Fig. 3. Serine biosynthesis and reductive carboxylation are anabolic pathways that support cell proliferation.

(A) The SBP converts glucose-derived 3PG into serine and glycine, which are precursors for lipid and nucleotide biosynthesis. Serine is also involved in folate-mediated one carbon metabolism by acting as a methyl group donor for THF to methylene-THF conversion. Key enzymes in this pathway are PHGDH, PSAT, and SHMT. (B) Reductive carboxylation is an alternate pathway of glutamine metabolism in which glutamine-derived α-KG is converted to citrate through reverse TCA cycle flux. Under conditions of hypoxia or mitochondrial dysfunction (right), isocitrate dehydrogenase (IDH1 in cytosol, IDH2 in mitochondria) uses CO₂ and NADPH to convert α-KG into isocitrate. Citrate produced downstream of this reaction is converted into cytosolic acetyl-CoA without passing through the conventional clockwise steps of the TCA cycle. Acetyl-CoA generated by this pathway can function as a precursor for fatty acid synthesis. α-KGDH, α–KG dehydrogenase.