Docosatetraenoic Acid
Docosatetraenoic acid (DTA, C22:4) is a polyunsaturated fatty acid (PUFA) that plays an important role in various biological processes, particularly as a component of cellular membranes. As an omega-6 fatty acid, it is derived through the metabolic elongation of arachidonic acid (C20:4).
Biological Basis
Section titled “Biological Basis”The metabolism of long-chain polyunsaturated fatty acids, including those related to docosatetraenoic acid, is critically regulated by enzymes such as fatty acid delta-5 desaturase. This enzyme is encoded by theFADS1 gene. [1] Genetic variations within FADS1, such as the single nucleotide polymorphism (SNP)rs174548 , have been shown to influence the efficiency of the fatty acid delta-5 desaturase reaction. [1] A reduced efficiency of this enzyme can lead to altered concentrations of various glycerophospholipids, which are fundamental components of cell membranes and are involved in cellular signaling. [1] These glycerophospholipids often incorporate arachidonyl-moieties (C20:4) and other related PUFAs. [1]
Clinical Relevance and Social Importance
Section titled “Clinical Relevance and Social Importance”Variations in genes like FADS1 that influence fatty acid metabolism can contribute to an individual’s unique metabolic profile, often referred to as a “genetically determined metabotype”. [1]Understanding these genetic influences on PUFA levels is significant for gaining insights into their roles in human health and disease. Genome-wide association studies (GWAS) have been instrumental in identifying these genetic associations, linking specific genetic markers to variations in metabolite profiles in human serum.[1] This research contributes to a broader understanding of how genetic predispositions affect metabolic pathways, potentially informing personalized approaches to nutrition and health.
Limitations
Section titled “Limitations”Research into the genetic underpinnings of docosatetraenoic acid, when conducted using genome-wide association studies (GWAS), is subject to several methodological and interpretative limitations that warrant careful consideration. These limitations arise from study design, population characteristics, and the inherent complexities of genetic and environmental interactions.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”A significant challenge in identifying genetic associations for traits such as docosatetraenoic acid involves the statistical power and coverage of genetic variants. Many studies acknowledge limitations due to moderate sample sizes, which can restrict the ability to detect genetic effects that explain only a small proportion of phenotypic variation, potentially leading to false negative findings ([2]). Early GWAS often utilized lower-density SNP arrays, such as 100K chips, which may not have captured comprehensive genetic variation across a gene region, thereby missing real associations or hindering the replication of previously reported findings (.
One notable variant, *rs174547 *, is located within the _FADS_ gene cluster and has been associated with altered desaturase activity, particularly impacting the efficiency of the fatty acid delta-5 desaturase reaction. Studies show that the _FADS1_ genotype, which can be influenced by variants like *rs174547 *, positively correlates with the concentrations of several phosphatidylcholines and phosphatidylethanolamines that have three or fewer double bonds in their polyunsaturated fatty acid side chains.[1] These include specific phosphatidylcholines such as PC aa C34:2, PC aa C36:2, PC ae C34:2, and PC ae C36:2, as well as phosphatidylethanolamines like PE aa C34:2 and PE aa C36:2, and phosphatidylinositol PI aa C36:2. The direction of these associations highlights how genetic variations can modulate the availability and interconversion of key lipid species.
Furthermore, the _FADS1_genotype and its influence on desaturase efficiency are linked to a broader impact on lipid homeostasis. A negative association has been observed with sphingomyelin concentrations, including SM C22:2, SM C24:2, and SM C28:4.[1] This suggests that changes in phosphatidylcholine levels, driven by _FADS_activity, can subsequently affect sphingomyelin production, as sphingomyelin can be synthesized from phosphatidylcholine. Similarly, a negative association with lysophosphatidylethanolamine PE a C10:0 is considered a consequence of the altered balance in glycerophospholipid metabolism, where this metabolite is produced from other phosphatidylethanolamines. These interconnected metabolic shifts, modulated by variants like*rs174547 *, collectively influence the synthesis and availability of LC-PUFAs like docosatetraenoic acid, impacting individual metabolic profiles and potentially influencing various physiological functions dependent on these essential fatty acids.[1]
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Definition and Chemical Nomenclature
Section titled “Definition and Chemical Nomenclature”Docosatetraenoic acid is precisely defined by its chemical structure as a fatty acid. In standardized lipid nomenclature, this molecule is systematically abbreviated as C22:4, where ‘C’ denotes carbon, ‘22’ represents the total number of carbon atoms in its side chain, and ‘4’ indicates the presence of four double bonds.[1] This Cx:ynotation serves as an operational definition, providing a clear and concise descriptor for the composition of lipid side chains. As such, docosatetraenoic acid is classified as a polyunsaturated fatty acid (PUFA) due to its multiple double bonds.[1]
Biological Classification and Metabolic Context
Section titled “Biological Classification and Metabolic Context”Docosatetraenoic acid is biologically classified within the broader category of polyunsaturated fatty acids (PUFAs) and is often found as a structural component of glycerophospholipids. Research indicates its involvement in the composition of complex lipids such as phosphatidylcholines (PC aa) and plasmalogen/plasmenogen phosphatidylcholines (PC ae) that possess four or more double bonds in their polyunsaturated fatty acid side chains.[1]The concentrations of these glycerophospholipids, potentially including those containing docosatetraenoic acid, have been observed to be lowest in individuals carrying a specific minor allele, suggesting a genetic influence on their metabolic levels.[1] This association points to a role in metabolic pathways, particularly those modulated by the fatty acid delta-5 desaturase enzyme, encoded by the FADS1 gene, which impacts the efficiency of fatty acid desaturation reactions. [1]
Measurement and Analytical Considerations
Section titled “Measurement and Analytical Considerations”The identification and quantification of docosatetraenoic acid are typically performed through advanced analytical techniques that measure serum concentrations of endogenous organic compounds, often as part of comprehensive metabolite profiling.[1] While these methods provide detailed insights into lipid side chain composition using the Cx:y abbreviation, they may face challenges in discerning subtle stereochemical differences or differentiating between isobaric fragments. [1] Such analytical ambiguities can necessitate the indication of possible alternative assignments when mapping metabolite names to their individual mass spectra. [1]For general lipid traits like triglycerides (TG), high-density lipoprotein (HDL), and total cholesterol (TC), enzymatic methods utilizing clinical chemistry analyzers are commonly employed, with blood samples collected after an overnight fast.[3]
Biological Background
Section titled “Biological Background”Docosatetraenoic acid (DTA) is a long-chain polyunsaturated fatty acid that plays a role in various physiological processes. Its endogenous synthesis and metabolism are intricately linked to a complex network of enzymes and genetic factors, primarily involving the desaturation and elongation of precursor fatty acids. The levels of such fatty acids in the body, including those that contribute to the pool from which docosatetraenoic acid is derived, are influenced by genetic variations and dietary intake.
Polyunsaturated Fatty Acid Metabolism and theFADS Gene Cluster
Section titled “Polyunsaturated Fatty Acid Metabolism and theFADS Gene Cluster”The biosynthesis of long-chain polyunsaturated fatty acids, including docosatetraenoic acid, is a critical metabolic pathway involving a series of desaturation and elongation steps. Central to this process are the fatty acid desaturase enzymes, particularly those encoded by theFADS1 and FADS2 genes, which are clustered together in the human genome. [4] The FADS1 gene encodes delta-5 desaturase, an enzyme responsible for introducing a double bond at the fifth carbon position from the carboxyl end of fatty acids. [1] For instance, delta-5 desaturase catalyzes the conversion of eicosatrienoyl-CoA (C20:3) into arachidonyl-CoA (C20:4), a key precursor for many biologically active lipids. [1] Similarly, the FADS2 gene encodes delta-6 desaturase, which performs an analogous function by introducing a double bond at the sixth carbon position, an initial rate-limiting step in converting dietary essential fatty acids into their longer, more unsaturated derivatives. [4] These enzymatic activities are fundamental for maintaining the balance of n-3 and n-6 fatty acids, which are crucial for cellular structure and function.
Genetic Regulation and Enzyme Efficiency
Section titled “Genetic Regulation and Enzyme Efficiency”Genetic variations, specifically single nucleotide polymorphisms (SNPs) within theFADS gene cluster, significantly influence the efficiency of these desaturase enzymes and, consequently, the circulating levels of various fatty acids. [5] These SNPs can impact the catalytic activity of delta-5 and delta-6 desaturases, leading to alterations in the ratios of substrate and product fatty acids. [1] For example, polymorphisms in the FADS1 gene have been shown to drastically affect the efficiency of the delta-5 desaturase reaction, with specific genetic variants leading to substantial differences in the concentrations of metabolites like eicosatrienoyl-CoA (C20:3) and arachidonyl-CoA (C20:4). [1] Beyond structural variations, the expression of these genes is also tightly regulated; for instance, the transcription of the human FADS1 gene is known to involve a functional direct repeat-1 element, highlighting the complex regulatory networks governing fatty acid metabolism. [6] Such genetic influences underscore the individual variability in fatty acid profiles and their potential health implications.
Systemic Distribution and Dietary Interactions
Section titled “Systemic Distribution and Dietary Interactions”The fatty acids produced through the FADSpathway, including those related to docosatetraenoic acid, are distributed systemically and integrated into various lipid pools throughout the body. These include plasma phospholipids, which serve as a circulating reservoir and indicator of dietary and endogenous fatty acid status.[4] Moreover, the metabolic output of these enzymes is vital for specific physiological fluids, such as human milk, where FADS1 and FADS2gene variants can modify the proportions of docosahexaenoic acid, reflecting their importance in maternal and infant nutrition.[7]Dietary intake profoundly interacts with these genetic mechanisms; for instance, manipulating the dietary ratio of linoleic acid to alpha-linolenic acid can alter plasma phospholipid levels of eicosapentaenoic acid, demonstrating how diet and genetics collectively shape an individual’s fatty acid profile and overall lipid homeostasis.[8]
Integration into Complex Lipid Structures
Section titled “Integration into Complex Lipid Structures”Beyond their free forms, the fatty acids synthesized via the FADS pathway are rapidly integrated into more complex lipid structures, such as phospholipids, which are essential components of cellular membranes. A prime example is the biosynthesis of phosphatidylcholines, where fatty acyl-CoAs, like eicosatrienoyl-CoA (C20:3) and arachidonyl-CoA (C20:4), are sequentially incorporated. [1]This process involves the addition of a glycerol 3-phosphate backbone, followed by a palmitoyl-moiety (C16:0), dephosphorylation, and finally, the addition of a phosphocholine moiety to form specific phosphatidylcholins, such as PC aa C36:3 and PC aa C36:4.[1] These complex lipids, which can be considered modified products of the desaturase reactions, are crucial for membrane integrity, cell signaling, and the transport of fatty acids within the body. [1]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Metabolic Pathways of Polyunsaturated Fatty Acid Synthesis
Section titled “Metabolic Pathways of Polyunsaturated Fatty Acid Synthesis”Long-chain polyunsaturated fatty acids (PUFAs), including docosatetraenoic acid, are synthesized through a complex series of desaturation and elongation reactions within the cell, originating from essential dietary fatty acids. Specifically, linoleic acid (C18:2) initiates the omega-6 pathway, while alpha-linolenic acid (C18:3) begins the omega-3 pathway, leading to the production of various PUFAs. A pivotal enzyme in this metabolic cascade is the fatty acid delta-5 desaturase, encoded by theFADS1gene, which is responsible for introducing a double bond at the delta-5 position of specific fatty acyl-CoAs. This enzymatic step is crucial for converting eicosatrienoyl-CoA (C20:3) into arachidonyl-CoA (C20:4), a key precursor that can then be elongated to form docosatetraenoic acid (C22:4) and other longer-chain omega-6 PUFAs.[1] The overall flux through these desaturation and elongation pathways is meticulously controlled, ensuring a balanced supply of diverse fatty acids necessary for various cellular functions, from membrane integrity to signaling molecule synthesis.
Genetic and Transcriptional Regulation in Lipid Metabolism
Section titled “Genetic and Transcriptional Regulation in Lipid Metabolism”The efficiency of long-chain PUFA synthesis and overall lipid metabolism is profoundly influenced by genetic factors and regulatory mechanisms at the transcriptional and post-translational levels. Single nucleotide polymorphisms (SNPs) within genes such asFADS1 can significantly impact enzyme activity, directly modulating the metabolic flux. For instance, the rs174548 SNP located within the FADS1 gene is strongly associated with varying concentrations of glycerophospholipids, indicating that this genetic variant reduces the efficiency of the delta-5 desaturase reaction. [1] This genetic regulation directly dictates the availability of specific fatty acyl-CoAs, thereby influencing the entire omega-3 and omega-6 fatty acid metabolic network.
Beyond desaturases, other key enzymes in lipid metabolism, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), also exhibit intricate regulatory mechanisms that affect their function and downstream metabolic effects. Common SNPs in the HMGCRgene have been shown to influence low-density lipoprotein (LDL)-cholesterol levels by altering the alternative splicing of exon 13.[9] This form of post-transcriptional regulation can lead to the production of different protein isoforms or changes in protein stability, highlighting how subtle genetic variations can exert significant control over enzyme function and, consequently, broader lipid profiles. Such hierarchical regulation ensures that cellular lipid homeostasis is maintained through coordinated genetic and molecular interactions.
Integration into Complex Lipid Structures
Section titled “Integration into Complex Lipid Structures”Polyunsaturated fatty acids, once synthesized or obtained, are not merely metabolic intermediates but are critically incorporated into complex lipid structures, thereby integrating into broader cellular lipid networks. Through pathways like the Kennedy pathway, these fatty acids, including docosatetraenoic acid, are esterified into glycerol-phosphatidylcholines (PC) and other glycerophospholipids, forming the essential building blocks of cellular membranes.[1] The precise composition of these membrane lipids, particularly the types and ratios of fatty acid side chains, is directly influenced by the availability of specific fatty acyl-CoAs, which in turn is modulated by the efficiency of enzymes like FADS1. For example, reduced delta-5 desaturase activity can alter the ratio of PC aa C36:4 to PC aa C36:3, reflecting changes in the fatty acid composition of these phospholipids.
The lipid metabolic network also demonstrates significant pathway crosstalk, where alterations in one class of lipids can have cascading effects on others. An example of this is the biosynthesis of sphingomyelin, an important membrane lipid, which can be produced from phosphatidylcholine.[1]This direct metabolic connection illustrates how changes in glycerophospholipid metabolism, such as those resulting from modified delta-5 desaturase activity, can lead to widespread shifts in the overall balance of glycerophospholipids and sphingolipids. Such interconnectedness is vital for maintaining cellular homeostasis, as it allows for compensatory mechanisms that respond to fluctuations in lipid availability.
Systems-Level Metabolic Interplay and Clinical Relevance
Section titled “Systems-Level Metabolic Interplay and Clinical Relevance”The intricate interplay of fatty acid and lipid metabolic pathways reveals a sophisticated systems-level integration, where genetic variations can give rise to distinct metabolic phenotypes. Polymorphisms in genes like FADS1 are strongly associated with circulating lipid concentrations, including various phosphatidylcholines and other glycerophospholipids, thereby contributing to the complex etiology of polygenic dyslipidemia. [1]These genetic influences on enzyme efficiency lead to an overall altered balance in glycerophospholipid metabolism, representing emergent properties of the interacting pathways that impact an individual’s unique metabolic profile.
Dysregulation within these lipid metabolic pathways, whether stemming from genetic predispositions or environmental factors, holds significant clinical relevance, particularly in the context of cardiovascular disease. Altered lipid profiles, such as those linked toFADS1variants that influence docosatetraenoic acid metabolism, are recognized risk factors for conditions like coronary artery disease.[10]A comprehensive understanding of these mechanistic links, from genetic variations to specific metabolite changes and ultimately to clinical outcomes, is essential for identifying effective therapeutic targets aimed at correcting pathway dysregulation and mitigating the risk of disease.
I am unable to provide a “Clinical Relevance” section for ‘docosatetraenoic acid’ based solely on the provided context, as this specific compound is not mentioned in the research materials.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs174547 | FADS1, FADS2 | metabolite measurement high density lipoprotein cholesterol measurement triglyceride measurement comprehensive strength index, muscle measurement heart rate |
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] Sabatti, Chiara, et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nature Genetics, vol. 41, no. 1, 2009, pp. 35-46.
[4] Lemaitre, R.N. “Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.” PLoS Genet.
[5] Bokor, S., Dumont, J., Spinneker, A., Gonzalez-Gross, M., Nova, E., et al. “Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios.”J Lipid Res.
[6] Tang, C., Cho, H.P., Nakamura, M.T., Clarke, S.D. “Regulation of human delta-6 desaturase gene transcription: identification of a functional direct repeat-1 element.” J Lipid Res.
[7] Molto-Puigmarti, C., Plat, J., Mensink, R.P., Muller, A., Jansen, E., et al. “FADS1 FADS2 gene variants modify the association between fish intake and the docosahexaenoic acid proportions in human milk.”Am J Clin Nutr.
[8] Liou, Y.A., King, D.J., Zibrik, D., Innis, S.M. “Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men.”J Nutr.
[9] 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, vol. 28, no. 10, 2008, pp. 1821-1827.
[10] 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. 161-169.