Isoleucine
Isoleucine is an essential amino acid, meaning the human body cannot synthesize it and must obtain it through dietary sources. It is one of the three branched-chain amino acids (BCAAs), alongside leucine and valine, playing a crucial role in various biological processes.
Biological Basis
Section titled “Biological Basis”As a fundamental building block of proteins, isoleucine’s unique branched side chain contributes significantly to the intricate three-dimensional structure and stability of proteins. This structural role is critical for protein function. Genetic variations, particularly those involving substitutions of one amino acid for another, can profoundly impact protein structure and function. For instance, research indicates that substitutions such as valine to isoleucine at key positions within proteins can lead to altered protein structure and function, potentially affecting biological processes.[1]The field of metabolomics, which involves the comprehensive measurement of metabolites in bodily fluids, has shown that genetic variants can be associated with changes in the homeostasis of key amino acids like isoleucine, offering insights into physiological states.[2]
Clinical Relevance
Section titled “Clinical Relevance”Given its essential role in protein synthesis and metabolism, disruptions in isoleucine levels or its proper incorporation into proteins can have clinical implications. Alterations in protein function due to amino acid substitutions, such as valine to isoleucine, have been linked to clinically relevant phenotypes in various disorders.[1]Furthermore, genetic studies have identified associations between genetic variants and metabolite profiles in human serum, including amino acids, which can serve as biomarkers for different health conditions. For example, genetic variants have been found to influence levels of serum uric acid and various lipid concentrations, which are important biomarkers for cardiovascular disease.[3]These findings suggest that genetic influences on amino acid metabolism, including isoleucine, may contribute to the risk or progression of metabolic and cardiovascular disorders.
Social Importance
Section titled “Social Importance”Understanding the genetic and metabolic aspects of isoleucine holds significant social importance. As an essential nutrient, dietary intake of isoleucine is vital for human health. Genetic variations affecting how individuals metabolize isoleucine or how proteins incorporating it function could lead to personalized nutritional recommendations or targeted therapeutic strategies for individuals predisposed to certain conditions. The broader study of genetic variants influencing metabolite levels, including amino acids, contributes to a more comprehensive understanding of human health and disease, potentially guiding public health initiatives and personalized medicine approaches.
Limitations
Section titled “Limitations”The current understanding of genetic influences on isoleucine levels, derived from genome-wide association studies (GWAS) and related research, is subject to several important limitations. These constraints stem from methodological choices, the characteristics of study populations, and the inherent complexity of biological systems, which collectively impact the interpretation and generalizability of findings.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The precision and comprehensiveness of genetic association studies are often constrained by their design and statistical power. Many GWAS, particularly earlier ones, may lack sufficient power to reliably detect genetic variants that exert modest effects on traits like isoleucine, especially when stringent statistical thresholds are applied to account for multiple testing .GCKRregulates glucokinase, a key enzyme in glucose phosphorylation, and its variants can impact triglyceride levels and susceptibility to type 2 diabetes.[4]Similarly, the carbohydrate response element binding protein gene,MLXIPL, contains variants like rs13234131 that are strongly associated with plasma triglyceride levels.[5] MLXIPLacts as a transcription factor, promoting the synthesis of fatty acids and triglycerides in response to glucose, thereby influencing overall metabolic load that can impact amino acid processing.
Other genes, such as PPM1K-DT and BCAT2, are more directly involved in branched-chain amino acid (BCAA) metabolism, critically affecting isoleucine concentrations.PPM1K(Protein Phosphatase, Mg2+/Mn2+ Dependent 1K) plays a role in regulating the branched-chain alpha-keto acid dehydrogenase complex (BCKDH), a key enzyme complex responsible for the irreversible catabolism of BCAAs, including isoleucine. Variants likers10018448 , rs10014755 , and rs1440581 within the PPM1K-DTlocus may influence the efficiency of BCAA breakdown, thereby affecting circulating isoleucine levels and contributing to metabolic conditions linked to BCAA dysregulation.[6] Likewise, BCAT2(Branched-Chain Amino Acid Transaminase 2) encodes an enzyme that catalyzes the first step in BCAA catabolism, transferring an amino group from BCAAs to alpha-ketoglutarate. The variantrs493841 in BCAT2could alter the activity of this enzyme, impacting the initial breakdown of isoleucine and influencing its availability for various metabolic pathways.[7]Genes involved in broader lipid metabolism and inflammatory responses also show variants that can indirectly affect isoleucine.LPL(Lipoprotein Lipase) is crucial for hydrolyzing triglycerides in circulating lipoproteins, making fatty acids available to tissues. Variants such asrs13702 , rs301 , and rs331 in LPLcan influence plasma lipid profiles, which are often correlated with BCAA levels and insulin resistance. Alterations in lipid metabolism can indirectly impact the metabolic pathways that handle amino acids, including isoleucine. Similarly,TRIB1 (Tribbles Homolog 1) is a gene that plays a role in lipid metabolism and inflammation, with variants like rs2001945 potentially affecting triglyceride levels and metabolic health. Given the interconnectedness of metabolic pathways, variations inTRIB1could indirectly influence systemic amino acid balance and contribute to metabolic phenotypes associated with isoleucine.
Finally, other variants in genes with diverse cellular functions may also contribute to the complex regulation of isoleucine. TheAARS1gene encodes alanyl-tRNA synthetase 1, an enzyme critical for protein synthesis by attaching alanine to its corresponding tRNA. A variant likers12149660 in AARS1could potentially affect overall cellular protein turnover and amino acid utilization.[7] ZPR1 (Zinc Finger Protein, Receptors Associated 1) is involved in cell proliferation and survival, and its variant rs964184 might have more general cellular impacts that could subtly influence metabolic states. The DDX19A-DT and DDX19B genes encode DEAD-box helicases involved in RNA metabolism, and their shared variant rs12325419 could affect gene expression regulation, thereby influencing the production of metabolic enzymes. Lastly, ST3GAL2 (ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 2) is involved in glycosylation, and its variant rs11647932 might alter protein function or cellular signaling in ways that indirectly modulate metabolic processes.[4]These broader influences highlight the polygenic nature of metabolic traits and the intricate web of interactions that govern isoleucine homeostasis.
The researchs context does not contain information regarding the classification, definition, or terminology of isoleucine.
Isoleucine as a Fundamental Building Block and its Molecular Properties
Section titled “Isoleucine as a Fundamental Building Block and its Molecular Properties”Isoleucine is an essential branched-chain amino acid, meaning the human body cannot synthesize it and must acquire it through dietary intake. As one of the 20 standard amino acids, isoleucine is a critical component for protein synthesis. It is characterized by its hydrophobic nature, a property it shares with valine, and this characteristic significantly influences the three-dimensional structure and stability of proteins.[1] The precise arrangement of hydrophobic amino acids within a protein determines how it folds into its functional shape, how it interacts with other cellular components, and ultimately, its specific biological role.
The exact identity of an amino acid at any given position within a protein is vital for its overall integrity and activity. Even seemingly similar amino acid substitutions, such as replacing valine with isoleucine, can lead to substantial alterations in protein structure and function if they occur at key sites.[1]These molecular changes can compromise a protein’s stability, modify its enzymatic capacity, or impair its ability to bind to target molecules, consequently affecting downstream cellular processes and overall physiological function.
Genetic Determinants of Isoleucine’s Functional Impact
Section titled “Genetic Determinants of Isoleucine’s Functional Impact”The blueprint for protein construction is encoded in DNA, which is transcribed into RNA and then translated into proteins, a fundamental process known as the central dogma of molecular genetics.[8]Variations in the DNA sequence, such as single nucleotide polymorphisms (SNPs), can result in changes to the amino acid sequence of a protein, known as missense mutations. When such a mutation leads to an isoleucine substitution, it can profoundly affect the characteristics of the resulting protein. These genetic variations can influence protein levels and modifications, thereby impacting their overall abundance and activity within cells.[8]Such amino acid substitutions can also modulate regulatory networks by altering how proteins interact with their partners, including enzymes, receptors, and transcription factors. For instance, a change involving isoleucine might affect the binding affinity of a transcription factor to DNA, consequently modulating gene expression patterns. The field of metabolomics, which involves the comprehensive measurement of endogenous metabolites, provides a functional readout of the physiological state and helps to link genetic variants to changes in the homeostasis of key amino acids like isoleucine.[2]A deeper understanding of these genetic determinants is crucial for unraveling the molecular mechanisms underlying various biological processes and individual susceptibilities to disease.
Isoleucine’s Role in Cellular Function and Systemic Homeostasis
Section titled “Isoleucine’s Role in Cellular Function and Systemic Homeostasis”Isoleucine’s integration into proteins is essential for a wide array of cellular functions, and any alterations involving this amino acid can disrupt critical homeostatic mechanisms. Proteins containing isoleucine participate in diverse biological roles, including metabolic processes, signaling pathways, and maintaining structural integrity across various cell types. When an isoleucine substitution occurs, particularly at a critical residue, it can lead to compromised protein function, initiating a cascade of cellular dysregulation.[1] These functional changes can manifest as altered enzymatic activity, impaired receptor signaling, or weakened structural components within cells.
At the tissue and organ level, the consequences of such molecular disruptions can have systemic impacts. For example, changes in proteins involved in lipid metabolism, such as those regulated by the transcription factor MLXIPL or enzymes like HMGCR, can affect overall metabolic health.[9]
Pathophysiological Consequences of Isoleucine-Related Variants
Section titled “Pathophysiological Consequences of Isoleucine-Related Variants”Clinically relevant phenotypes and disease mechanisms are frequently linked to specific amino acid substitutions that alter protein structure and function.[1], [8]For instance, a valine-to-isoleucine substitution, even if it appears conservative due to similar hydrophobicity, can lead to significant functional changes in certain proteins. A direct example of this is the Val64Ile polymorphism in the C-C chemokine receptor 2, which has been associated with reduced coronary artery calcification.[10]This demonstrates how a single amino acid change involving isoleucine can influence disease progression and impact cardiovascular health.
Beyond this specific example, the general principle holds that alterations to proteins can influence human diseases.[8]Other examples of missense mutations leading to disease, such as those in the amyloid precursor protein gene causing familial Alzheimer’s disease, or variants affecting hemoglobin solubility in sickle cell disease, further underscore the profound impact of even single amino acid changes on human health.[11], [12]These pathophysiological processes highlight that the precise molecular identity of isoleucine within a protein is crucial for maintaining normal biological function and preventing the development of various diseases.
Metabolic Homeostasis and Genetic Regulation
Section titled “Metabolic Homeostasis and Genetic Regulation”Isoleucine, as a branched-chain amino acid, is an integral component of the human metabolome, with its concentrations routinely assessed in comprehensive metabolite profiles from human serum.[2]These metabolic profiles serve as a functional readout reflecting the physiological state of the body, positioning isoleucine levels as a critical intermediate phenotype.[2]Genetic variants have been identified that significantly associate with alterations in the homeostasis of key amino acids, including isoleucine, thereby exerting a substantial regulatory influence on its circulating levels and metabolic flux.[2]This genetic control underscores how individual genetic makeup can modulate the availability and utilization of isoleucine, impacting broader metabolic processes.
Structural and Functional Roles in Protein Integrity
Section titled “Structural and Functional Roles in Protein Integrity”The precise incorporation of isoleucine into protein sequences is crucial for maintaining proper protein structure and function, owing to its specific hydrophobic properties. Substitutions involving isoleucine, such as a valine to isoleucine change at critical positions within a protein, are known to significantly alter its three-dimensional structure and subsequent biological activity.[1] These molecular alterations can manifest as clinically relevant phenotypes and are implicated in the etiology of various disorders.[1]Thus, the integrity of isoleucine’s presence in proteins is a fundamental regulatory mechanism ensuring cellular function and preventing disease.
Systems-Level Metabolic Profiling and Crosstalk
Section titled “Systems-Level Metabolic Profiling and Crosstalk”Isoleucine’s role extends beyond individual metabolic reactions, participating in complex systems-level interactions illuminated through metabolomics. Analyzing isoleucine within the context of extensive metabolite profiles provides invaluable insights into pathway crosstalk and network interactions across diverse biological systems.[2]Such studies reveal how isoleucine levels, as intermediate phenotypes, offer a detailed perspective on potentially affected pathways and their hierarchical regulation.[2]This integrative approach helps to understand the emergent properties of metabolic networks, where the interplay of various metabolites, including isoleucine, contributes to the overall physiological response.
Clinical and Disease-Relevant Mechanisms
Section titled “Clinical and Disease-Relevant Mechanisms”Dysregulation in the pathways involving isoleucine has significant clinical implications, contributing to disease-relevant mechanisms. The alteration of protein structure and function through specific amino acid substitutions, such as valine to isoleucine, directly underpins various clinically relevant phenotypes and associated disorders.[1]Furthermore, genetic variants that influence amino acid homeostasis, including isoleucine concentrations, are anticipated to correlate with a spectrum of physiological traits and an elevated risk for certain diseases.[2] Identifying these pathway dysregulations and associated genetic factors can reveal potential therapeutic targets and inform strategies to support compensatory mechanisms in metabolic diseases.
Clinical Relevance of Isoleucine Variants
Section titled “Clinical Relevance of Isoleucine Variants”Isoleucine, as an amino acid, can be involved in clinically significant genetic variations that impact human health, particularly in metabolic and cardiovascular contexts. Specific single nucleotide polymorphisms (SNPs) leading to isoleucine substitutions at key positions within proteins have been identified to influence phenotypes related to uric acid levels and lipid profiles, offering insights into disease risk and potential avenues for personalized patient care.
Isoleucine Variants and Uric Acid Homeostasis
Section titled “Isoleucine Variants and Uric Acid Homeostasis”Genetic variants involving isoleucine have demonstrated a notable clinical relevance in the regulation of serum uric acid levels. A common nonsynonymous variant, Val253Ile in theGLUT9 gene (rs16890979 ), has been significantly associated with lower serum uric acid concentrations. Studies in populations like the Old Order Amish have shown that individuals carrying the isoleucine allele tend to have reduced uric acid levels, with the magnitude of this effect varying by sex and menopausal status; for instance, pre-menopausal women exhibit the most pronounced reduction in uric acid per Ile allele.[1]While serum uric acid itself is a known risk factor associated with various cardiovascular, inflammatory, and metabolic traits, including percent body fat, triglycerides, HDL, LDL, glucose, insulin, and estimated glomerular filtration rate (eGFR), direct significant associations between the Val253IleGLUT9variant and these specific cardiovascular risk factors have not been consistently identified.[1]Nevertheless, the strong genetic influence on uric acid levels suggests that this isoleucine variant could be a factor in risk stratification for hyperuricemia, a condition linked to gout and other health issues.[3]
Isoleucine’s Influence on Lipid Metabolism and Cardiovascular Disease Risk
Section titled “Isoleucine’s Influence on Lipid Metabolism and Cardiovascular Disease Risk”Isoleucine substitutions also play a role in modulating lipid profiles, thereby impacting cardiovascular disease risk. A specific coding SNP, I4399M in theLPA gene (rs3798220 ), which involves an isoleucine to methionine substitution, has been linked to circulating lipid concentrations. This variant is associated with altered LDL cholesterol levels and shows a particularly strong association with lipoprotein(a) levels.[13]Lipoprotein(a) is an established independent risk factor for coronary artery disease, and genetic variants affecting its concentration can have significant prognostic value. Identifying individuals carrying this isoleucine variant could contribute to personalized risk assessment for dyslipidemia and coronary artery disease, guiding more targeted monitoring strategies and potentially informing treatment selection for lipid-lowering therapies.[13]
Personalized Medicine and Prognostic Implications
Section titled “Personalized Medicine and Prognostic Implications”The identification of specific isoleucine-related genetic variants offers potential for personalized medicine approaches and prognostic insights. For instance, understanding a patient’s genotype for the Val253IleGLUT9variant could help in risk stratification for hyperuricemia, especially considering the differential effects observed across sexes and menopausal states. This could guide preventative strategies or early interventions for high-risk individuals. Similarly, theLPAI4399M variant provides direct prognostic information regarding LDL cholesterol and lipoprotein(a) levels, which are critical biomarkers for cardiovascular disease. Integrating such genetic information into clinical practice allows for a more nuanced assessment of an individual’s predisposition to metabolic and cardiovascular conditions, moving beyond traditional risk factors to more precisely predict outcomes and tailor treatment responses.[13]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs1260326 rs780093 | GCKR | urate measurement total blood protein measurement serum albumin amount coronary artery calcification lipid measurement |
| rs10018448 rs10014755 rs1440581 | PPM1K-DT | alpha-hydroxyisovalerate measurement isoleucine measurement leucine measurement amino acid measurement valine measurement |
| rs964184 | ZPR1 | very long-chain saturated fatty acid measurement coronary artery calcification vitamin K measurement total cholesterol measurement triglyceride measurement |
| rs12325419 | DDX19A-DT, DDX19B | urate measurement isoleucine measurement |
| rs12149660 | AARS1 | body mass index body height valine measurement isoleucine measurement leucine measurement |
| rs2001945 | TRIB1 - TRIB1AL | triglyceride measurement glomerular filtration rate Hypertriglyceridemia gout FURIN/INHBC protein level ratio in blood |
| rs11647932 | ST3GAL2 | isoleucine measurement leucine measurement body height |
| rs13234131 | MLXIPL | HbA1c measurement triglyceride measurement metabolic syndrome triglycerides:totallipids ratio, low density lipoprotein cholesterol measurement cholesterol:totallipids ratio, intermediate density lipoprotein measurement |
| rs493841 | BCAT2 | isoleucine measurement leucine measurement |
| rs13702 rs301 rs331 | LPL | triglyceride measurement, high density lipoprotein cholesterol measurement level of phosphatidylcholine sphingomyelin measurement triglyceride measurement diacylglycerol 36:2 measurement |
References
Section titled “References”[1] McArdle, P. F., et al. “Association of a Common Nonsynonymous Variant in GLUT9 with Serum Uric Acid Levels in Old Order Amish.”Arthritis & Rheumatism, vol. 58, no. 10, 2008, pp. 3274–81.
[2] Gieger, C., et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet. 4.11 (2008): e1000282.
[3] Aulchenko, Y. S., et al. “Loci Influencing Lipid Levels and Coronary Heart Disease Risk in 16 European Population Cohorts.”Nature Genetics, vol. 41, no. 1, 2009, pp. 47–55.
[4] Saxena, Richa, et al. “Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.”Science, vol. 316, no. 5829, 2007, pp. 1331-1336.
[5] Kooner, J. S., et al. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet. 40.2 (2008): 149-51.
[6] Melzer, D., et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genet. 4.5 (2008): e1000072.
[7] Benjamin, E. J., et al. “Genome-Wide Association with Select Biomarker Traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, suppl. 1, 2007, S11.
[8] Dehghan, A., et al. “Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.”The Lancet, vol. 372, no. 9654, 2008, pp. 1896–1906.
[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. PMID: 18802019.
[10] Valdes, A. M., et al. “Val64Ile polymorphism in the C-C chemokine receptor 2 is associated with reduced coronary artery calcification.”Arterioscler Thromb Vasc Biol. 26.12 (2006): 2728-34.
[11] Goate, A., et al. “Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease.”Nature. 349.6311 (1991): 704-6.
[12] Monplaisir, N., et al. “Hemoglobin S Antilles: a variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes.”Proc Natl Acad Sci U S A. 83.24 (1986): 9363-7.
[13] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 11, 2009, pp. 1191-1198.