O Methylcatechol Sulfate
Introduction
Section titled “Introduction”o-Methylcatechol sulfate is a naturally occurring metabolite in the human body, typically formed as a product of the detoxification and elimination pathways of catechol compounds. Catechols, including certain neurotransmitters and environmental toxins, undergo various enzymatic modifications to facilitate their excretion. Sulfation is a key metabolic process involved in this, where a sulfate group is added to the catechol structure.
Biological Basis
Section titled “Biological Basis”The formation of o-methylcatechol sulfate involves two primary enzymatic steps. First, catechols can be methylated by catechol-O-methyltransferase (COMT), an enzyme that adds a methyl group to one of the hydroxyl groups of the catechol ring. This methylation can occur at either the meta or ortho position. Following methylation, the resulting O-methylated catechol derivative can then be sulfated by sulfotransferase enzymes (SULT). The addition of a sulfate group significantly increases the compound’s water solubility, enabling its efficient removal from the body via urine. This pathway is crucial for maintaining metabolic homeostasis and protecting against the accumulation of potentially toxic catechol metabolites.
Clinical Relevance
Section titled “Clinical Relevance”As a metabolite of catechol compounds, o-methylcatechol sulfate can serve as a biomarker in various clinical contexts. Its levels in bodily fluids, such as urine or serum, can reflect the activity of related metabolic pathways or the exposure to certain environmental agents. For instance, alterations in catecholamine metabolism, which can be affected by genetic variations in enzymes likeCOMT, may influence the production and excretion of such sulfated metabolites. Monitoring these metabolites can be important in the study of neurodegenerative diseases, stress responses, and the metabolism of certain drugs. While specific genetic variants impacting o-methylcatechol sulfate levels are an active area of research, studies in metabolomics broadly aim to identify genetic variants that associate with changes in the homeostasis of key metabolites in human serum.[1]
Social Importance
Section titled “Social Importance”The study of metabolites like o-methylcatechol sulfate contributes to a broader understanding of human health and disease. By elucidating the genetic and environmental factors that influence metabolite levels, researchers can identify potential risk factors for complex diseases and develop new diagnostic tools or therapeutic strategies. In the field of pharmacogenomics, understanding how genetic variations affect the metabolism of catechol-containing drugs can help personalize treatment plans. Furthermore, the ability to profile metabolites in human serum through methods like genome-wide association studies (GWAS) on metabolite profiles provides functional readouts of the physiological state of the human body and can reveal metabotypes that influence susceptibility to multifactorial diseases.[1] This knowledge is vital for advancing precision medicine and public health initiatives.
Limitations of Research on o-Methylcatechol Sulfate
Section titled “Limitations of Research on o-Methylcatechol Sulfate”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Research into genetic factors influencing o-methylcatechol sulfate levels faces several methodological and statistical limitations. Many studies have limited statistical power to detect genetic effects of modest size, especially when accounting for extensive multiple testing inherent in genome-wide association studies (GWAS).[2] This constraint means that associations explaining less than 4% of phenotypic variation may be missed, necessitating large populations for robust identification of novel genetic variants. [1] Furthermore, the use of SNP arrays that cover only a subset of all genetic variation, such as the Affymetrix 100K gene chip, limits the ability to comprehensively study candidate genes or detect all relevant loci due to incomplete coverage. [3]
The possibility of false-positive findings remains a significant concern, particularly when results have not been independently replicated. [4] The effect sizes of genetic associations with complex clinical phenotypes are often small, making definitive identification challenging and emphasizing the critical need for replication in independent cohorts to validate discoveries. [1] While some studies present moderate-strength associations, these require further scrutiny and external validation to be considered true genetic associations. [4]
Generalizability and Phenotype Assessment Challenges
Section titled “Generalizability and Phenotype Assessment Challenges”A prominent limitation of current genetic studies on o-methylcatechol sulfate is the restricted generalizability of findings to diverse populations. Many investigations are predominantly conducted in cohorts of White individuals of European descent, which means the applicability of these results to other ethnicities remains uncertain.[2] This lack of ethnic diversity limits the understanding of how genetic variants and their associations may differ across global populations.
Phenotype measurement also introduces challenges in accurately characterizing o-methylcatechol sulfate. For instance, averaging traits over extended periods, sometimes spanning decades, can mask age-dependent gene effects or introduce misclassification due to evolving measurement equipment and methodologies.[2]Additionally, relying on proxy markers or conducting only sex-pooled analyses might overlook sex-specific genetic associations, potentially obscuring important biological distinctions in how genetic variants influence o-methylcatechol sulfate levels.[3] The suitability of certain analytical methods, such as transforming equations developed in small, selected samples, for large population-based cohorts also poses a limitation. [5]
Environmental Influences and Remaining Knowledge Gaps
Section titled “Environmental Influences and Remaining Knowledge Gaps”Current research often does not fully account for the complex interplay between genetic factors and environmental influences on o-methylcatechol sulfate levels. Genetic variants can influence phenotypes in a context-specific manner, with associations modulated by environmental factors.[2] For example, the effects of certain genes like ACE and AGTR2 on physiological traits have been shown to vary with dietary salt intake, highlighting the need for comprehensive investigation of gene-environmental interactions. [2]Without such analyses, the full picture of how genetics contributes to o-methylcatechol sulfate levels remains incomplete, and specific environmental triggers or protective factors are not identified.
A significant knowledge gap remains in inferring the precise disease-causing mechanisms solely from associations between genotypes and clinical outcomes.[1]While GWAS identify statistical links, they do not inherently explain the biological pathways or functional consequences through which genetic variants influence o-methylcatechol sulfate. Further functional validation and detailed follow-up studies are essential to translate genetic associations into a deeper understanding of molecular and cellular processes underlying o-methylcatechol sulfate metabolism, which is crucial for therapeutic development and personalized medicine.[4]
Variants
Section titled “Variants”The landscape of human metabolism is intricately shaped by genetic variations, with specific single nucleotide polymorphisms (SNPs) influencing the function of genes involved in diverse physiological processes. Variations in genes such asSLC17A1, CARNS1, and SPNS2are implicated in metabolic pathways, potentially affecting the levels of various endogenous compounds, including phase II detoxification products like o-methylcatechol sulfate. Genome-wide association studies (GWAS) have demonstrated the power of identifying such genetic determinants of metabolic traits in human serum.[1]Understanding these genetic influences offers insights into individual differences in metabolic health and disease risk.[4]
The gene SLC17A1 (Solute Carrier Family 17 Member 1) encodes a protein primarily known for its role in transporting various organic anions and phosphates across cell membranes, particularly in the kidney and liver. This transporter system is critical for the excretion of metabolic waste products and xenobiotics, thereby influencing systemic metabolite levels and drug pharmacokinetics. [1] A variant like rs9461218 within or near SLC17A1could potentially alter the gene’s expression or the protein’s transport efficiency, leading to changes in the cellular uptake or efflux of its substrates. Such alterations might impact the circulating concentrations of various metabolites, including the detoxification product o-methylcatechol sulfate, by affecting its renal clearance or distribution across tissues .
CARNS1 (Carnosine Synthase 1) is responsible for synthesizing carnosine, a dipeptide abundantly found in muscle and brain tissues, where it acts as an antioxidant, pH buffer, and antiglycation agent. Carnosine plays a crucial role in maintaining cellular homeostasis and protecting against oxidative stress and metabolic dysfunction.[1] A variant such as rs578222450 could affect the activity of the carnosine synthase enzyme, potentially altering the body’s carnosine levels and its capacity to manage oxidative stress. Changes in overall antioxidant status and metabolic burden influenced byCARNS1variants could indirectly impact the demand for and efficiency of other detoxification pathways, including those involved in the methylation and sulfation of catechol compounds to form o-methylcatechol sulfate.[4]
Furthermore, SPNS2 (Sphingolipid Transporter 2) functions as a transporter for sphingosine-1-phosphate (S1P), a bioactive lipid signaling molecule central to immune cell trafficking, vascular development, and inflammatory responses. By mediating the export of S1P from cells,SPNS2 significantly influences systemic S1P levels, which in turn affect a wide range of physiological processes. [1] A genetic variant like rs1076073 associated with SPNS2might modify its expression or the protein’s transport efficiency, thereby altering S1P concentrations in the blood and tissues. While directly involved in lipid metabolism, systemic effects on inflammation, cellular health, and overall metabolic regulation could indirectly influence the production or breakdown of other metabolites, including o-methylcatechol sulfate, as the body’s detoxification demands shift in response to immune or metabolic challenges.[6]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs9461218 | SLC17A1 | guilt measurement etiocholanolone glucuronide measurement O-methylcatechol sulfate measurement 3-methyl catechol sulfate (1) measurement metabolite measurement |
| rs578222450 | CARNS1 | vanillylmandelate (VMA) measurement X-21358 measurement X-21658 measurement arabitol measurement, xylitol measurement 5-acetylamino-6-amino-3-methyluracil measurement |
| rs1076073 | SPNS2 | X-21658 measurement O-methylcatechol sulfate measurement X-24513 measurement 2,3-dihydroxy-5-methylthio-4-pentenoate (DMTPA) measurement |
Biological Background
Section titled “Biological Background”‘o methylcatechol sulfate’ is an endogenous metabolite, and its presence and concentrations are part of the broader metabolome, which represents a functional readout of the human body’s physiological state.[1]The study of metabolite profiles through advanced techniques like metabolomics aims to comprehensively measure these compounds in body fluids such as serum, providing insights into various biological processes and their genetic underpinnings.[1]Understanding the biological context of metabolites involves exploring the molecular pathways they participate in, the genetic mechanisms that regulate their levels, the key biomolecules facilitating their transformations, and their overall impact on health and disease at tissue and systemic levels.
Metabolic Pathways and Regulation
Section titled “Metabolic Pathways and Regulation”The concentrations of metabolites like ‘o methylcatechol sulfate’ are intrinsically linked to complex metabolic networks within the body. These networks involve the synthesis, breakdown, and modification of various biomolecules, including lipids, carbohydrates, and amino acids.[1] For instance, lipid metabolism encompasses critical processes such as the transport and beta-oxidation of fatty acids into mitochondria, where enzymes like medium-chain acyl-CoA dehydrogenase (MCAD) play a crucial role in converting longer-chain fatty acids into shorter ones. [1] Similarly, the delta-5 desaturase enzyme, encoded by FADS1, is essential for the desaturation of fatty acids, directly influencing the conversion of eicosatrienoyl-CoA (C20:3) to arachidonyl-CoA (C20:4) and subsequently impacting the levels of glycerol-phosphatidylcholins like PC aa C36:3 and PC aa C36:4. [1] These interconnected pathways demonstrate how the balance of various lipids and their derivatives is meticulously maintained through enzymatic activities.
Genetic Influences on Metabolite Homeostasis
Section titled “Genetic Influences on Metabolite Homeostasis”Genetic variations, particularly single nucleotide polymorphisms (SNPs), significantly influence the homeostasis of key metabolites. Genome-wide association studies (GWAS) have identified specific genetic variants that associate with changes in metabolite concentrations, highlighting a genetic basis for individual differences in metabolic profiles.[1] For example, polymorphisms within the FADS1 gene can impact the efficiency of the delta-5 desaturase reaction, leading to altered concentrations of its substrates and products, with minor allele homozygotes often exhibiting reduced enzymatic turnover. [1] Beyond direct enzymatic activity, genetic variants can also affect regulatory elements or alternative splicing, as seen with SNPs in HMGCR, which influence the alternative splicing of exon 13 and consequently impact LDL-cholesterol levels. [7] Such genetic predispositions contribute to distinct “metabotypes” that can influence an individual’s susceptibility to various conditions.
Key Biomolecules and Cellular Functions
Section titled “Key Biomolecules and Cellular Functions”Specific biomolecules, including enzymes and transporters, are fundamental to regulating metabolite levels and ensuring proper cellular function. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is a central component of the mevalonate pathway, which is critical for cholesterol biosynthesis. [8] Its activity is tightly regulated, and genetic variants affecting its expression or splicing can profoundly impact cellular cholesterol metabolism. [7] Furthermore, membrane transporters are vital for moving metabolites across cellular membranes; for example, SLC2A9, a member of the facilitative glucose transporter family, functions as a key urate transporter.[9]This transporter is crucial for regulating serum urate concentrations and its excretion, thereby maintaining uric acid homeostasis within the body.[10]
Systemic Consequences and Pathophysiological Links
Section titled “Systemic Consequences and Pathophysiological Links”Disruptions in metabolite homeostasis, often influenced by genetic factors and environmental interactions, can have systemic consequences and contribute to various pathophysiological processes. Genetically determined metabotypes can act as discriminating cofactors in the etiology of common multi-factorial diseases, influencing an individual’s susceptibility to certain phenotypes. [1]Alterations in lipid profiles, such as those affecting LDL-cholesterol or triglycerides, are associated with dyslipidemia and an increased risk of coronary artery disease.[11]Similarly, dysregulation of uric acid levels due to genetic variants in transporters likeSLC2A9is strongly linked to conditions like gout, demonstrating how specific metabolite imbalances can manifest as significant health issues.[10] These systemic effects highlight the interconnectedness of metabolic pathways and their profound impact on overall health.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Metabolic Pathways and Regulation
Section titled “Metabolic Pathways and Regulation”The homeostasis of key metabolites, including compounds like o-methylcatechol sulfate, is intricately regulated through various metabolic pathways, which are often influenced by genetic variants. Metabolomics studies aim to comprehensively measure endogenous metabolites, providing a functional readout of an individual’s physiological state and identifying genetically determined metabotypes. These metabotypes reveal how genetic variations alter the steady-state concentrations of a wide array of biomolecules, reflecting underlying metabolic activity and flux. The broad spectrum of metabolic intermediates encompasses lipids, carbohydrates, and amino acids, all subject to precise enzymatic control and regulatory feedback mechanisms within cellular networks.[1]
Specific examples highlight the complexity of these pathways. Lipid metabolism involves the mevalonate pathway, critical for cholesterol biosynthesis, where the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is a central regulatory point. [8] Additionally, the FADS1 FADS2 gene cluster plays a significant role in determining the composition of fatty acids within phospholipids, influencing the balance of polyunsaturated fatty acids. [12] Similarly, the processing of acylcarnitines, which are essential for fatty acid transport and beta-oxidation in mitochondria, demonstrates how enzymatic activities, such as those of medium-chain acyl-CoA dehydrogenase (MCAD), directly impact the levels of these metabolites. [1]
Beyond lipid metabolism, other critical pathways include the regulation of uric acid levels in the body, primarily managed by the urate transporterSLC2A9 (also known as GLUT9). This transporter is crucial for influencing serum uric acid concentrations and its excretion by the kidneys.[13] The coordinated function of such transporters and metabolic enzymes ensures proper flux through these pathways, maintaining the balance of vital metabolites and preventing accumulation or deficiency that could lead to physiological imbalances.
Genetic and Post-Translational Regulatory Mechanisms
Section titled “Genetic and Post-Translational Regulatory Mechanisms”Genetic variants significantly contribute to the regulation of metabolic pathways by affecting gene expression, protein structure, and ultimately, enzyme activity. For instance, common single nucleotide polymorphisms (SNPs) in theHMGCR gene have been shown to influence alternative splicing of exon 13, which can impact the production of different HMGCR isoforms and subsequently alter LDL-cholesterol levels. [7] This alternative splicing mechanism represents a crucial post-transcriptional regulatory layer that can generate diverse protein products from a single gene, each potentially possessing distinct functions or stabilities. [7]
Further regulatory control is exerted at the post-translational level, where modifications to proteins can alter their activity, localization, or stability. For example, the degradation rate of HMGCR is influenced by its oligomerization state, demonstrating a mechanism where protein-protein interactions modulate enzyme turnover and overall activity. [14] Such mechanisms allow for fine-tuning of metabolic flux in response to cellular needs and environmental cues, ensuring that metabolic enzymes are appropriately active or inactive through mechanisms beyond simple transcriptional control.
Systems-Level Metabolic Integration
Section titled “Systems-Level Metabolic Integration”The understanding of metabolic processes extends beyond individual pathways to encompass a systems-level view, where pathways interact and genetic variants exert their effects across complex networks. Genome-wide association studies (GWAS) combined with metabolomics provide a powerful approach to identify how genetic variations collectively shape the human metabolic network, revealing intricate pathway crosstalk and network interactions. [1] This integrated perspective recognizes that alterations in one metabolic pathway can have cascading effects on others, leading to emergent properties of the overall system that are not predictable from individual components.
This systems-level integration aims to achieve a functional understanding of the genetics underlying complex diseases by identifying major genetically determined metabotypes. These metabotypes represent characteristic metabolic profiles that arise from the interplay of multiple genetic loci and their influence on the vast web of metabolic reactions. [1]Such an approach moves beyond single-gene analyses to elucidate how the human metabolic network, with its myriad associated genetic variants, contributes to physiological states and disease susceptibility.
Dysregulation in Disease Contexts
Section titled “Dysregulation in Disease Contexts”Dysregulation within these intricate metabolic and regulatory pathways is directly implicated in the etiology of common multifactorial diseases. Alterations in lipid metabolism, for example, contribute significantly to conditions like dyslipidemia and increase the risk of coronary artery disease. Studies have identified numerous genetic loci that influence concentrations of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides, demonstrating a polygenic basis for lipid-related disorders.[15]These genetic predispositions, in concert with environmental factors such as diet and lifestyle, determine an individual’s susceptibility to adverse lipid profiles.
Similarly, dysregulation in uric acid metabolism is a significant factor in diseases like gout. Genetic variants in theSLC2A9gene, which encodes a urate transporter, have been strongly associated with serum uric acid concentrations and an individual’s predisposition to gout.[13]Understanding these disease-relevant mechanisms, including pathway dysregulation and compensatory responses, is crucial for identifying potential therapeutic targets. By correlating genetic variants with intermediate phenotypes (metabolite levels), researchers can gain insights into the specific pathways affected and develop targeted interventions to restore metabolic balance and mitigate disease progression.[1]
References
Section titled “References”[1] Gieger C, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.” PLoS Genet, 2008.
[2] Vasan, R. S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, vol. 8 Suppl 1, 2007, p. S2.
[3] Yang, Q, et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Med Genet (2007).
[4] Benjamin EJ, et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, 2007.
[5] Hwang SJ, et al. “A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study.” BMC Med Genet, 2007.
[6] Melzer D, et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genet, 2008.
[7] Burkhardt, R, et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol (2008).
[8] Goldstein, J. L., and M. S. Brown. “Regulation of the mevalonate pathway.” Nature, vol. 343, no. 6257, 1990, pp. 425-30.
[9] Phay, J. E. et al. “Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9).”Genomics, vol. 66, no. 2, 2000, pp. 217-20.
[10] Vitart, V, et al. “SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.”Nat Genet, 2008.
[11] Kathiresan, S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, 2008.
[12] Schaeffer, L, Gohlke, H, Muller, M, Heid, IM, Palmer, LJ, et al. “Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids.” Hum Mol Genet, 2006.
[13] Döring, A, Gieger, C, Mehta, D, Gohlke, H, Prokisch, H, et al. “SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.”Nat Genet, 2008.
[14] Cheng, HH, Xu, L, Kumagai, H, Simoni, RD. “Oligomerization state influences the degradation rate of 3-hydroxy-3-methylglutaryl-CoA reductase.” J Biol Chem, 1999.
[15] Willer, C. J. et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 2, 2008, pp. 161-9.