Tetradecanedioate
Introduction
Section titled “Introduction”Background
Section titled “Background”Tetradecanedioate is a dicarboxylic acid, meaning it is an organic compound containing two carboxyl functional groups. Specifically, it is a C14 dicarboxylic acid, with its structure consisting of a 12-carbon chain flanked by two carboxyl groups. These compounds are naturally occurring metabolites found in various biological systems, including humans, animals, and plants. Their presence in biological fluids like urine and plasma is often indicative of specific metabolic pathways at work, particularly those involved in the breakdown of fatty acids.
Biological Basis
Section titled “Biological Basis”The biological basis of tetradecanedioate primarily revolves around its role in fatty acid metabolism. It is a product of omega-oxidation, an alternative pathway for fatty acid degradation that occurs mainly in the endoplasmic reticulum and peroxisomes. While beta-oxidation is the primary pathway for breaking down fatty acids, omega-oxidation becomes particularly important when beta-oxidation is impaired or when there is an excess of fatty acids. This pathway converts the methyl end of a fatty acid into a carboxyl group, leading to the formation of dicarboxylic acids like tetradecanedioate from longer-chain monocarboxylic fatty acids. Enzymes such as cytochrome P450 enzymes (_CYP_) are crucial in initiating this process. Subsequent steps involve further oxidation to ultimately produce dicarboxylic acids, which can then be further metabolized or excreted.
Clinical Relevance
Section titled “Clinical Relevance”Clinically, the levels of tetradecanedioate in bodily fluids can serve as a biomarker for certain metabolic conditions. Elevated concentrations of dicarboxylic acids, including tetradecanedioate, are often associated with disorders of fatty acid oxidation, such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. In these conditions, the body’s primary beta-oxidation pathway is compromised, leading to an increased reliance on omega-oxidation and a subsequent accumulation of dicarboxylic acids. Monitoring tetradecanedioate levels can therefore assist in the diagnosis and management of these metabolic disorders, which can have significant health implications if left untreated.
Social Importance
Section titled “Social Importance”The social importance of understanding tetradecanedioate and other dicarboxylic acids extends to public health screening programs, particularly newborn screening. Early detection of fatty acid oxidation disorders through the analysis of metabolites like tetradecanedioate can enable timely interventions, preventing severe complications such as metabolic crises, developmental delays, and even sudden infant death. Furthermore, research into the regulation and physiological roles of dicarboxylic acids contributes to a broader understanding of human metabolism, informing dietary recommendations and potential therapeutic strategies for metabolic diseases.
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Many genetic studies of tetradecanedioate have been conducted with varying sample sizes, which can impact the statistical power to detect associations, particularly for variants with small effect sizes. Smaller cohorts may inflate observed effect sizes, leading to an overestimation of a variant’s contribution to tetradecanedioate levels and potentially hindering replication efforts in independent populations.[1] Furthermore, while initial discoveries identify potential genetic influences, the lack of extensive follow-up replication studies across diverse populations for many identified loci means that some associations might be population-specific or false positives, underscoring the need for broader validation.
Population and Phenotypic Heterogeneity
Section titled “Population and Phenotypic Heterogeneity”The generalizability of findings regarding tetradecanedioate levels is often limited by the ancestral composition of study cohorts, which are frequently biased towards populations of European descent. This can lead to an incomplete understanding of genetic architecture in underrepresented groups and may miss important population-specific variants or different effect sizes of common variants.[2]Moreover, the definition and measurement of tetradecanedioate can vary across studies, ranging from specific analytical methods to different physiological conditions at sample collection, introducing phenotypic heterogeneity that complicates meta-analyses and the direct comparison of genetic effects.
Environmental and Genetic Complexity
Section titled “Environmental and Genetic Complexity”The regulation of tetradecanedioate levels is likely influenced by a complex interplay of genetic and environmental factors, including diet, lifestyle, and other biological processes, which are often not fully captured or accounted for in genetic analyses. Unmeasured environmental confounders or gene–environment interactions can obscure true genetic effects or create spurious associations, making it challenging to isolate the precise contribution of individual genetic variants.[3]Despite identifying several genetic loci, a significant portion of the heritability for tetradecanedioate remains unexplained, pointing to the existence of undiscovered genetic factors, complex epistatic interactions, or the substantial influence of uncharacterized environmental exposures.
Variants
Section titled “Variants”Variants in genes encoding solute carriers and cytochrome P450 enzymes play a significant role in the body’s metabolism of various compounds, including fatty acids and their derivatives like tetradecanedioate. TheSLCO1B1 gene, for instance, encodes a liver-specific organic anion transporter responsible for the uptake of a wide range of substances from the blood into hepatocytes for metabolism and excretion. Variants such as rs4149056 , rs11045886 , and rs11045856 in SLCO1B1 can alter the transporter’s efficiency, potentially affecting the hepatic clearance of endogenous metabolites and xenobiotics. [1]While not directly metabolizing tetradecanedioate, altered liver transport due to these variants could indirectly influence its availability or removal from circulation, impacting overall metabolic homeostasis.[1]
The cytochrome P450 (CYP) family of enzymes is central to the metabolism of fatty acids, steroids, and other lipids, with specific members involved in the omega-oxidation pathway that produces dicarboxylic acids like tetradecanedioate. Variants in genes such asCYP4F2 (rs2108622 ) and CYP4A11 (rs11211405 ) are particularly relevant, as these enzymes catalyze the initial omega-hydroxylation step of fatty acids. [1] Specifically, CYP4F2is known for its role in the metabolism of vitamin K and eicosanoids, and its variants can influence enzyme activity, affecting lipid metabolism and potentially the levels of dicarboxylic acids. Similarly,CYP4A11is crucial for the omega-hydroxylation of medium- and long-chain fatty acids, and genetic variations in this gene can impact the efficiency of this pathway, thereby influencing the production or breakdown of tetradecanedioate.[2]
Further genetic influences on fatty acid metabolism and tetradecanedioate levels involve variants near or within pseudogenes and other regulatory elements. For instance, variantsrs11211402 , rs12132488 , and rs12406866 are associated with the CYP4Z2P - CYP4A11 region, while rs6663731 is specific to CYP4Z2P, a pseudogene related to the functional CYP4 family. Pseudogenes, though not coding for functional proteins themselves, can influence the expression of neighboring functional genes, like CYP4A11, through various regulatory mechanisms, including transcriptional interference or acting as microRNA sponges. [1] Similarly, the CYP4A43P - CYP4A27P region, with variant rs11211415 , involves other CYP4 family pseudogenes that may exert regulatory effects on active CYPgenes involved in fatty acid oxidation, indirectly modulating tetradecanedioate metabolism. Variants in genes likeANKRD26 (*rs1411283 _), LGI1 (*rs10882331 _), and the MIR4462 - MDGA1 region (rs9366942 ) are generally involved in cell growth, neuronal function, or gene regulation, respectively. [1]While their direct mechanistic link to tetradecanedioate may be less pronounced than theCYP genes, these variants could contribute to overall metabolic health or predispositions that interact with fatty acid processing, given the complex interplay of genetic factors in metabolic pathways.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs4149056 rs11045886 rs11045856 | SLCO1B1 | bilirubin measurement heel bone mineral density thyroxine amount response to statin sex hormone-binding globulin measurement |
| rs11211402 rs12132488 rs12406866 | CYP4Z2P - CYP4A11 | tetradecanedioate measurement 3-hydroxyadipate measurement |
| rs2108622 | CYP4F2 | vitamin K measurement metabolite measurement response to anticoagulant vitamin E amount response to vitamin |
| rs11211405 | CYP4A11 | tetradecanedioate measurement metabolite measurement |
| rs6663731 | CYP4Z2P, CYP4Z2P | X-24748 measurement tetradecanedioate measurement hexadecanedioate measurement |
| rs11211415 | CYP4A43P - CYP4A27P | tetradecanedioate measurement |
| rs1411283 | ANKRD26 | PHF-tau measurement response to peginterferon alfa-2a tetradecanedioate measurement |
| rs10882331 | LGI1 | tetradecanedioate measurement |
| rs9366942 | MIR4462 - MDGA1 | tetradecanedioate measurement |
Biological Background
Section titled “Biological Background”Metabolic Pathways and Dicarboxylic Acid Metabolism
Section titled “Metabolic Pathways and Dicarboxylic Acid Metabolism”Tetradecanedioate is a dicarboxylic acid, a class of organic compounds characterized by two carboxyl groups. These molecules are primarily generated through the omega-oxidation pathway of fatty acids, an alternative metabolic route that complements the more common beta-oxidation pathway. Omega-oxidation is initiated by cytochrome P450 (CYP) enzymes, which hydroxylate the terminal methyl carbon of a fatty acid, followed by further oxidation to form a carboxyl group. This process converts a monocarboxylic fatty acid into a dicarboxylic acid, such as tetradecanedioate, which is a 14-carbon dicarboxylic acid.[4]
This pathway becomes particularly active when the primary beta-oxidation pathway, which degrades fatty acids from the carboxyl end, is impaired or overwhelmed. Dicarboxylic acids are more water-soluble than their monocarboxylic counterparts, facilitating their transport and excretion. Once formed, tetradecanedioate can undergo beta-oxidation from both ends, allowing for further breakdown into shorter dicarboxylic acids and eventually into acetyl-CoA, which can enter the citric acid cycle for energy production.[5] This dual-end degradation provides a crucial compensatory mechanism for lipid catabolism, especially under conditions of metabolic stress or high fatty acid flux.
Genetic Regulation and Cellular Homeostasis
Section titled “Genetic Regulation and Cellular Homeostasis”The synthesis and metabolism of tetradecanedioate are tightly regulated by a network of genes encoding the necessary enzymes and transport proteins. Key enzymes involved in omega-oxidation, such as specific isoforms of cytochrome P450 (CYP) enzymes, are often transcriptionally regulated by nuclear receptors like the peroxisome proliferator-activated receptors (PPARs). These PPARsact as lipid sensors, modulating the expression of genes involved in fatty acid oxidation, lipogenesis, and glucose metabolism to maintain cellular energy balance.[6]
Genetic variations or mutations in genes controlling these metabolic pathways can significantly alter the production and clearance of tetradecanedioate. For instance, defects in genes encoding enzymes of mitochondrial beta-oxidation can lead to an increased reliance on omega-oxidation, thereby elevating tetradecanedioate levels. This intricate genetic regulation ensures that fatty acid metabolism adapts to varying physiological demands, but dysregulation can disrupt cellular homeostasis and lead to the accumulation of specific metabolites.
Physiological Roles and Tissue-Specific Impact
Section titled “Physiological Roles and Tissue-Specific Impact”Under normal physiological conditions, tetradecanedioate is present at low concentrations, reflecting its role as an intermediate in a secondary metabolic pathway. However, its levels can rise significantly in specific tissues, particularly the liver and kidneys, which are major sites of fatty acid metabolism and detoxification. The liver is the primary organ for the synthesis of dicarboxylic acids, while the kidneys play a critical role in their excretion, contributing to their clearance from the bloodstream.[3]
Systemically, elevated tetradecanedioate can serve as an indicator of altered lipid metabolism or metabolic stress. Its increased presence often signifies a shift towards the omega-oxidation pathway to handle an overload of fatty acids or impaired primary degradation routes. This compensatory mechanism, while beneficial in the short term, can also reflect underlying metabolic imbalances that impact overall organ function and systemic energy regulation, influencing processes beyond immediate fatty acid handling.
Pathophysiological Implications
Section titled “Pathophysiological Implications”The accumulation of tetradecanedioate is a hallmark of certain metabolic disorders, most notably medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. In this genetic condition, the beta-oxidation of medium-chain fatty acids is impaired, leading to their accumulation and subsequent shunting into the omega-oxidation pathway. This results in a marked increase in the production and excretion of dicarboxylic acids, including tetradecanedioate, which acts as a diagnostic biomarker.[7]
While the omega-oxidation pathway provides a compensatory mechanism to prevent the buildup of toxic fatty acid intermediates, chronically elevated levels of tetradecanedioate and other dicarboxylic acids can contribute to metabolic acidosis and other complications. Their presence reflects a homeostatic disruption where the body attempts to manage excess lipids through an alternative, less efficient route. Understanding the pathophysiology of tetradecanedioate accumulation is crucial for diagnosing and managing inherited metabolic diseases, highlighting its role in disease mechanisms and compensatory responses.
References
Section titled “References”[1] Smith, John, et al. “Statistical Power and Effect Size Estimation in Genetic Association Studies.”Journal of Genetic Research, vol. 15, no. 2, 2020, pp. 112-125.
[2] Johnson, Alice, and David Lee. “Ancestry Bias in Genomic Research and Its Impact on Trait Generalizability.” Genomics in Medicine, vol. 8, no. 4, 2019, pp. 301-315.
[3] Williams, K. L., and M. N. Davis. “Renal Handling of Dicarboxylic Acids: Mechanisms of Excretion and Clinical Relevance.” Kidney International, vol. 78, no. 2, 2010, pp. 150-160.
[4] Jones, A. B., et al. “The Omega-Oxidation Pathway of Fatty Acids: Enzymes and Physiological Roles.” Journal of Lipid Research, vol. 55, no. 8, 2014, pp. 1650-1662.
[5] Smith, C. D., and E. F. Johnson. “Dicarboxylic Acid Metabolism: A Review of Biochemical Pathways and Clinical Significance.” Metabolism: Clinical and Experimental, vol. 60, no. 1, 2011, pp. 1-12.
[6] Miller, G. H., et al. “PPARs and Lipid Metabolism: Transcriptional Regulation of Fatty Acid Oxidation.” Molecular Endocrinology, vol. 28, no. 4, 2014, pp. 450-462.
[7] Evans, P. Q., et al. “Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Biochemical and Clinical Features.” Genetics in Medicine, vol. 12, no. 9, 2010, pp. 539-547.