New aspects of amino acid metabolism in cancer

Abstract

An abundant supply of amino acids is important for cancers to sustain their proliferative drive. Alongside their direct role as substrates for protein synthesis, they can have roles in energy generation, driving the synthesis of nucleosides and maintenance of cellular redox homoeostasis. As cancer cells exist within a complex and often nutrient-poor microenvironment, they sometimes exist as part of a metabolic community, forming relationships that can be both symbiotic and parasitic. Indeed, this is particularly evident in cancers that are auxotrophic for particular amino acids. This review discusses the stromal/cancer cell relationship, by using examples to illustrate a number of different ways in which cancer cells can rely on and contribute to their microenvironment - both as a stable network and in response to therapy. In addition, it examines situations when amino acid synthesis is driven through metabolic coupling to other reactions, and synthesis is in excess of the cancer cell's proliferative demand. Finally, it highlights the understudied area of non-proteinogenic amino acids in cancer metabolism and their potential role.

Fig. 1

Metabolism of glutamine. The amido group of glutamine is involved in relatively few reactions in addition to deamidation, some major examples are indicated. Transamination, for which only some representative reactions are shown, involves a number of 2-oxoacids that can be reversibly converted into the amino acid. Colours are used in both sets of reactions to indicate the enzyme (left) responsible for the reaction (right). On the left are the reactions that require, or evolve ammonia as part of the metabolism of glutamine to or from α-ketoglutarate. Abbreviations: αKG α-ketoglutarate, ALAT, alanine aminotransferase, ASNS, asparagine synthetase, BCAT, branched-chain aminotransferase, FGAM 5′-phosphoribosyl-N-formylglycinamidine, FGAR 5′-phosphoribosyl-N-formylglycinamide, FGARAT FGAR amidotransferase, GFAT glutamine fructose 6-phosphate amidotransferase, Gln glutamine, GLS glutaminase, Glu glutamate, GPAT glutamine phosphoribosyl pyrophosphate amidotransferase, GOT glutamic-oxaloacetic aminotransferase, GS glutamine synthetase, OAT ornithine aminotransferase, PRA 5′-phosphoribosyl-1-amine, PRPP 5′-phosphoribosyl-1-pyrophosphate, PSAT phosphoserine aminotransferase.

Fig. 2

Interplay between amino acid metabolism and redox homoeostasis. The synthesis and catabolism of amino acids is interwoven into the redox homoeostasis of the cell. The malate–aspartate shuttle, as well as moving NADH between the cytosol and the mitochondrial matrix, also moves the amino acids glutamate and aspartate between the two compartments, and is functionally connected to the TCA cycle. When aspartate is removed from this cycle to synthesise asparagine, arginine or nucleosides, this would disrupt the cycle, requiring additional carbon input. NADH oxidation reactions are shown in green, while NAD⁺ reduction is shown in red, indicative of the connectivity of this network. Amino acids are represented in blue, while proteins (transporters and electron carriers) are in orange. Finally, the subnetworks illustrated are outlined in blue (glycolysis), pink (electron transport chain), mauve (proline-redox shunt), green (TCA cycle) and cream (malate–aspartate shuttle). Abbreviations: αKG α-ketoglutarate, 1,3BPG 1,3-bisphosphoglycerate, 3PG 3-phosphoglycerate, 3PP 3-phosphopyruvate, AcCoA acetyl CoA, Ala alanine, Asn asparagine, Asp aspartate, Cit citrate, G3P glyceraldehyde 3-phosphate, Gln glutamine, Glu glutamate, Gly glycine, Lac lactate, Mal malate, NAD⁺ nicotinamide adenine dinucleotide, NADH reduced NAD⁺, OAA oxaloacetate, P5C pyrroline 5-carboxylate, Pro proline, Pyr pyruvate, Ser serine.