The redox requirements of proliferating mammalian cells

Abstract

Cell growth and division require nutrients, and proliferating cells use a variety of sources to acquire the amino acids, lipids, and nucleotides that support macromolecule synthesis. Lipids are more reduced than other nutrients, whereas nucleotides and amino acids are typically more oxidized. Cells must therefore generate reducing and oxidizing (redox) equivalents to convert consumed nutrients into biosynthetic precursors. To that end, redox cofactor metabolism plays a central role in meeting cellular redox requirements. In this Minireview, we highlight the biosynthetic pathways that involve redox reactions and discuss their integration with metabolism in proliferating mammalian cells.

Keywords: cell metabolism; cell proliferation; metabolism; mitochondrial metabolism; oxidation-reduction (redox).

Figure 1.

Oxidation and reduction reactions and their relationship to biosynthesis. A, NADPH is used to reduce oxidized precursors, and NADPH can be regenerated from NADP⁺ by the oxidative pentose pathway, malic enzymes, and other reactions. B, NAD⁺ is used to oxidize reduced precursors in glycolysis, the TCA cycle, and biosynthetic pathways. NAD⁺ is regenerated from NADH by lactate dehydrogenase and by the electron transport chain, which reduce pyruvate and oxygen, respectively. C, transamination reactions involve a change in redox state for the substrates and products. Oxidation of glutamate to α-ketoglutarate reduces NAD⁺ to NADH or transaminates an α-keto acid to an amino acid. For all panels, the half-reactions in red are reduction reactions, and those in blue are oxidations. Abbreviations used are: αKG, α-ketoglutarate; pentose-P, pentose phosphate.

Figure 2.

Redox reactions used to synthesize nonessential amino acids from glucose and glutamine. Simplified pathways illustrating the interconversion of glycolytic and TCA cycle intermediates are shown, with redox reactions highlighted. Many of these reactions are oxidations and consume NAD⁺ (or FAD), although others are reductions and require NAD(P)H. As shown in Fig. 1, transamination reactions are also oxidation/reduction reactions. Major pathways involved in regenerating NAD⁺ and FAD are also shown for reference. Substrate oxidation is indicated in blue; substrate reduction is in pink; and transamination is in green. Abbreviations used are: αKG, α-ketoglutarate; OAA, oxaloacetate.

Figure 3.

Redox reactions involved in fatty acid synthesis. A, acetyl-CoA can be synthesized from glucose, glutamine, or free acetate, and each pathway relies on different redox cofactors. B, fatty acid synthesis and elongation use two molecules of NADPH per molecule of acetyl-CoA. In this figure, two carbon atoms from acetyl-CoA are added to a fatty acyl-CoA containing n carbon atoms. Substrate oxidation is indicated in blue; substrate reduction is in pink; and transamination is in green. Abbreviations used are: αKG, α-ketoglutarate; OAA, oxaloacetate.

Figure 4.

Oxidation reactions are important for nucleotide synthesis. A, simplified schematic of de novo nucleotide biosynthesis highlighting the redox reactions involved. Ribose is produced via the pentose phosphate pathway, and synthesis of purine and pyrimidine nucleotides involve oxidation reactions. Both purine and pyrimidine synthesis use aspartate, which is generated from the oxidation of either glucose or glutamine (see Fig. 2). The use of oxygen to regenerate ubiquinone (Q) is also shown. B, formyl-THF, required for purine synthesis, is produced following the oxidation of one-carbon units derived from serine. Substrate oxidation is indicated in blue; substrate reduction is in pink; and products of oxidation reactions are in orange. Abbreviations used are: PRPP, phosphoribosyl pyrophosphate; Q, ubiquinone; QH₂, ubiquinol; ribose-5-P, ribose-5-phosphate; THF, tetrahydrofolate.