Mechanistic and metabolomic underpinnings of ALDH1L1 polymorphisms in the regulation of glycine metabolism

ALDH1L1 多态性调节甘氨酸代谢的机制和代谢组学基础

• 批准号: 10663183
• 负责人: SERGEY A KRUPENKO
• 金额: $ 62.59万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663183
• 关键词: Address; Affect; Anabolism; Carbon; Cell Line; Cells; Child; Coenzymes; Diet; Disease; Enzymes; Ethnic Population; Etiology; Evaluation; Folic Acid; Folic Acid Deficiency; Formyltetrahydrofolates; Frequencies; Generations; Genes; Genetic Polymorphism; Genotype; Glycine; Haplotypes; Health; Hispanic; Holoenzymes; Homeostasis; Homocysteine; Human; Individual; Intake; Knock-out; Knockout Mice; Knowledge; Left; Link; Liver; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic Pathway; Metabolic stress; Metabolism; Methylation; Mus; Nutrient; Obesity; Outcome; Oxidoreductase; Pathology; Pathway interactions; Play; Population; Predisposition; Property; Proteins; Purines; Reaction; Regulation; Reporting; Research; Risk Factors; Role; Route; Serine; Serum; Single Nucleotide Polymorphism; Source; Tetrahydrofolates; Variant; Vitamins; cohort; design; dietary; disorder risk; folic acid metabolism; folic acid supplementation; insight; metabolic phenotype; metabolomics; prevent; response; response biomarker

ALDH1L1, a common enzyme in folate metabolism, converts 10-formyltetrahydrofolate (10-formyl-THF) to tetrahydrofolate (THF). This reaction is known to regulate the de novo purine biosynthesis and folate-dependent homocysteine re-methylation cycle. It could also play a key role in controlling the flux of one-carbon groups to anabolic pathways. In support of the role in the regulation of folate metabolism, we have recently shown that the loss of the ALDH1L1 gene in knockout mice causes functional folate deficiency, even when the mice had sufficient folate intake. Analysis of Aldh1l1 knockout mice also showed that the enzyme is the main regulator of glycine metabolism in the liver: KO mice have lower levels of glycine and glycine conjugates, indicating that the enzyme is involved in the folate-dependent synthesis of glycine from serine. We have further reported that human ALDH1L1 has six common non-synonymous exonic SNPs at the polymorphic loci rs3796191, rs2886059, rs9282691, rs2276724, rs1127717 and rs4646750 with the occurrence of haplotypes associated with these SNPs being remarkably different between ethnic populations. Our analysis of an established cohort of Hispanic children, Viva La Familia, has shown a significant reduction of serum glycine and increase in serine/glycine ratio in children with rs2276724 and rs3796191, indicating deregulation of serine to glycine conversion and re- capitulating our mouse findings. ALDH1L1 non-synonymous SNPs were also associated with markers of metabolic stress and adiposity in this cohort. Based on our findings, we hypothesize that non-synonymous ALDH1L1 SNPs produce enzyme variants with altered catalytic activity and/or stability that affects their ability to metabolize 10-formyl-THF and thus deregulates glycine metabolism. Accordingly, individuals with specific haplotypes have different ratios of THF/10-formyl-THF and serine/glycine, and altered levels of glycine and its conjugates, with perturbations in the metabotype representing a signature of metabolic health. This proposal will address the question of how haplotype-specific ALDH1L1 variants affect folate metabolism and the overall cellular metabotype, and how the haplotype-specific effect is modified by folate supplementation, by pursuing the following specific aims. Aim 1. Functionally characterize the ALDH1L1 enzyme variants from common human haplotypes. Aim 2. Determine the impact of major ALDH1L1 haplotypes on cellular metabolism and haplotype- specific responses to various folate supplementations. Aim 3. Link ALDH1L1 haplotypes to the folate-dependent regulation of glycine metabolism and health outcomes in humans. ALDH1L1 variants are very common in different populations but their role in folate homeostasis and in the etiology of metabolic disease is largely unexplored. It is expected that ALDH1L1 haplotypes differently mediate the metabolic response to dietary folate that might require adjustments of folate intake for individuals bearing certain ALDH1L1 SNPs. By filling this knowledge gap, the proposed research will provide mechanistic insight into the metabolic regulation by ALDH1L1 SNPs and will lay ground for the evaluation of population-specific ALDH1L1 haplotypes as a disease risk factor.

AldH1L1是叶酸代谢中的一种常见酶，将10型甲基四氢叶酸（10-甲基THF）转化为四氢叶酸盐（THF）。已知该反应调节从头嘌呤的生物合成和叶酸依赖性同型半胱氨酸重甲基化周期。它还可以在控制一碳基团到合成代谢途径的通量中起关键作用。为了支持叶酸代谢调节的作用，我们最近表明，即使小鼠具有足够的叶酸摄入，敲除小鼠中AldH1L1基因的丧失也会引起功能性叶酸缺乏症。对ALDH1L1基因敲除小鼠的分析还表明，该酶是肝脏中甘氨酸代谢的主要调节剂：KO小鼠的甘氨酸和甘氨酸偶联物水平较低，表明该酶与甘油中甘氨酸的叶酸依赖性合成有关。 We have further reported that human ALDH1L1 has six common non-synonymous exonic SNPs at the polymorphic loci rs3796191, rs2886059, rs9282691, rs2276724, rs1127717 and rs4646750 with the occurrence of haplotypes associated with these SNPs being remarkably different between ethnic populations.我们对既定的西班牙裔儿童Viva la Familia的群体的分析显示，血清甘氨酸的降低显着降低，丝氨酸/甘氨酸比率的增加，rs2276724和RS3796191的儿童中的丝氨酸/甘氨酸比率增加，这表明丝氨酸对丝氨酸对甘氨酸的转化和重新质量的capition和Re-Capiting siffings sipersine coptsion和3796191。 ALDH1L1非同义SNP也与该队列中的代谢应力和肥胖标记有关。根据我们的发现，我们假设非同义ALDH1L1 SNP会产生具有改变催化活性和/或稳定性的酶变体，从而影响其代谢10-甲胺THF的能力，从而影响甘氨酸代谢。因此，具有特定单倍型的个体具有不同比率的THF/10-甲胺-THF和丝氨酸/甘氨酸，并且甘氨酸及其结合物的水平改变了，并且在分类中扰动，代表代表代谢健康的特征。该建议将解决一个问题，即单倍型特异性的ALDH1L1变体如何影响叶酸代谢和整体细胞代谢，以及如何通过追求以下特定目标来通过补充叶酸来改变单倍型特异性效应。 AIM 1。在功能上表征来自常见人类单倍型的AldH1L1酶变体。 AIM 2。确定主要ALDH1L1单倍型对细胞代谢和对各种叶酸补充的特异性反应的影响。 AIM 3。将ALDH1L1单倍型与人类甘氨酸代谢和健康结果的叶酸依赖性调节联系起来。 ALDH1L1在不同人群中非常普遍，但是它们在叶酸稳态中的作用和代谢疾病的病因在很大程度上没有探索。预计ALDH1L1单倍型会不同地介导对饮食叶酸的代谢反应，这可能需要调整具有某些AldH1L1 SNP的个体的叶酸摄入量。通过填补这一知识差距，拟议的研究将为ALDH1L1 SNP的代谢调节提供机械洞察力，并将为评估人群特异性ALDH1L1单倍型评估作为疾病危险因素而奠定基础。