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.
Highlights
ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism highly expressed in liver, metabolizes 10-formyltetrahydrofolate to produce tetrahydrofolate (THF)
Studies of mice with knockouts of folate-related genes have shown that the loss of certain key folate-metabolizing enzymes is embryonically lethal, the effect associated with the crucial role of folate pathways for nucleic acid biosynthesis and methylation processes[4,5,6,7,8,9,10]
We have evaluated levels of a panel of enzymes relevant to metabolism of 10-formyl-THF (Fig. 1c,e; GNMT was included in the panel because it is one of the most abundant folate-relevant protein in the liver and it regulates the flux of one-carbon groups from folate pools towards methylation or nucleotide biosynthesis[24]; full-size images are shown in Supplementary Fig. S1)
Summary
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. 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. The enzyme converts 10-formyl-THF to THF and CO2 in an NADP+-dependent reaction This reaction could be important for replenishing the cellular THF pool, which is involved in several metabolic processes in the cell including serine to glycine conversion, histidine degradation, and formate oxidation[11,12]. Our study provides experimental evidence that ALDH1L1 regulates reduced folate pools as well as glycine metabolism in the liver
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