Serine
Background
Section titled “Background”Serine is an alpha-amino acid with the chemical formula HO2CCH(NH2)CH2OH. It is characterized by its hydroxyl group-containing side chain, which makes it a polar amino acid. While vital for numerous biological processes, serine is considered non-essential in humans because the body can synthesize it from other metabolites, meaning it does not typically need to be obtained directly from the diet.
Biological Basis
Section titled “Biological Basis”Serine plays a fundamental role as a building block for proteins and is a crucial intermediate in various metabolic pathways. It is a precursor for the biosynthesis of several other amino acids, including glycine and cysteine. Serine also participates in one-carbon metabolism, a pathway essential for the synthesis of nucleotides and methylation reactions, by contributing its side-chain carbon atom. Beyond its role in amino acid and nucleotide synthesis, serine is integral to the formation of phospholipids, such as phosphatidylserine, and sphingolipids, which are critical components of cell membranes and signaling molecules. The hydroxyl group of serine is also a common site for phosphorylation, a key post-translational modification involved in cell signaling and regulation of protein activity.
Clinical Relevance
Section titled “Clinical Relevance”Dysregulation of serine metabolism can have various clinical implications, particularly affecting neurological function. Furthermore, genetic variations in certain genes whose names contain “serine” are associated with specific health conditions. For instance, the_SERPINE2_gene, which encodes a serpin peptidase inhibitor, has been associated with Chronic Obstructive Pulmonary Disease (COPD).[1]A specific single nucleotide polymorphism (SNP),rs3820928 , has been identified in relation to pulmonary function measures, showing a strong linkage disequilibrium with non-synonymous coding SNPs in the _COL4A4_ gene.[1] Other serpin genes, such as _SERPINE1_(serpin peptidase inhibitor, clade E, member 1), have been investigated in genome-wide association studies for their influence on hemostatic factors and hematological phenotypes.[2] Additionally, _SERPINA1_ (Alpha-1-antitrypsin) and _SERPINA3_ (Alpha-1-antichymotrypsin) are recognized as candidate genes in the context of pulmonary function measures.[1]
Social Importance
Section titled “Social Importance”While serine is synthesized endogenously, it is also present in many protein-rich foods, including meat, dairy, nuts, seeds, and legumes. Research into serine’s roles in metabolism and disease contributes to a broader understanding of human health, nutrition, and the genetic underpinnings of complex conditions. This knowledge can inform dietary guidelines, therapeutic strategies, and genetic counseling for individuals at risk of serine-related metabolic disorders or conditions linked to associated genes.
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”The interpretation of genetic associations for the trait under study is subject to several methodological and statistical limitations. Many investigations face challenges related to cohort size, which can lead to inadequate statistical power and an increased risk of false negative findings, particularly for associations with smaller effect sizes.[1]Other variants affect genes that regulate broader metabolic processes, indirectly influencing serine metabolism. TheGCKR(Glucokinase Regulator) gene, for instance, encodes a protein that regulates glucokinase, a key enzyme in glucose metabolism. Variants likers1260326 in GCKRhave been associated with altered glucose and triglyceride levels, and dyslipidemia, suggesting an impact on overall metabolic flux that could affect the availability of glycolytic intermediates, such as 3-phosphoglycerate, for serine synthesis.[3], [4] Similarly, PHKG1(Phosphorylase Kinase G1) is a component of phosphorylase kinase, an enzyme central to glycogenolysis, the breakdown of glycogen to glucose. A variant likers2242508 in PHKG1could influence glucose availability for glycolysis, thereby indirectly impacting serine synthesis.TRIB1AL (Tribbles Homolog 1), a pseudokinase, is known for its role in lipid metabolism, with variants like rs28601761 potentially affecting triglyceride levels and overall lipid homeostasis.[5]Such broad metabolic changes can shift cellular resource allocation, indirectly affecting amino acid pathways including serine.
Variants in genes involved in general cellular functions, such as protein folding or nitrogen metabolism, also hold relevance. CPS1(Carbamoyl Phosphate Synthetase 1) is an enzyme in the urea cycle, crucial for nitrogen detoxification and amino acid catabolism. Variants likers715 and rs1047891 in CPS1could affect nitrogen balance and the broader amino acid pool, indirectly influencing serine’s role in one-carbon metabolism.[2] SUMF2(Sulphatase Modifying Factor 2) plays a role in activating sulfatase enzymes, which are involved in various catabolic processes. While not directly linked to serine, a variant such asrs13244654 in SUMF2could influence the metabolism of sulfated compounds, some of which may interact with serine pathways.CCT6A(Chaperonin Containing TCP1 Subunit 6A) is part of a chaperonin complex vital for protein folding, and proper protein function is essential for all metabolic enzymes, including those in serine metabolism. The variantrs7793921 in CCT6Acould subtly impact overall cellular proteostasis, thereby affecting the efficiency of serine-related enzymes.[6] Finally, mitochondrial function genes, like NIPSNAP2 (NipSnap Homolog 2) and CHCHD2 (Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2), can have widespread metabolic implications. NIPSNAP2 is a mitochondrial protein, and variants such as rs4470984 and rs4535700 could affect mitochondrial dynamics or signaling, thereby influencing overall cellular energy production and amino acid metabolism, including serine catabolism. Similarly,CHCHD2 is a mitochondrial protein involved in maintaining mitochondrial integrity and function, relevant to oxidative phosphorylation and cellular energy states. Variants like rs816411 , rs4948106 , and rs57427081 in CHCHD2 could impact mitocho.[7]
Metabolic Significance and Homeostasis
Section titled “Metabolic Significance and Homeostasis”Serine is an amino acid, a type of fundamental endogenous metabolite that plays a crucial role in various cellular processes throughout the human body. The field of metabolomics, which involves the comprehensive measurement of all endogenous metabolites in a cell or body fluid, aims to provide a functional readout of an individual’s physiological state.[8]Maintaining the delicate balance, or homeostasis, of amino acid levels is essential for supporting proper biological function and overall health.
Genetic Influences on Metabolite Levels
Section titled “Genetic Influences on Metabolite Levels”Genetic variations present in an individual’s genome can significantly affect the homeostasis of key metabolites, including amino acids.[8]These genetic variants are expected to be associated with alterations in the physiological balance of these essential biomolecules. Genome-wide association studies (GWAS) are employed to identify specific genetic markers that influence metabolite profiles observed in human serum, providing insights into the genetic architecture underlying metabolic traits.[8]
Research Methodologies for Metabolite Profiling
Section titled “Research Methodologies for Metabolite Profiling”The study of amino acid profiles and other metabolites often utilizes advanced analytical techniques, such as targeted metabolite profiling by electrospray ionization (ESI) tandem mass spectrometry (MS/MS).[8] This technology enables the quantitative measurement of a wide array of metabolites, offering detailed biochemical snapshots of an individual’s metabolic state. Such methods are vital for identifying how genetic factors impact the circulating levels of amino acids and other biomolecules within bodily fluids like serum.[8]
Genetic Influences on Hematological and Cardiovascular Health
Section titled “Genetic Influences on Hematological and Cardiovascular Health”Genetic variations in or near the SERPINE1gene, which encodes a serpin peptidase inhibitor, have been associated with hematological phenotypes, specifically hematocrit levels, in genome-wide association studies.[2] These findings, observed in population-based cohorts such as the Framingham Heart Study, suggest that genetic differences affecting SERPINE1 expression or function can influence blood composition and hemostatic balance.[2]Such genetic markers hold potential for improving risk assessment for individuals predisposed to certain blood disorders or cardiovascular conditions where hematocrit is a relevant factor, thereby contributing to personalized medicine approaches by identifying high-risk individuals for targeted monitoring. However, the direct prognostic value and utility in treatment selection require further comprehensive clinical validation.
Association with Pulmonary Disease and Prognosis
Section titled “Association with Pulmonary Disease and Prognosis”The SERPINE2gene, another member of the serpin peptidase inhibitor family, has been identified through genetic linkage and association studies as a novel gene linked to Chronic Obstructive Pulmonary Disease (COPD).[1]This association, observed in cohorts like the Boston Early-Onset COPD cohort, highlights the crucial role that serine protease inhibition pathways may play in the susceptibility, pathogenesis, or progression of pulmonary diseases.[1] Understanding the genetic contribution of SERPINE2offers a promising avenue for enhancing prognostic assessments related to lung function decline and for identifying individuals at higher risk for developing COPD, which could inform early prevention strategies and disease management. Further research is needed to translate these genetic insights into definitive diagnostic tools or treatment selection criteria.
Broader Clinical Applications and Risk Stratification
Section titled “Broader Clinical Applications and Risk Stratification”The collective findings regarding genetic associations with serpin-related genes, such as SERPINE1 and SERPINE2, underscore their potential for broader clinical applications beyond single disease phenotypes. For instance, integrating information aboutSERPINE1variants associated with hematocrit into comprehensive risk stratification models could refine predictions for cardiovascular events or other conditions influenced by blood parameters.[2] Similarly, SERPINE2 genetic markers could contribute to a more nuanced understanding of individual susceptibility to pulmonary diseases, facilitating personalized prevention and monitoring strategies for those identified as high-risk.[1] While these genetic insights offer a foundation for developing diagnostic utility and guiding treatment selection, their clinical implementation requires rigorous validation in diverse patient populations and well-designed prospective studies to establish their definitive impact on patient care and long-term outcomes.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs477992 rs561931 rs839614 | PHGDH | metabolite measurement serine measurement hematocrit total cholesterol measurement red blood cell density |
| rs715 rs1047891 | CPS1 | circulating fibrinogen levels plasma betaine measurement eosinophil percentage of leukocytes platelet crit macular telangiectasia type 2 |
| rs4947534 rs11238389 rs4948102 | PSPH | glycine measurement serum alanine aminotransferase amount serine measurement |
| rs4470984 rs4535700 | NIPSNAP2 | serine measurement |
| rs1260326 | GCKR | urate measurement total blood protein measurement serum albumin amount coronary artery calcification lipid measurement |
| rs28601761 | TRIB1AL | mean corpuscular hemoglobin concentration glomerular filtration rate coronary artery disease alkaline phosphatase measurement YKL40 measurement |
| rs13244654 | SUMF2 | serine measurement amino acid measurement, threonine measurement methionine measurement, amino acid measurement body height |
| rs2242508 | PHKG1 | serine measurement multiple sclerosis |
| rs7793921 | CCT6A | body height serine measurement pulse pressure measurement |
| rs816411 rs4948106 rs57427081 | CHCHD2 | dementia serine measurement |
References
Section titled “References”[1] Wilk JB, et al. “Framingham Heart Study genome-wide association: results for pulmonary function measures.” BMC Med Genet. 2007; PMID: 17903307
[2] Yang Q, et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.” BMC Med Genet. 2007; PMID: 17903294
[3] Saxena R, et al. “Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.” Science. 2007; PMID: 17463246
[4] Wallace C, et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.” Am J Hum Genet. 2008; PMID: 18179892
[5] Kathiresan S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet. 2008; PMID: 19060906
[6] Benjamin EJ, et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet. 2007; PMID: 17903293
[7] Doring A, et al. “SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.” Nat Genet. 2008; PMID: 18327256
[8] Gieger C, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.” PLoS Genet. 2009; PMID: 19043545