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. Author manuscript; available in PMC: 2020 Apr 1.
Published in final edited form as: Mol Cancer Ther. 2019 Jul 9;18(10):1787–1799. doi: 10.1158/1535-7163.MCT-19-0037

Figure 1. C1 metabolism is compartmentalized in the cytosol and mitochondria.

Figure 1.

Folates enter the cell through the plasma membrane facilitated folate transporters, PCFT and RFC, and enter the mitochondria via SLC25A32. Serine catabolism in the mitochondria beginning with SHMT2 generates glycine and formate, the latter of which is required for downstream cytosolic de novo purine biosynthesis (by GARFTase and AICARFTase) as 10-formyl-THF, and thymidylate biosynthesis, following conversion to 5,10-me-THF by MTHFD1. SHMT1 catalyzes conversion of glycine to serine in the cytosol. AICA is metabolized to AICAR (ZMP), the AICARFTase substrate which circumvents the GARFTase step. The arrows denote the net flux of C1 metabolism in proliferating cells, although most reactions are reversible. Both SHMT1 and TS are also localized to the nucleus; however, nuclear SHMT1 is not an important source of C1 units for TS (6,10) .