N-Palmitoylglycine
Background
Section titled “Background”N-palmitoylglycine is a bioactive lipid categorized as an N-acylated amino acid. These molecules are characterized by the covalent attachment of a fatty acid, specifically palmitic acid, to an amino acid, glycine. As a metabolite, n-palmitoylglycine is a component of the complex network of biochemical reactions within the human body. Its presence has been identified in human serum through large-scale metabolomic studies, indicating its role as a detectable and potentially significant element of the human metabolic profile.[1]
Biological Basis
Section titled “Biological Basis”N-acylated amino acids are known to play diverse biological roles, including involvement in cellular signaling, inflammation, and energy regulation. Palmitoylation, the enzymatic addition of palmitic acid to various molecules, is a critical post-translational modification that influences protein function, localization, and interactions with cellular membranes. While n-palmitoylglycine itself is not a protein, its structure suggests potential involvement in pathways related to fatty acid conjugation, lipid-protein interactions, or as a signaling molecule. Its detection in human serum highlights its active participation in systemic metabolic processes. [1]
Clinical Relevance
Section titled “Clinical Relevance”Variations in the levels of metabolites, such as n-palmitoylglycine, are increasingly recognized as potential indicators of health status and risk for various diseases. Dysregulation in lipid metabolism is implicated in a range of conditions, including metabolic syndrome, cardiovascular diseases, and certain neurodegenerative disorders. Investigating the factors that influence n-palmitoylglycine levels, including genetic predispositions identified through genome-wide association studies (GWAS), can offer valuable insights into disease mechanisms and potential targets for therapeutic intervention. Metabolite profiling, which includes the analysis of compounds like n-palmitoylglycine, contributes to a more comprehensive understanding of human health that complements traditional genetic and proteomic approaches.[1]
Social Importance
Section titled “Social Importance”The study of metabolites like n-palmitoylglycine holds considerable social importance by advancing the fields of personalized medicine and preventive healthcare. By identifying specific metabolic signatures associated with health or disease states, there is potential to develop more precise diagnostic tools, predict individual responses to treatments, and inform targeted dietary or lifestyle recommendations. Increasing public understanding of how genetic factors interact with metabolic processes to influence health can empower individuals to make more informed decisions about their well-being, fostering a proactive approach to health management.
Limitations
Section titled “Limitations”Constraints in Generalizability and Population Representation
Section titled “Constraints in Generalizability and Population Representation”The primary studies underlying the current understanding of n palmitoylglycine and related lipid traits predominantly involve individuals of European ancestry. [2] While some research attempted to extend findings to multiethnic samples, such as participants from Singapore (comprising Chinese, Malays, and Asian Indians) or the distinct population of Kosrae, Federated States of Micronesia [2]the initial discoveries and main associations are largely derived from European cohorts. This significant ancestral focus limits the direct generalizability of these findings to other global populations, where genetic architectures, allele frequencies, linkage disequilibrium patterns, and environmental exposures may differ substantially. Consequently, the observed genetic associations with lipid phenotypes may not fully capture the complete genetic landscape or disease risk across diverse populations, indicating a critical need for extensive research in underrepresented ancestral groups to ensure broader applicability of scientific insights.
Methodological and Measurement Limitations
Section titled “Methodological and Measurement Limitations”The methodologies employed in various studies, while effective for discovery, contained inherent limitations. Genome-wide association studies (GWAS) often utilize a subset of all available single nucleotide polymorphisms (SNPs), leading to potential gaps in genomic coverage and the possibility of missing important genetic variants or genes.[3] Furthermore, the use of imputation to infer ungenotyped SNPs, while facilitating data integration, introduces a degree of uncertainty and potential for error, even with reported low error rates. [4] A common analytical simplification across studies is the assumption of an additive mode of inheritance for genetic variants, which might overlook more complex non-additive genetic interactions or epistasis. [5] Additionally, performing sex-pooled analyses, often a strategy to manage the burden of multiple testing, risks obscuring sex-specific genetic effects that could be biologically relevant for lipid phenotypes. [6]
Measurement of metabolic traits also presented challenges; for instance, the precise structural details of metabolites, such as the exact position of double bonds, stereochemical differences, or the distribution of carbon atoms in fatty acid side chains, could not always be fully determined by the analytical technologies utilized. [1] This imprecision in phenotyping can impact the granularity and accuracy of genetic associations. Furthermore, while the exclusion of individuals on lipid-lowering therapies enhances study validity by reducing confounding, it simultaneously limits the generalizability of findings to populations receiving such treatments. The reliance on statistical transformations, such as log-transformation for non-normally distributed traits like triglycerides, further modifies the direct interpretation of raw measurement data. [7]
Remaining Knowledge Gaps and Environmental Influences
Section titled “Remaining Knowledge Gaps and Environmental Influences”Despite the identification of numerous genetic loci, these variants frequently explain only a fraction of the observed variance in lipid concentrations [1] highlighting the persistent challenge of “missing heritability.” For example, some identified SNPs explain as little as 10% of the variance for specific glycerophospholipids [1] indicating that a substantial portion of the genetic or environmental contribution to these traits remains unexplained. This considerable gap suggests that many other genetic factors, including rare variants, copy number variations, or complex epistatic interactions, are yet to be discovered, necessitating larger sample sizes and improved statistical power for comprehensive gene discovery. [5] Moreover, the current research primarily focuses on identifying genetic associations, with less explicit detail on the comprehensive interplay of various environmental factors and gene-environment interactions, which are known to significantly influence lipid metabolism. These unaddressed confounders and complex biological interactions represent crucial knowledge gaps that impede a complete understanding of the underlying physiological mechanisms and their population-wide implications.
Variants
Section titled “Variants”The Variants section examines genetic variations influencing various biological pathways that may intersect with the metabolism and functions of n-palmitoylglycine. These genetic differences can modify enzyme activity, protein function, or gene expression, leading to diverse physiological effects. [1] Understanding these variants provides insight into potential genetic predispositions related to broad metabolic health and specific lipid-mediated signaling.
Variations in the FAAH gene, specifically rs324420 and rs324419 , are associated with the body’s endocannabinoid system. The FAAHgene encodes fatty acid amide hydrolase, an enzyme responsible for breaking down a range of fatty acid amides, including the endocannabinoid anandamide, which plays roles in pain, mood, and appetite regulation.[7] The rs324420 variant, often known to lead to reduced FAAHenzyme activity, results in higher levels of anandamide and other endogenous fatty acid amides, potentially influencing neurobehavioral traits and pain perception.rs324419 is another single nucleotide polymorphism within theFAAH gene that may impact gene expression or enzyme function, either independently or through linkage with other variants. [1] While n-palmitoylglycine is not a direct FAAH substrate, altered endocannabinoid signaling and the broader lipid milieu influenced by FAAH activity could indirectly affect the synthesis, degradation, or biological roles of other lipid-derived signaling molecules like n-palmitoylglycine.
The rs1047891 variant in the CPS1gene affects a crucial enzyme in the urea cycle, carbamoyl phosphate synthetase 1.CPS1is located in the mitochondria and is essential for the detoxification of ammonia by converting it into carbamoyl phosphate, the first step in the synthesis of urea. This variant is known to be associated with alteredCPS1 enzyme activity, which can influence nitrogen metabolism and the balance of amino acids in the body. [8]Disruptions in the urea cycle or amino acid metabolism, as potentially influenced byrs1047891 , could impact the availability of glycine, an amino acid component of n-palmitoylglycine. Furthermore,rs3737744 is an intronic variant located within the NSUN4 gene, which encodes a mitochondrial ribosomal RNA methyltransferase critical for mitochondrial protein synthesis and overall mitochondrial function. This variant could affect NSUN4gene expression or splicing, leading to impaired mitochondrial activity, which can broadly influence cellular energy metabolism, fatty acid oxidation, and the synthesis of lipid-amino acid conjugates like n-palmitoylglycine.
Lastly, the intergenic variant rs1998545 is located in a region encompassing LINC01398 and DMBX1. LINC01398 is a long non-coding RNA, a class of RNA molecules known to regulate gene expression at various levels, impacting cellular processes and development. DMBX1 is a transcription factor important for the development of the central nervous system, particularly specific brain regions. [7] As an intergenic SNP, rs1998545 may influence the expression or regulation of either LINC01398 or DMBX1, or other nearby regulatory elements, potentially affecting neural development and function. Such alterations in neurodevelopmental or broad regulatory pathways could indirectly impact the intricate lipid signaling networks within the body, including the metabolism and cellular roles of n-palmitoylglycine.[1]
No information regarding ‘n palmitoylglycine’ is present in the provided context. Therefore, a Classification, Definition, and Terminology section for this specific trait cannot be generated based on the given research materials.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs324420 rs324419 | FAAH | oleoyl ethanolamide measurement N-palmitoylglycine measurement linoleoyl ethanolamide measurement X-16570 measurement X-17325 measurement |
| rs1047891 | CPS1 | platelet count erythrocyte volume homocysteine measurement chronic kidney disease, serum creatinine amount circulating fibrinogen levels |
| rs3737744 | NSUN4 | N-palmitoylglycine measurement hemoglobin measurement |
| rs1998545 | LINC01398 - DMBX1 | N-palmitoylglycine measurement |
Biological Background
Section titled “Biological Background”APOC3 as a Key Regulator of Plasma Lipids
Section titled “APOC3 as a Key Regulator of Plasma Lipids”APOC3, or Apolipoprotein C-III, is a crucial protein component found on the surface of plasma lipoproteins, including triglyceride-rich lipoproteins (TRLs) like chylomicrons and very-low-density lipoproteins (VLDLs), as well as high-density lipoproteins (HDLs).[9] Its primary biological function is to regulate the metabolism of triglycerides, the main form of fat stored in the body and a significant energy source. By associating with these lipid particles, APOC3 directly influences how efficiently fats are processed and cleared from the bloodstream.
A key mechanism through which APOC3exerts its influence is by inhibiting lipoprotein lipase (LPL), an enzyme that plays a critical role in breaking down triglycerides within TRLs.[10] This inhibition by APOC3 slows down the hydrolysis of triglycerides into fatty acids, consequently delaying the removal of TRLs and their remnants from circulation. Additionally, APOC3 also impairs the hepatic uptake of these remnant particles by the liver, further contributing to elevated levels of triglycerides in the plasma. [10]
Genetic Influence on APOC3 Function and Lipid Profile
Section titled “Genetic Influence on APOC3 Function and Lipid Profile”The levels and activity of APOC3 in an individual are significantly determined by the APOC3 gene. Genetic variations within this gene can lead to profound alterations in its function and, subsequently, in plasma lipid profiles. For instance, specific null mutations in the human APOC3 gene have been identified that result in the absence of functional APOC3 protein. [10]
These genetic changes disrupt the normal production or structure of APOC3, leading to its diminished or complete absence. The lack of functional APOC3 removes its inhibitory effect on LPL, allowing the enzyme to more efficiently break down triglycerides and facilitate the clearance of TRLs from the blood. This genetic mechanism directly translates into changes in an individual’s lipid metabolism, highlighting the critical link between APOC3 genotype and circulating lipid concentrations.
Pathophysiological Impact on Cardiovascular Health
Section titled “Pathophysiological Impact on Cardiovascular Health”The role of APOC3in lipid metabolism has significant pathophysiological consequences, particularly concerning cardiovascular health. Elevated levels of triglycerides, often exacerbated by the normal function ofAPOC3, are recognized as a risk factor for various cardiovascular diseases, including atherosclerosis. The prolonged circulation of triglyceride-rich particles can contribute to arterial plaque formation and progression.
Conversely, conditions characterized by reduced or absent APOC3 activity have been observed to confer a favorable plasma lipid profile and offer apparent cardioprotection. [10] Individuals with null mutations in APOC3typically exhibit significantly lower levels of plasma triglycerides and, notably, higher levels of HDL-cholesterol. This beneficial lipid profile is associated with a reduced risk of cardiovascular events, underscoringAPOC3as a crucial determinant in maintaining lipid homeostasis and influencing susceptibility to heart disease.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Lipid Biosynthesis and Fatty Acid Metabolism
Section titled “Lipid Biosynthesis and Fatty Acid Metabolism”The synthesis of complex lipids, such as phosphatidylcholines, involves the crucial incorporation of fatty acyl chains, including the palmitoyl-moiety (C16:0). This process typically initiates with the addition of metabolites to glycerol 3-phosphate, followed by the incorporation of a palmitoyl-moiety, a dephosphorylation step, and finally, the addition of a phosphocholine moiety.[1]Such intricate steps lead to the formation of specific glycerol-phosphatidylcholines, exemplified by PC aa C36:3 and PC aa C36:4, which are characterized by their carbon chain length and degree of unsaturation.[1] These phosphatidylcholines often contain an arachidonyl-moiety (C20:4) alongside either a palmitoyl- (C16:0) or stearoyl-moiety (C18:0), highlighting the diversity of fatty acid components in membrane lipids. [1]
Central to the metabolism of these fatty acyl chains is the FADS1 enzyme, which catalyzes the delta-5 desaturase reaction, converting eicosatrienoyl-CoA (C20:3) into arachidonyl-CoA (C20:4). [1] This enzymatic activity is directly reflected in the composition of downstream glycerophospholipids, as PC aa C36:3 and PC aa C36:4 are considered modified substrates and products of this reaction. [1] Genetic variations within the FADS1 FADS2 gene cluster are known to influence the fatty acid composition within phospholipids, underscoring the genetic control over fundamental lipid metabolism. [11] The efficient regulation of this pathway is vital for maintaining membrane lipid biosynthesis and overall lipid homeostasis. [12]
Enzymatic Regulation and Post-Translational Control
Section titled “Enzymatic Regulation and Post-Translational Control”Regulation of lipid metabolic pathways occurs at multiple molecular levels, from gene expression to protein modification, ensuring precise control over lipid synthesis and catabolism. The enzyme FADS1, central to fatty acid desaturation, exemplifies an area where genetic polymorphisms can significantly impact metabolic efficiency, as evidenced by drastic decreases in p-values of associations when analyzing metabolite concentration ratios. [1] Beyond enzymatic activity, gene regulation mechanisms, such as alternative splicing, play a critical role in shaping the proteome and its functional diversity. [13]For instance, common single nucleotide polymorphisms (SNPs) inHMGCR, a key enzyme in the mevalonate pathway, are associated with low-density lipoprotein cholesterol levels and specifically affect the alternative splicing of exon 13.[14]
Furthermore, post-translational modifications provide another layer of regulatory complexity. O-linked glycosylation, mediated by enzymes like polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2), is a crucial regulatory mechanism for numerous proteins involved in lipid metabolism. [5] This type of modification can influence protein stability, activity, or localization, thereby fine-tuning the metabolic flux within lipid pathways. Such precise control mechanisms are essential for responding to physiological demands and maintaining the delicate balance of lipid species within cells and systemic circulation.
Metabolic Crosstalk and Homeostatic Integration
Section titled “Metabolic Crosstalk and Homeostatic Integration”Lipid metabolism does not operate in isolation but is intricately integrated within a broader network of metabolic pathways, demonstrating significant crosstalk with other key biological processes. The strong association of certain phospholipids, such as phosphatidylethanolamines, with genetic polymorphisms, prompts further research into their role within the cholesterol pathway, suggesting direct functional links and potential regulatory interplay between phospholipid and cholesterol metabolism. [1]This interconnectedness means that genetic variants affecting the homeostasis of specific lipids can have cascading effects, influencing the overall balance of carbohydrates and amino acids, thereby acting as intermediate phenotypes that link genetic variation to complex disease states.[1]
The impact of genes like hepatic lipase (LIPC) on metabolite profiles, where genetic polymorphisms can affect its substrate specificity, further illustrates how a single enzyme can influence multiple aspects of lipid homeostasis.[1] The interplay extends to systemic levels, as genetic variation can influence both lipid metabolism and other physiological processes like blood pressure regulation, highlighting the hierarchical and networked nature of metabolic control. [15] Understanding these network interactions and emergent properties is crucial for a comprehensive view of metabolic health.
Genetic Variants and Disease Associations
Section titled “Genetic Variants and Disease Associations”Dysregulation within lipid metabolic pathways is a significant contributor to various human diseases, making these pathways important targets for therapeutic intervention. Genetic variants in genes involved in fatty acid desaturation and phospholipid synthesis, such as the FADS1 FADS2gene cluster, are associated with polyunsaturated fatty acid composition and have been linked to an increased risk of cardiovascular disease and dyslipidemia.[16] Similarly, associations between polymorphisms impacting phospholipid levels and blood cholesterol levels suggest a causal relationship with complex diseases. [1]
Specific genetic variants have shown associations with conditions beyond classical lipid disorders. For instance, some polymorphisms linked to phospholipid profiles have also been associated with type 2 diabetes, bipolar disorder, and rheumatoid arthritis, suggesting broader systemic implications of altered lipid metabolism.[1] The impact of SNPs in HMGCR on LDL-cholesterol levels through alternative splicing further underscores how genetic variations, by influencing fundamental regulatory mechanisms, contribute to common metabolic disorders. [14] These insights into pathway dysregulation provide potential avenues for identifying therapeutic targets to manage and prevent a spectrum of metabolic and complex diseases.
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 Nov;4(11):e1000282.
[2] Kathiresan, S. et al. “Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.”Nat Genet, vol. 40, no. 2, 2008, pp. 189-197.
[3] Benjamin, E. J. et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, suppl. 1, 2007, S11.
[4] 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.
[5] Kathiresan, S. et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56-65.
[6] Yang, Q. et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Med Genet, vol. 8, suppl. 1, 2007, S12.
[7] Melzer D, et al. A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet. 2008 May 2;4(5):e1000072.
[8] Reiner AP, et al. Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet. 2008 May;82(5):1193-201.
[9] Havel, RJ.; Kane, JP. “Structure and Metabolism of Plasma Lipoproteins.” Structure and Metabolism of Plasma Lipoproteins, 8th ed., McGraw-Hill, 2005.
[10] Pollin TI, et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, 2009.
[11] Schaeffer, Lucie, et al. “Common Genetic Variants of the FADS1 FADS2 Gene Cluster and Their Reconstructed Haplotypes Are Associated with the Fatty Acid Composition in Phospholipids.” Human Molecular Genetics, vol. 15, no. 10, 2006, pp. 1745–1756.
[12] Vance, Jean E. “Membrane Lipid Biosynthesis.” Encyclopedia of Life Sciences, John Wiley & Sons, Ltd, 2001.
[13] Caceres, Javier F., and Alberto R. Kornblihtt. “Alternative Splicing: Multiple Control Mechanisms and Involvement in Human Disease.”Trends in Genetics, vol. 18, no. 4, 2002, pp. 186–193.
[14] 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. 11, 2008, pp. 2071-2078.
[15] Crawford, Dana C., et al. “Haplotype Diversity across 100 Candidate Genes for Inflammation, Lipid Metabolism, and Blood Pressure Regulation in Two Populations.” The American Journal of Human Genetics, vol. 74, no. 4, 2004, pp. 610–622.
[16] Malerba, Giovanni, et al. “SNPs of the FADSGene Cluster Are Associated with Polyunsaturated Fatty Acids in a Cohort of Patients with Cardiovascular Disease.”Lipids, vol. 43, no. 4, 2008, pp. 289–299.