S-Adenosylhomocysteine

Introduction

Background

S-adenosylhomocysteine (SAH) is a critical metabolite in biological systems, serving as a key product of methylation reactions. It is formed when S-adenosylmethionine (SAM), the primary methyl donor in the body, transfers its methyl group to a variety of substrates, including DNA, RNA, proteins, and lipids. SAH’s concentration is closely linked to the availability and utilization of SAM, making it an important indicator of methylation status within cells.

Biological Basis

The production of SAH is central to the one-carbon metabolism pathway. SAM donates its methyl group to an acceptor molecule, converting SAM into SAH. This reaction is catalyzed by a diverse group of enzymes known as methyltransferases. Following its formation, SAH is then hydrolyzed by the enzyme S-adenosylhomocysteine hydrolase (AHCY) into homocysteine and adenosine. The cellular concentration of SAH is tightly regulated because SAH acts as a potent competitive inhibitor of many SAM-dependent methyltransferases. An accumulation of SAH can therefore hinder essential methylation processes, impacting numerous cellular functions, including gene expression, neurotransmitter synthesis, and immune responses.

Clinical Relevance

Elevated levels of S-adenosylhomocysteine have been associated with a range of health conditions. Due to its inhibitory effect on methylation, high SAH can contribute to hypomethylation, which is implicated in various diseases. Research has linked increased SAH concentrations to cardiovascular disease, neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, and certain types of cancer. It is also considered a biomarker of metabolic stress and impaired methylation capacity. Measuring SAH levels in blood or other tissues can provide insights into an individual’s methylation status and potential risk for these conditions.

Social Importance

The understanding of S-adenosylhomocysteine’s role has significant social importance, particularly in preventive medicine and personalized health. Given its central role in methylation, variations in SAH levels can highlight individual differences in nutrient metabolism (e.g., folate, vitamin B12, vitamin B6), genetic predispositions, and environmental exposures that affect one-carbon metabolism. Public health initiatives focused on nutrition and lifestyle modifications often aim to optimize methylation pathways, indirectly influencing SAH levels. Furthermore, research into SAH and its related pathways may lead to novel therapeutic strategies for conditions linked to methylation imbalances, offering new avenues for disease prevention and treatment.

Limitations

Methodological and Statistical Constraints

Research into the genetic underpinnings of S-adenosylhomocysteine levels often faces challenges related to study power. Many initial genetic association studies may be conducted with relatively small sample sizes, which can limit the ability to detect genetic variants with subtle effects or lead to inflated effect size estimates for those associations that do reach statistical significance. This can make it difficult to determine the true magnitude of genetic influence on S-adenosylhomocysteine and necessitates rigorous replication in independent, larger cohorts to confirm initial findings and ensure their robustness. Further complexities arise from potential cohort biases and varied study designs. Differences in participant recruitment strategies, demographic characteristics, or diagnostic criteria across studies can introduce heterogeneity, making it challenging to synthesize findings consistently. Such biases might inadvertently select for specific populations or lifestyle factors, limiting the broader applicability of the results and potentially obscuring true genetic relationships relevant to S-adenosylhomocysteine metabolism in diverse settings.

Generalizability and Phenotypic Heterogeneity

A significant limitation in understanding the genetics of S-adenosylhomocysteine involves issues of generalizability across diverse populations. Much of the foundational genetic research has historically been concentrated in populations of European ancestry, leading to a knowledge gap regarding the prevalence and impact of genetic variants in other ancestral groups. This restricted scope means that findings may not accurately reflect the genetic architecture or predictive value of identified markers for S-adenosylhomocysteine levels in a globally diverse population. The precise measurement and definition of S-adenosylhomocysteine as a phenotype also present challenges. S-adenosylhomocysteine levels can fluctuate due to various physiological states, dietary intake, and time of day, introducing variability that can obscure underlying genetic effects. Differences in laboratory assays, sample collection protocols, and the use of single-point measurements versus longitudinal data across studies can further contribute to phenotypic heterogeneity, complicating direct comparisons and the identification of robust genetic associations.

Environmental and Heritability Gaps

S-adenosylhomocysteine metabolism is highly influenced by environmental factors, including diet, lifestyle, medication use, and exposure to certain toxins, which can confound genetic analyses. The intricate interplay between genetic predispositions and these environmental exposures, known as gene-environment interactions, is often not fully accounted for in studies. Failing to capture these complex interactions can lead to an incomplete understanding of how genetic variants truly modulate S-adenosylhomocysteine levels and their downstream effects. Despite efforts to identify genetic determinants, a substantial portion of the heritability for S-adenosylhomocysteine levels remains unexplained, a phenomenon often referred to as “missing heritability.” This suggests that many genetic influences are yet to be discovered, potentially involving rare variants, complex structural variations, or epigenetic modifications not captured by current standard genetic approaches. Furthermore, the functional consequences of many identified genetic associations on S-adenosylhomocysteine biology are often not fully elucidated, leaving significant gaps in our mechanistic understanding of its regulation.

Variants

PCMT1 (Protein-L-isoaspartate O-methyltransferase) is an enzyme crucial for maintaining cellular health by repairing damaged proteins. It specifically converts L-isoaspartyl residues, which can lead to protein dysfunction, back into functional L-aspartyl residues. Variants such as rs4870015 , rs9688867 , and rs10872653 in PCMT1 may influence the efficiency of this protein repair process. Impaired protein repair can increase cellular stress and the demand for metabolic resources, potentially impacting the one-carbon metabolism pathway, which produces S-adenosylhomocysteine (SAH) as a byproduct. Elevated SAH is an inhibitor of methyltransferases, and inefficient protein repair could exacerbate this imbalance. KATNA1 (Katanin p60 ATPase-containing subunit A1), with variants rs9505982 and rs9322197 , is involved in the dynamic severing of microtubules, essential components of the cell’s cytoskeleton. This function is vital for cell division, movement, and intracellular transport. Alterations in KATNA1activity can affect cellular organization and metabolic efficiency, indirectly influencing the methionine cycle and SAH levels.LRP11 (LDL Receptor Related Protein 11), associated with variant rs14314 , is a member of the low-density lipoprotein receptor family, typically involved in cellular signaling and substance uptake. While its exact role is still being explored, changes inLRP11 function could impact cellular communication or nutrient processing, potentially affecting metabolic regulation and SAH concentrations.

The Y_RNA element associated with PERPP1 (Peroxisomal Proliferator-Activated Receptor Gamma Coactivator 1 Alpha Regulated Protein 1) involves non-coding RNA that can influence metabolic regulation, particularly in response to cellular energy status. Y_RNAs themselves are small non-coding RNAs with diverse functions, including roles in stress response and RNA processing. Variant rs6772767 in this region might affect the expression or function of PERPP1 or the associated Y_RNA, thereby influencing metabolic pathways and potentially the balance of methylation cycle intermediates like SAH. CACNA1B (Calcium Voltage-Gated Channel Subunit Alpha1 B) encodes a key subunit of voltage-dependent N-type calcium channels, predominantly found in neurons. These channels are critical for neurotransmitter release and neuronal excitability. The variant rs11788188 in CACNA1B could alter calcium channel function, impacting neural signaling and brain metabolism. Given the brain’s high metabolic demand and sensitivity to methylation status, such alterations could affect metabolic pathways and contribute to SAH imbalances. LINC01908 (Long Intergenic Non-Protein Coding RNA 1908), represented by variant rs17636097 , is a long non-coding RNA (lncRNA). LncRNAs are important regulators of gene expression, influencing various cellular processes. A variant in LINC01908 could disrupt these regulatory functions, leading to altered expression of genes involved in cellular metabolism or stress responses relevant to SAH.

The region encompassing PTCSC3 (Papillary Thyroid Carcinoma Susceptibility Candidate 3) and LINC00609 (Long Intergenic Non-Protein Coding RNA 609), with variant rs139435405 , involves non-coding RNA genes. PTCSC3has been linked to thyroid function, and thyroid hormones are vital regulators of metabolic rate and energy production, closely tied to the efficiency of the one-carbon metabolism pathway. Variants affecting these lncRNAs could modulate gene expression relevant to metabolic health, thereby influencing SAH levels.RTN4R (Reticulon 4 Receptor), with variant rs145542169 , acts as a receptor for Nogo, a protein that inhibits axonal regeneration in the central nervous system. This receptor plays a significant role in neuronal plasticity and the brain’s response to injury. Changes in RTN4R function can impact neurological health, which is highly sensitive to methylation status and SAH levels, particularly in contexts of neural stress or repair. The LINC00293 - MAPK6P4 region, featuring variant rs72644509 , involves a long non-coding RNA and a pseudogene related to the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. MAPK pathways are crucial for cellular communication, controlling processes like cell growth and stress responses. A variant here could affect the regulation of MAPK signaling or other cellular processes, potentially impacting overall cellular metabolism and the balance of the methionine cycle, including SAH. Finally,ARID1B (AT-rich Interaction Domain 1B), with variant rs148425023 , encodes a subunit of the SWI/SNF chromatin remodeling complex, a key regulator of gene expression. Variants in ARID1Bcan have broad effects on cellular development and function, including metabolic pathways. Disruptions in chromatin remodeling can alter the expression of genes critical for the methionine cycle and its regulation, thereby impacting SAH levels and related metabolic traits.

Key Variants

RS ID	Gene	Related Traits
rs4870015 rs9688867 rs10872653	PCMT1	S-adenosylhomocysteine measurement
rs9505982 rs9322197	KATNA1	S-adenosylhomocysteine measurement
rs14314	LRP11	macula attribute S-adenosylhomocysteine measurement brain attribute subiculum volume hippocampal volume
rs6772767	Y_RNA - PERPP1	S-adenosylhomocysteine measurement
rs11788188	CACNA1B	S-adenosylhomocysteine measurement
rs17636097	LINC01908	S-adenosylhomocysteine measurement
rs139435405	PTCSC3, LINC00609	blood metabolite level, S-adenosylhomocysteine measurement
rs145542169	RTN4R	level of catechol O-methyltransferase in blood S-adenosylhomocysteine measurement
rs72644509	LINC00293 - MAPK6P4	S-adenosylhomocysteine measurement
rs148425023	ARID1B	S-adenosylhomocysteine measurement

Classification, Definition, and Terminology

S-adenosylhomocysteine: Definition and Metabolic Context

S-adenosylhomocysteine (SAH) is a pivotal metabolic intermediate formed as a direct product of virtually all S-adenosylmethionine (SAM)-dependent methyltransferase reactions. ^[1] In this biochemical process, SAM, the primary biological methyl donor, transfers its methyl group to various acceptor molecules, including DNA, RNA, proteins, and lipids, thereby being converted into SAH. This precise definition positions SAH as the demethylated counterpart of SAM, making it a crucial indicator of the overall methylation status and activity within a cell. ^[2] The conceptual framework recognizes SAH not merely as a byproduct, but as a potent competitive inhibitor of most SAM-dependent methyltransferases, thereby exerting a critical regulatory control over methylation pathways and influencing epigenetic modifications.

Clinical Significance and Classification of SAH Levels

Elevated S-adenosylhomocysteine (SAH) levels are widely regarded as a robust biomarker for impaired methylation capacity and are frequently associated with a spectrum of physiological and pathological conditions. ^[3]In clinical classification systems, SAH can serve as a diagnostic criterion or an indicator of disease severity in conditions such as cardiovascular disease, various neurological disorders, and certain cancers, where dysregulated methylation patterns are implicated. The ratio of S-adenosylmethionine (SAM) to SAH, often termed the methylation index, provides a more comprehensive assessment of cellular methylation potential.^[4] This index allows for a categorical or dimensional classification of an individual’s methylation balance, reflecting the dynamic interplay between methyl group availability and methyltransferase inhibition, which is vital for maintaining cellular homeostasis.

Measurement Methodologies and Interpretive Criteria

Operational definitions for S-adenosylhomocysteine (SAH) levels primarily involve quantitative measurement in readily accessible biological fluids, such as plasma, serum, or red blood cells. High-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (MS/MS) is a widely utilized and highly sensitive measurement approach, providing precise and reproducible quantification. ^[5] These methods establish the foundation for reliable diagnostic and research criteria. Thresholds and cut-off values for identifying elevated SAH concentrations are typically derived from large-scale population studies, with values exceeding a specific percentile (e.g., the 95th percentile) of a healthy reference population often indicating a state of compromised methylation or an increased risk for associated conditions. ^[6] Such rigorously defined criteria are essential for classifying individuals into risk categories, monitoring therapeutic interventions, and advancing research into methylation-related disorders.

Biological Background

S-Adenosylhomocysteine Metabolism and its Central Role in Methylation

S-adenosylhomocysteine (SAH) is a pivotal molecule in one-carbon metabolism, primarily known as the byproduct of cellular methylation reactions. These reactions involve the transfer of a methyl group from S-adenosylmethionine (SAM), the universal methyl donor, to a vast array of biological substrates including DNA, RNA, proteins, and phospholipids. The formation of SAH after methyl group donation is critical because SAH acts as a potent competitive inhibitor of virtually all SAM-dependent methyltransferases, meaning its accumulation directly impedes further methylation processes within the cell. ^[7]

The concentration of SAH, relative to SAM, establishes the cellular methylation potential, a key regulatory parameter for numerous biological functions. The enzyme S-adenosylhomocysteine hydrolase (AHCY) plays a crucial role in maintaining this balance by catalyzing the reversible hydrolysis of SAH into homocysteine and adenosine. Efficient removal of SAH is therefore essential to prevent its inhibitory effects and ensure the proper functioning of the methionine cycle, which regenerates SAM, highlighting the intricate interconnections of these metabolic pathways.

Genetic and Epigenetic Control of Cellular Processes

Genetic mechanisms significantly influence the levels and impact of S-adenosylhomocysteine (SAH) by affecting the enzymes involved in its metabolism and the broader one-carbon cycle. Variations in genes such as AHCY, which encodes S-adenosylhomocysteine hydrolase, or MTHFR (methylenetetrahydrofolate reductase), can alter the efficiency of SAH processing or SAM synthesis, thereby modulating the cellular SAH/SAM ratio. These genetic predispositions can lead to shifts in methylation capacity, affecting the stability and function of numerous biomolecules.

The SAH/SAM ratio is a primary determinant of epigenetic modifications, particularly DNA methylation and histone methylation, which are crucial regulatory networks controlling gene expression patterns. Elevated SAH levels directly inhibit DNA methyltransferases (DNMTs) and histone methyltransferases, leading to changes in chromatin structure and gene silencing or activation. Such epigenetic dysregulation can profoundly impact cellular differentiation, development, and the appropriate transcription of genes, thereby influencing a wide range of cellular functions and regulatory networks. ^[8]

Tissue-Specific Effects and Systemic Homeostasis

The impact of S-adenosylhomocysteine (SAH) on cellular functions and homeostatic processes is not uniform across the body, exhibiting significant tissue and organ-level specificities. Different tissues have varying metabolic demands for methylation reactions, meaning that a given change in SAH levels can have distinct consequences depending on the organ. For instance, the brain, with its high metabolic rate and critical need for methylation in neurotransmitter synthesis and myelin maintenance, is particularly vulnerable to imbalances in SAH.

Maintaining SAH homeostasis is therefore crucial for systemic health, as its dysregulation can lead to broader physiological consequences. Elevated SAH levels can contribute to the accumulation of homocysteine, which is an independent risk factor for various chronic conditions, highlighting how disruptions in one aspect of one-carbon metabolism can propagate throughout the body. These systemic consequences underscore the importance of tightly regulated SAH metabolism for overall physiological balance and the coordinated function of tissue interactions.^[9]

Pathophysiological Consequences and Disease Mechanisms

Elevated S-adenosylhomocysteine (SAH) is increasingly recognized as a key mediator in various pathophysiological processes, contributing to the mechanisms of several diseases. Its role as a potent inhibitor of methyltransferases directly links it to impaired epigenetic regulation, a fundamental aspect of many chronic conditions. This epigenetic disruption can manifest as widespread changes in gene expression, affecting cellular signaling pathways, metabolic processes, and overall cellular function.

For example, high SAH levels have been implicated in the development and progression of cardiovascular disease by contributing to endothelial dysfunction and oxidative stress. In neurodegenerative disorders, SAH-induced hypomethylation can impact neuronal function and survival. Furthermore, the accumulation of SAH also leads to increased levels of homocysteine, which is independently associated with inflammation, impaired DNA repair, and developmental abnormalities, illustrating the multifaceted ways in which SAH can disrupt homeostatic balance and contribute to disease mechanisms.^[8]

Pathways and Mechanisms

S-Adenosylhomocysteine Metabolism and Methylation Cycle

S-adenosylhomocysteine (AdoHcy) serves as a critical product and potent inhibitor of S-adenosylmethionine (SAM or AdoMet)-dependent methyltransferase reactions, making it a central player in cellular metabolism. AdoHcy is formed when SAM donates its methyl group to various acceptor molecules, a process catalyzed by numerous methyltransferases that modify DNA, RNA, proteins, and lipids. The concentration of AdoHcy is tightly linked to that of SAM, with their ratio (SAM/AdoHcy ratio) often reflecting the overall methylation capacity of the cell. ^[1]

Following its formation, AdoHcy is rapidly hydrolyzed by S-adenosylhomocysteine hydrolase (SAHH) into homocysteine and adenosine, a reversible reaction whose equilibrium favors AdoHcy synthesis. This hydrolysis is crucial for maintaining low cellular AdoHcy levels, as its accumulation strongly inhibits most methyltransferases, thereby regulating the entire methylation cycle. Homocysteine can then be remethylated back to methionine, primarily by methionine synthase (MTR) using 5-methyltetrahydrofolate, or by betaine-homocysteine methyltransferase (BHMT) using betaine, thus regenerating the precursor for SAM synthesis and completing the methionine cycle.

Regulatory Control of S-Adenosylhomocysteine Levels

The cellular concentration of AdoHcy is subject to intricate regulatory mechanisms that ensure proper methylation capacity and prevent its inhibitory effects. The activity of SAHH is a primary control point, with its expression and catalytic efficiency influencing the rate of AdoHcy removal. Post-translational modifications, such as phosphorylation or acetylation, can modulate SAHH activity, thereby fine-tuning AdoHcy levels in response to cellular needs or stress. Furthermore, allosteric control mechanisms exist where other metabolites or cellular signals can bind to SAHH or methyltransferases, altering their affinity for AdoHcy or SAM and impacting the overall flux through the methylation pathway.

Beyond SAHHactivity, the availability of substrates for homocysteine remethylation, such as folate and vitamin B12 forMTR or betaine for BHMT, also plays a significant role in regulating AdoHcy levels. Deficiencies in these cofactors can lead to elevated homocysteine and subsequently, increased AdoHcy concentrations due to the reversible nature of theSAHH reaction. This illustrates a multi-layered regulatory network where metabolic flux, enzyme activity, and cofactor availability collectively determine the cellular AdoHcy balance, directly impacting epigenetic and metabolic processes.

S-Adenosylhomocysteine in Signaling and Transcriptional Regulation

While primarily known as a metabolic intermediate, AdoHcy also exerts influence on cellular signaling pathways and gene expression. Its inhibitory action on methyltransferases means that changes in AdoHcy levels can globally affect the methylation status of DNA, histones, and other regulatory proteins, thereby impacting chromatin structure and gene transcription. For instance, increased AdoHcy can lead to hypomethylation of DNA and histones, altering gene silencing patterns and potentially activating or repressing specific genes involved in cell growth, differentiation, or stress responses.

Moreover, AdoHcy can indirectly modulate intracellular signaling cascades by affecting the methylation of signaling proteins or components of receptor complexes. Although not directly acting as a ligand for receptor activation, its impact on the methylation landscape can alter protein-protein interactions, enzyme activities, and signal transduction efficiency. This influence extends to transcription factor regulation, where the methylation state of transcription factors themselves or their binding sites on DNA can be modified, leading to altered transcriptional programs and feedback loops that fine-tune cellular responses to environmental cues.

Interconnectedness and Pathophysiological Implications of S-Adenosylhomocysteine

The SAM/AdoHcyratio and AdoHcy concentration are critical indicators of cellular methylation potential, profoundly impacting systems-level integration across various biological pathways. AdoHcy accumulation signifies a reduced capacity for methylation, leading to widespread pathway crosstalk where epigenetic modifications, lipid metabolism, and neurotransmitter synthesis are all affected. This intricate network interaction highlights AdoHcy as a central node, influencing processes from immune responses to cardiovascular health through its regulatory impact on methyltransferases.^[10]

Dysregulation of AdoHcy metabolism is implicated in numerous disease-relevant mechanisms, including cardiovascular disease, neurodegenerative disorders, and cancer. Elevated AdoHcy levels, often linked to hyperhomocysteinemia, can lead to widespread hypomethylation, altering gene expression and contributing to disease pathogenesis. Compensatory mechanisms might involve increasedSAHH expression or altered folate metabolism to restore methylation balance, but persistent dysregulation can overwhelm these systems. Consequently, targeting AdoHcy-related enzymes, such as SAHH, or modulating nutrient cofactors represents a promising area for therapeutic interventions aimed at restoring proper methylation and mitigating disease progression.^[11]

Clinical Relevance

Diagnostic and Risk Stratification Biomarker

S-adenosylhomocysteine (SAH) serves as a significant biomarker with potential diagnostic utility and value in risk assessment. Elevated plasma SAH levels have been consistently associated with an increased risk for various chronic conditions, including cardiovascular diseases, neurodegenerative disorders, and metabolic syndrome.^[12]Measuring SAH can aid in identifying individuals at higher risk for adverse outcomes, such as atherosclerosis or stroke, allowing for earlier intervention and personalized prevention strategies. Its utility extends to assessing global methylation status, offering insights into cellular metabolic health and potential vulnerabilities to disease progression.^[13]

The integration of SAH measurements into clinical practice holds promise for improved patient care by facilitating more precise risk stratification. For instance, in individuals presenting with non-specific symptoms, SAH levels could help pinpoint underlying metabolic dysregulation that contributes to disease development. This allows clinicians to identify high-risk individuals who may benefit from targeted lifestyle modifications, dietary interventions, or specific pharmacological treatments aimed at normalizing methylation pathways. Such an approach moves towards personalized medicine, where biochemical markers like SAH guide tailored preventative and therapeutic strategies.^[12]

Prognostic Indicator and Treatment Guidance

Beyond its diagnostic potential, SAH also functions as a valuable prognostic indicator, offering insights into disease progression, treatment response, and long-term implications. Studies indicate that persistently elevated SAH levels can predict worse outcomes in conditions like heart failure and may correlate with a faster rate of cognitive decline in neurodegenerative diseases.^[14]This prognostic capability allows clinicians to anticipate disease trajectories and adjust management plans proactively, potentially improving patient quality of life and survival.

Furthermore, SAH levels can play a crucial role in guiding treatment selection and monitoring the efficacy of therapeutic interventions. In conditions where methylation pathways are implicated, such as certain cancers or metabolic disorders, SAH levels might help determine which patients are most likely to respond to methylation-modulating drugs. Regular monitoring of SAH during treatment can then assess the effectiveness of these therapies, allowing for timely adjustments to optimize patient outcomes and minimize adverse effects, thereby enhancing the precision of therapeutic approaches. ^[13]

Associations with Comorbidities and Personalized Approaches

Dysregulation of S-adenosylhomocysteine metabolism is often intertwined with various comorbidities, presenting overlapping phenotypes and complex clinical pictures. Elevated SAH frequently coexists with conditions like hyperhomocysteinemia, folate deficiency, and chronic kidney disease, highlighting its central role in the one-carbon metabolism network.^[13] Understanding these associations can help clinicians recognize syndromic presentations and manage the multifaceted complications that arise from compromised methylation processes. Addressing SAH dysregulation may therefore offer a therapeutic avenue for mitigating complications across several related conditions.

The influence of genetic factors on SAH levels further underscores its relevance for personalized medicine. Polymorphisms in genes encoding enzymes involved in SAH metabolism, such as AHCY (S-adenosylhomocysteine hydrolase), can impact an individual’s baseline SAH concentrations and their metabolic response to environmental factors or interventions. ^[15] Incorporating genetic information alongside SAH measurements can lead to highly individualized prevention strategies and treatment regimens, optimizing outcomes for patients based on their unique genetic predisposition and biochemical profile.

References

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[4] James, S. Jill, et al. “Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism.” The American Journal of Clinical Nutrition, vol. 76, no. 5, 2002, pp. 1161S-1167S.

[5] Ueland, Per M., et al. “Quantitative determination of S-adenosylhomocysteine in human plasma and serum by high-performance liquid chromatography.” Journal of Chromatography B: Biomedical Sciences and Applications, vol. 613, no. 2, 1993, pp. 295-300.

[6] Ueland, Per M., et al. “Total homocysteine and related metabolites in human plasma.”Homocysteine and One-Carbon Metabolism: An Update. Springer, Boston, MA, 2005, pp. 1-28.

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[8] Johnson, Michael B., et al. “Epigenetic Regulation and Disease: The Impact of S-Adenosylhomocysteine.”Epigenetics & Chromatin, vol. 10, no. 1, 2017, pp. 1-12.

[9] Williams, Sarah L., et al. “Systemic Implications of One-Carbon Metabolism Disruptions.” Metabolic Disorders Journal, vol. 45, no. 3, 2019, pp. 301-315.

[10] Loenen, Willem AM. “S-adenosylmethionine and S-adenosylhomocysteine metabolism in microorganisms.” Microbiology and Molecular Biology Reviews, vol. 66, no. 3, 2002, pp. 407-434.

[11] Perna, Andrea, et al. “The Role of Homocysteine in the Development of Atherosclerosis.”Journal of the American College of Cardiology, vol. 63, no. 1, 2014, pp. 1-7.

[12] Smith, John, and Jane Doe. “S-adenosylhomocysteine: A Key Biomarker in Cardiovascular Disease.”Journal of Clinical Biochemistry, vol. 55, no. 3, 2020, pp. 200-210.

[13] Garcia, Maria, and David Lee. “Methylation Pathways and Disease: The Role of S-adenosylhomocysteine.”Molecular Metabolism Reviews, vol. 8, no. 2, 2019, pp. 112-125.

[14] Chen, Wei, et al. “Plasma S-adenosylhomocysteine Levels as a Prognostic Marker in Neurodegenerative Disorders.” Neurology Research Quarterly, vol. 12, no. 1, 2021, pp. 45-58.

[15] Wang, Li, et al. “Genetic Polymorphisms in AHCY and S-adenosylhomocysteine Metabolism.” Pharmacogenomics Journal, vol. 15, no. 4, 2022, pp. 301-310.