20might modify its role in ubiquitination, potentially impacting the stability of proteins involved in oxidative stress or methionine metabolism, and thus indirectly affecting methionine sulfone concentrations.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs10201159 | ALMS1 - NAT8 | 2-aminooctanoate measurement metabolite measurement N-acetyl-3-methylhistidine measurement N-acetylglutamine measurement N-acetylarginine measurement |
| rs121434346 | SLC6A19 | serum creatinine amount cystatin C measurement glomerular filtration rate N-delta-acetylornithine measurement 3-methoxytyrosine measurement |
| rs13538 rs4547554 | NAT8, ALMS1P1, ALMS1P1 | chronic kidney disease, serum creatinine amount hydroxy-leucine measurement serum metabolite level serum creatinine amount, glomerular filtration rate urinary metabolite measurement |
| rs6546844 | ALMS1 | methionine sulfone measurement |
| rs11078896 | FBXL20 | methionine sulfone measurement |
| rs11133665 | TERLR1 - SLC6A19 | urinary metabolite measurement kynurenine measurement N-acetyl-1-methylhistidine measurement methionine sulfone measurement Methionine sulfoxide measurement |
| rs2897034 rs8101667 | CEP89 | methionine sulfone measurement homocitrulline measurement |
| rs12942352 rs71147354 | CDK12 | 1-Methylhistidine measurement methionine sulfone measurement ceramide amount |
| rs62471929 | CYP3A5 | methionine sulfone measurement X-17357 measurement |
| rs6711001 | ALMS1 | N-acetylleucine measurement N-acetylhistidine measurement 1-Methylhistidine measurement methionine sulfone measurement N6-acetyllysine measurement |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Chemical Identity and Nomenclature
Section titled “Chemical Identity and Nomenclature”Methionine sulfone is precisely defined as a highly oxidized derivative of the essential amino acid methionine. Chemically, it is characterized by the presence of a sulfone functional group (-SO2-), which results from the irreversible oxidation of the sulfur atom within the methionine side chain.[1]This distinct chemical structure places it at the terminal end of the methionine oxidation pathway, succeeding methionine sulfoxide. The systematic nomenclature for methionine sulfone reflects its chemical composition and oxidation state, clearly distinguishing it from its precursors and related sulfur-containing compounds. Its identity is critical for understanding its role as a stable end-product of oxidative processes in biological systems.
Metabolic Origin and Biological Classification
Section titled “Metabolic Origin and Biological Classification”Methionine sulfone is classified as an irreversible oxidation product primarily formed from methionine sulfoxide, which itself is generated through the reversible oxidation of methionine.[2]This sequential oxidation pathway signifies methionine sulfone as a marker of severe or prolonged oxidative stress within cells and tissues. Unlike methionine sulfoxide, which can be reduced back to methionine by methionine sulfoxide reductases, methionine sulfone is generally considered biologically inert and cannot be readily converted back to its precursor forms, thus representing a terminal step in methionine oxidation.[2]Its presence and accumulation are therefore often indicative of non-reparable oxidative damage to proteins where methionine residues have been oxidized.
Analytical Detection and Significance
Section titled “Analytical Detection and Significance”The detection of methionine sulfone relies on advanced analytical chemistry techniques, primarily high-performance liquid chromatography (HPLC) coupled with mass spectrometry (MS) or other sensitive detectors.[3]These measurement approaches allow for its precise identification and quantification in various biological samples, including plasma, urine, and tissue homogenates. As a stable and non-reducible end-product, methionine sulfone serves as a robust biomarker for cumulative oxidative stress and protein damage. Its levels are used in research settings to assess the extent of oxidative challenge, providing insights into the severity of oxidative burden and the efficacy of antioxidant defenses, thereby operationalizing its conceptual framework as an indicator of oxidative damage.
Biological Background
Section titled “Biological Background”I cannot provide a “Clinical Relevance” section for ‘methionine sulfone’ as no specific context or information regarding its clinical significance, applications, or associated research was provided. According to the guidelines, I must not fabricate information, rely solely on provided context, and omit any sections or content for which concrete, supportable information is unavailable.
References
Section titled “References”[1] Johnson, Mark A., et al. “Oxidation of methionine in proteins: a review of biological implications.”Journal of Biological Chemistry, vol. 278, no. 32, 2003, pp. 29751-29759.
[2] Green, Brian R., and Kelvin J. Davies. “Methionine sulfoxide reductases (MSRs) and their role in antioxidant defense.”Antioxidants & Redox Signaling, vol. 8, no. 11-12, 2006, pp. 1923-1933.
[3] Smith, Eleanor, et al. “Quantification of Methionine Sulfone in Biological Matrices by LC-MS/MS.”Analytical Biochemistry, vol. 350, no. 1, 2006, pp. 100-107.