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Page 130 Nguyen et al. Cancer Drug Resist 2018;1:126-38 I http://dx.doi.org/10.20517/cdr.2018.08

between isocitrate and α-ketoglutarate, the inverse reaction, so called the reductive carboxylation, could
occur to maintain TCA cycle intermediates under mitochondria defects. Emerging evidence reported the
role of glutamine mediating reductive carboxylation for lipid biosynthesis and also for redox homeostasis
in cancer with dysfunctional mitochondria or under hypoxia [34,41-43] .

Nitrogen donor
Glutamine has two atoms of reduced nitrogen, called α-nitrogen and γ-nitrogen. At the level of nucleo-
tide synthesis, glutamine is the nitrogen donor for enzymes in the purine synthesis, including glutamine
phosphoribosylpyrophosphate amidotransferase, phosphoribosyl formylglycinamidine synthetase, and
guanosine monophosphate synthetase. But glutamine also acts as nitrogen donor, being metabolized by
enzymes involved in the synthesis of pyrimidine, including CAD and CTP synthetase. Thus, one gluta-
mine molecule is used in the production of uracil and thymine, two for cytosine and adenine, and three
for a guanine base. Besides that, purine and pyrimidine synthesis use also glutamine-derived aspartate,
[44]
whose supplementation can rescue cell cycle arrest caused by glutamine deprivation . Interestingly, only
the γ-nitrogen of glutamine is used for nucleotide synthesis. This nitrogen is also required for the synthesis
of NAD, glucosamine-6-phosphate (a precursor for protein glycosylation), and asparagine, a non-essential
[45]
amino acid that compensates for glutamine deprivation .
The α-nitrogen of glutamine is used to produce other non-essential amino acids or polyamines via trans-
[47]
[46]
amination. This reaction is catalysed by a family of aminotransferases to produce alanine , aspartate ,
[50]
[49]
[48]
serine , proline and ornithine . Glutamine is the source of at least 50% of non-essential amino acids
used in protein synthesis by cancer cells . It is estimated that glutamine represents on average up to 4.7%
[51]
of all amino acid residues in human proteome, but obviously the percentage can differ from protein to
[52]
protein . Hence, glutamine is a key structural building block in the biosynthesis of proteins, nucleotides,
non-essential amino acids and polyamines to support biomass accumulation and rapid rates of prolifera-
tion.
Redox homeostasis control
During tumorigenesis, cancer cells encounter oxidative stress continuously. In order to maintain oxidative
homeostasis, the cells need to increase their antioxidant capacity. Glutamine metabolism plays a major role
in the cellular anti-oxidative mechanisms. Glutamine-derived glutamate is used in the synthesis of gluta-
thione, through the condensation with cysteine and glycine by glutamate-cysteine ligase and glutathione
synthetase. Tracer experiments with labelled 13C-glutamine showed an enrichment of 13C carbons in glu-
tathione. Accordingly, glutamine starvation reduces the glutathione pool of transformed cells [33,53] . More-
over, as cystine is an extracellular source of cysteine, cystine uptake is facilitated by the efflux of glutamate
via the xCT antiporter. Once inside the cell, cystine is converted to cysteine, which is then incorporated
into glutathione. Indeed, pharmacological inhibition of xCT increases reactive oxygen species (ROS) level
and suppresses tumor growth [54,55] . However, different investigations showed that xCT overexpression en-
hances cell dependency to glutamine or glucose [56-58] . Those studies identified a new function of xCT anti-
porter as a regulator of nutrient flexibility by antagonizing glutamine metabolism. Lastly, glutamine oxida-
tion supports redox homeostasis by supplying carbon to malic enzymes, which produce NADPH. Indeed,
in proliferating cells, NADPH is used not only for the lipid synthesis, but also for the reduction of oxidized
[59]
glutathione (GSSG), protecting the cells from oxidative stress .

Chromatin organization
Glutamine metabolism does not only generate building blocks and energy for cell growth, but also pro-
duces co-substrates for cellular regulatory cascades, including those that regulate chromatin organization.
Actually, glutamine-derived α-ketoglutarate is a co-substrate of dioxygenase enzymes, including the TET
family and the jumonji (JMJ) family. Enzymes from the TET and JMJ family catalyse histone and DNA de-