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Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60 Page 621

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 CH by methyl- THF in the folate cycle.
3
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; CH : a methyl group; GLS: glutaminase; GPRC6A: G protein-
3
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.
cellular processes, it is also a precursor for the synthesis of polyamines, which are organic compounds that
facilitate cell proliferation and are upregulated in a variety of cancers [126-128] . Similarly, nitric oxide synthase
(NOS) metabolizes arginine to nitric oxide (NO), which promotes angiogenesis and metastasis, and
dampens the immune response .
[129]

In malignant cells, arginine helps sustain tumor-promoting functions, and arginine starvation results in
detrimental effects, such as ROS formation, mitochondrial dysfunction, and cell death [130-135] . Despite this,
metabolic rewiring of the urea cycle in tumor cells results in increased ornithine and proline synthesis and
[131]
decreased arginine synthesis . Moreover, many cancer types have decreased expression of arginosuccinate
synthase 1 (ASS1), which catalyzes the penultimate step in arginine synthesis . As such, arginine is
[130]
considered an essential amino acid in malignant cells, and they must rely on exogenous uptake to sustain
their metabolic demands [130-132] . On the other hand, T cells are completely reliant on exogenous arginine