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The 5-formyl-tetrahydrofolate proteome links folates with C/N metabolism and reveals feedback regulation of folate biosynthesis.
Li, W, Liang, Q, Mishra, RC, Sanchez-Mu Oz, R, Wang, H, Chen, X, Van Der Straeten, D, Zhang, C, Xiao, Y
The Plant cell. 2021;(10):3367-3385
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Abstract
Folates are indispensable for plant development, but their molecular mode of action remains elusive. We synthesized a probe, "5-F-THF-Dayne," comprising 5-formyl-tetrahydrofolate (THF) coupled to a photoaffinity tag. Exploiting this probe in an affinity proteomics study in Arabidopsis thaliana, we retrieved 51 hits. Thirty interactions were independently validated with in vitro expressed proteins to bind 5-F-THF with high or low affinity. Interestingly, the interactors reveal associations beyond one-carbon metabolism, covering also connections to nitrogen (N) metabolism, carbohydrate metabolism/photosynthesis, and proteostasis. Two of the interactions, one with the folate biosynthetic enzyme DIHYDROFOLATE REDUCTASE-THYMIDYLATE SYNTHASE 1 (AtDHFR-TS1) and another with N metabolism-associated glutamine synthetase 1;4 (AtGLN1;4), were further characterized. In silico and experimental analyses revealed G35/K36 and E330 as key residues for the binding of 5-F-THF in AtDHFR-TS1 and AtGLN1;4, respectively. Site-directed mutagenesis of AtGLN1;4 E330, which co-localizes with the ATP-binding pocket, abolished 5-F-THF binding as well as AtGLN1;4 activity. Furthermore, 5-F-THF was noted to competitively inhibit the activities of AtDHFR-TS1 and AtGLN1;4. In summary, we demonstrated a regulatory role for 5-F-THF in N metabolism, revealed 5-F-THF-mediated feedback regulation of folate biosynthesis, and identified a total of 14 previously unknown high-affinity binding cellular targets of 5-F-THF. Together, this sets a landmark toward understanding the role of folates in plant development.
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Effectiveness of community-based folate-oriented tertiary interventions on incidence of fetus and birth defects: a protocol for a single-blind cluster randomized controlled trial.
Li, M, Zhang, Y, Chen, X, Wang, D, Ji, M, Jiang, Y, Dou, Y, Ma, X, Sheng, W, Yan, W, et al
BMC pregnancy and childbirth. 2020;(1):475
Abstract
BACKGROUND Birth defects are the main cause of fetal death, infant mortality and morbidity worldwide. However, the etiology of birth defects remains largely unknown. Maternal folate status during periconception plays an important role in organogenesis and folic acid supplement reduces the risk of neural tube defects, congenital heart diseases, and several other birth defects. This trial seeks to evaluate the effectiveness of folate-oriented tertiary interventions during periconception on the incidence of fetus and birth defects. METHODS This is a single-blind, two-arm cluster randomized controlled trial in Shanghai, China. Eligible women from 22 clusters are recruited at pre-pregnancy physical examinations clinical settings. Compared to the routine perinatal care group (control arm), folate-oriented tertiary interventions will be provided to the intervention arm. The core interventions consist of assessments of folate status and metabolism, folate intake guidance, and re-evaluation of folate status to ensure red blood cell folate level above 400 ng/ml (906 nmol/L) before pregnancy. Screening and consulting of fetus and birth defects, and treatments of birth defects during pregnancy and afterward will be provided to both arms. The primary outcome is a composite incidence of fetus defects, stillbirth, and neonatal birth defects identified from the confirmation of pregnancy to 28 days after birth. Secondary outcomes include maternal and offspring adverse complications and cost-effectiveness of folate-oriented tertiary interventions. This protocol adheres to the SPIRIT Checklist. DISCUSSION To achieve the recommended folate status before or during pregnancy is still a challenge worldwide. This community-based cluster-randomized controlled intervention trial will evaluate the effectiveness of a package of interventions aiming at achieving recommended maternal folate status covering pre- and during pregnancy in reducing fetus and birth defects. Our study has the potential to improve the community-based practice of reducing modifiable risk factors of disease and improving primary prevention of the defects in China. The procedures would formulate the policy on folic acid supplementation during periconception against birth defects in primary care settings. TRIAL REGISTRATION Clinical Trial Registry, NCT03725878 . Prospectively registered on 31 October 2018.
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A Meta-Analysis of the Relationship Between Maternal Folic Acid Supplementation and the Risk of Congenital Heart Defects.
Xu, A, Cao, X, Lu, Y, Li, H, Zhu, Q, Chen, X, Jiang, H, Li, X
International heart journal. 2016;(6):725-728
Abstract
Controversial opinions exist with respect to the relationship between maternal folic acid (FA) supplementation and birth prevalence of congenital heart defects (CHDs).Eligible articles were retrieved by searching databases, including PubMed, Cochrane library, EMBASE, CNKI, and WanFang up to September 2015. A meta-analysis was performed to evaluate the effects of FA on CHDs. Odds ratios (ORs) and 95% confidence interval (CIs) were merged using STATA 12.0. Meta-regression analysis was used to explore the possible sources of heterogeneity. Subgroup analysis according to the selected sources was also performed. Publication bias was assessed by Egger's test.Twenty studies were included in the meta-analysis. The overall analysis showed that FA supplementation was significantly associated with decreased risk of CHDs. The meta-regression analysis showed that geographical area could be an important source of heterogeneity. The subgroup analysis based on the geographical area revealed that FA supplementation during pregnancy was a protective factor against CHDs in Chinese and European patients, but not in American patients. Subgroup analysis according to literature quality also displayed positive associations between FA supplementation and the decreased risk of CHDs of China.FA supplementation during pregnancy significantly decreases the risk of CHDs in newborns in China and Europe.
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Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa.
Wallace, K, Grau, MV, Levine, AJ, Shen, L, Hamdan, R, Chen, X, Gui, J, Haile, RW, Barry, EL, Ahnen, D, et al
Cancer prevention research (Philadelphia, Pa.). 2010;(12):1552-64
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Abstract
Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.