Cytosolic 10-formyltetrahydrofolate dehydrogenase regulates glycine metabolism in mouse liver

Abstract

ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism highly expressed in liver, metabolizes 10-formyltetrahydrofolate to produce tetrahydrofolate (THF). This reaction might have a regulatory function towards reduced folate pools, de novo purine biosynthesis, and the flux of folate-bound methyl groups. To understand the role of the enzyme in cellular metabolism, Aldh1l1−/− mice were generated using an ES cell clone (C57BL/6N background) from KOMP repository. Though Aldh1l1−/− mice were viable and did not have an apparent phenotype, metabolomic analysis indicated that they had metabolic signs of folate deficiency. Specifically, the intermediate of the histidine degradation pathway and a marker of folate deficiency, formiminoglutamate, was increased more than 15-fold in livers of Aldh1l1−/− mice. At the same time, blood folate levels were not changed and the total folate pool in the liver was decreased by only 20%. A two-fold decrease in glycine and a strong drop in glycine conjugates, a likely result of glycine shortage, were also observed in Aldh1l1−/− mice. Our study indicates that in the absence of ALDH1L1 enzyme, 10-formyl-THF cannot be efficiently metabolized in the liver. This leads to the decrease in THF causing reduced generation of glycine from serine and impaired histidine degradation, two pathways strictly dependent on THF.

Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder

“…One of the goals of this study was to differentiate the function of the ALDH1L2 enzyme from the function of its cytosolic counterpart ALDH1L1. We previously reported that the Aldh1l1 KO in mice affected genes associated with inflammation [ 12 ]. The role of the folate metabolism in inflammation and immunity has been underscored [ 29 , 30 ].…”

“…Experimental data suggest that this reaction is important for the regulation of the overall cellular folate pool as well as the proliferative capacity of the cell [ 10 , 11 ]. We have recently generated mice with targeted Aldh1l1 knockout and demonstrated that the animals lacking the enzyme display metabolic signs of folate deficiency and have impaired glycine metabolism in the liver [ 12 ]. The cause of these metabolic perturbations was the inability, in the absence of ALDH1L1, to convert 10-formyl-THF to THF resulting in the shortage of the latter metabolite required for the generation of glycine from serine [ 12 ].…”

“…We have recently generated mice with targeted Aldh1l1 knockout and demonstrated that the animals lacking the enzyme display metabolic signs of folate deficiency and have impaired glycine metabolism in the liver [ 12 ]. The cause of these metabolic perturbations was the inability, in the absence of ALDH1L1, to convert 10-formyl-THF to THF resulting in the shortage of the latter metabolite required for the generation of glycine from serine [ 12 ]. These findings support the hypothesis that in non-proliferating cells the ALDH1L1-catalyzed reaction is important to restore the THF pool [ 13 ].…”

“…The overlapping function of the two enzymes is perhaps suggested by the fact that birds and reptiles have lost the gene for the cytosolic enzyme [ 9 ]. In our previous study, Aldh1l1 knockout mice were viable and did not have apparent phenotype [ 12 ] raising the question of whether the mitochondrial enzyme can compensate for the loss of the cytosolic counterpart. Here, we have generated and characterized Aldh1l2 knockout mice and demonstrate that in contrast to ALDH1L1, the mitochondrial enzyme is important for the regulation of lipid metabolism.…”

Amino acid metabolism in fate decision of porcine immune cells: advances and beyond

“…此外, 有研究表 明, 左旋肉碱合成过程中也能生成甘氨酸 [11] . 在甘氨 酸合成途径中, 丝氨酸合成甘氨酸以及甜菜碱转化为 甘氨酸的后两步反应依赖于叶酸, 其中10-甲酰基四氢 叶酸脱氢酶(肝脏中高度表达的叶酸代谢酶)可代谢10-甲酰基四氢叶酸产生四氢叶酸, 从而影响叶酸依赖的 甘氨酸生成 [12] .…”