Magana Armando Alcazar, Reed Ralph L, Koluda Rony, Miranda Cristobal L, Maier Claudia S, Stevens Jan F
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331, USA.
Linus Pauling Institute, Oregon State University, 2900 SW Campus way, Corvallis, OR 97331, USA.
Antioxidants (Basel). 2020 Mar 5;9(3):217. doi: 10.3390/antiox9030217.
Vitamin C (L-ascorbic acid, AA) is an essential cellular antioxidant and cofactor for several α-ketoglutarate-dependent dioxygenases. As an antioxidant, AA interacts with vitamin E to control oxidative stress. While several reports suggest an interaction of AA with folate (vitamin B9) in animals and humans, little is known about the nature of the interaction and the underlying molecular mechanisms at the cellular level. We used an untargeted metabolomics approach to study the impact of AA on the metabolome of C2C12 myoblast cells. Compared to untreated cells, treatment of C2C12 cells with AA at 100 µM resulted in enhanced concentrations of folic acid (2.5-fold) and 5-methyl-tetrahydrofolate (5-methyl-THF, 10-fold increase) whereas the relative concentrations of 10-formyl-tetrahydrofolate decreased by >90% upon AA pretreatment, indicative of increased utilization for the biosynthesis of active THF metabolites. The impact of AA on the folate-mediated one-carbon cycle further manifested itself as an increase in the levels of methionine, whose formation from homocysteine is 5-methyl-THF dependent, and an increase in thymidine, whose formation from deoxyuridine monophosphate (dUMP) is dependent on 5,10-methylene-THF. These findings shed new light on the interaction of AA with the folate-mediated one-carbon cycle and partially explain clinical findings that AA supplementation enhances erythrocyte folate status and that it may decrease serum levels of homocysteine, which is considered as a biomarker of cardiovascular disease risk.
维生素C（L-抗坏血酸，AA）是一种重要的细胞抗氧化剂，也是几种α-酮戊二酸依赖性双加氧酶的辅助因子。作为一种抗氧化剂，AA与维生素E相互作用以控制氧化应激。虽然有几份报告表明AA在动物和人类中与叶酸（维生素B9）存在相互作用，但对于这种相互作用的本质以及细胞水平上潜在的分子机制知之甚少。我们采用非靶向代谢组学方法研究AA对C2C12成肌细胞代谢组的影响。与未处理的细胞相比，用100μM的AA处理C2C12细胞会导致叶酸浓度升高（2.5倍）和5-甲基四氢叶酸（5-甲基-THF，增加10倍），而在AA预处理后，10-甲酰四氢叶酸的相对浓度下降了>90%，这表明活性THF代谢物生物合成的利用率增加。AA对叶酸介导的一碳循环的影响还表现为蛋氨酸水平的升高，其从同型半胱氨酸的形成依赖于5-甲基-THF，以及胸苷水平的升高，其从脱氧尿苷单磷酸（dUMP）的形成依赖于5,10-亚甲基-THF。这些发现为AA与叶酸介导的一碳循环的相互作用提供了新的线索，并部分解释了临床研究结果，即补充AA可提高红细胞叶酸水平，且可能降低同型半胱氨酸的血清水平，而同型半胱氨酸被认为是心血管疾病风险的生物标志物。
