fig2

Figure 2. Metabolic pathways of arginine, glutamine, and methionine. Extracellular arginine binds to GPRC6A to drive intracellular arginine signaling or it is imported through various SLC transporters depending on the cell type. Arginine can also be formed through metabolism of citrulline in the urea cycle. Once inside the cell, arginine is catabolized through NOS to form NO or ARG into urea and ornithine, the latter of which is converted back into citrulline to fuel the urea cycle. Glutamine is similarly imported through a variety of SLCs, with SLC1A5 being the predominant transporter on T cells. Intracellular glutamine is used for amino acid/protein synthesis or transported to the mitochondria and converted to glutamate via GLS. In the mitochondria, glutamate is converted to a-Ketoglutarate to fuel the TCA cycle. In the cytosol, glutamate combines with cysteine to form glutathione to combat oxidative stress. Cysteine is generated in part through metabolism of homocysteine in the methionine cycle, which generates methionine for various cellular processes. Methionine is generated by re-methylation of homocysteine through donation of CH₃ by methyl- THF in the folate cycle. Methionine is then converted to SAM, an indispensable methyl donor, and subsequently SAH following loss of the methyl group. SAM is also involved in the methionine salvage pathway that restores intracellular methionine levels. AHCY: Adenosylhomocysteinase; ARG: arginase; ASL: argininosuccinate lyase; ASS1: argininosuccinate synthase 1; CH₃: a methyl group; GLS: glutaminase; GPRC6A: G protein-coupled receptor family C group 6 member A; MAT2A: methionine adenosyltransferase 2A; MS: methionine synthase; MTA: 5′-methylthioadenosine; MTs: methyltransferases; NO: nitric oxide; NOS: nitric oxide synthase; OCT: ornithine transcarbamoylase; SAH: S-adenosyl-L-homocysteine; SAM: S-adenosylmethionine; SLC: solute carrier; TCA: tricarboxylic acid; THF: tetrahydrofolate.