Page 360 - Read Online

Rizzieri et al. J Cancer Metastasis Treat 2019;5:26 I http://dx.doi.org/10.20517/2394-4722.2019.05 Page 3 of 16

respiration and anaerobic respiration. In aerobic respiration, pyruvate is transported into the mitochondria
through a specific transporter and then decarboxylated by pyruvate dehydrogenase to produce acetyl-CoA
which serves as the initial substrate for the tricarboxylic acid (TCA) cycle (see section 2 below). In anaerobic
respiration, which in eukaryotes is typically limited to cells without mitochondria or poorly vascularized
tissue (either endogenous or induced by states of physiologic stress), pyruvate accepts a hydrogen from
NADH to produce lactate and NAD+. The NAD+ produced can then be used for glycolysis reactions or even
react with TCA intermediates. Energy yield from anaerobic glycolysis is significantly reduced compared
[22]
to its aerobic counterpart, however this process is more rapid and can occur in oxygen deprived tissues .
Notably, some cancerous cells have been shown to preferentially undergo anaerobic respiration even
under optimal conditions for aerobic respiration [24-26] . This effect, which is thought to be due to metabolic
reprograming related to their hyperproliferative state, has been termed the “Warburg effect” after German
physiologist and Nobel laureate Otto Warburg whose initial observations of increased glucose consumption
coupled with increased lactate excretion from cancer cells led to the hypothesis of its existence [27-29] .

Cells have developed several mechanisms to increase or decrease glycolysis in response to metabolic needs.
Furthermore, metabolic control of glycolysis occurs through various feedback mechanisms. Inhibition of
insulin receptor signaling or key enzymes in the pathway (especially PFK) typically occur in fasting states
or high energy states when the ratio of ATP to ADP is high. In these situations metabolism is shifted away
from glycolysis and can instead result in a reciprocal induction of gluconeogenesis (see section 4 below) [22,23] .
Typically, glycolysis follows the general steps as reviewed above. However, there is some redundancy in the
metabolic processes of the cell and some molecules may be synthesized in a different way and still be used
in glycolysis. This can be seen in the way in which cells breakdown disaccharides like sucrose. If energy
is needed, then the sucrose will be converted into fructose-6-phosphate molecules and continue through
[22]
glycolysis .

The TCA cycle
The TCA cycle allows for complete catabolism of organic molecules in the presence of oxygen, and
results in the majority of ATP production in eukaryotes. The reactions of the TCA allow for breakdown
of carbohydrates as well amino acids and fatty acids through various metabolites that can enter the
pathway at different steps. For glucose metabolism the process begins with the production of acetyl Co-A
in the mitochondrial matrix through oxidative decarboxylation of pyruvate in a reaction catalyzed by
the pyruvate dehydrogenase complex (a complex of 3 component enzymes, 2 regulatory enzymes, and 5
coenzymes). Acetyl Co-A and oxaloacetate combine to form citrate in a condensation reaction catalyzed
by citrate synthase. Citrate is then isomerized to isocitrate by aconitase which is subsequently converted
to a-ketoglutarate by oxidative decarboxylation in a reaction catalyzed by isocitrate dehydrogenase. The
a-ketoglutarate dehydrogenase complex catalyzes the conversion of a-ketoglutarate to succinyl Co-A and
producing NADH. Succinyl Co-A is then cleaved to succinate by succinate thiokinase in a reaction that
generates GTP via substrate level phosphorylation. Succinate is subsequently oxidized to fumarate by
succinate dehydrogenase with FAD being reduced to FADH in the process. Fumarate is then hydrated
2
to malate in a reaction catalyzed by fumarase, with malate being oxidized to oxaloacetate by malate
dehydrogenase producing another molecule NADH in the process.

There are many ways that the TCA cycle is regulated. The first regulatory step is known as the bridge
reaction where pyruvate is converted to acetyl-CoA. If the cell has too many high energy molecules, then
this “bridge reaction” will not occur and pyruvate will be utilized in other fashions. Other regulatory steps
include the synthesis of citrate, and the oxidative decarboxylations of isocitrate and a-ketoglutarate all of
which result in the production of high energy molecules (NADH, FADH2, ATP, GTP) which then undergo
oxidative phosphorylation. These steps will be inhibited if the concentration of the high energy molecules
is increased. Similarly, if the concentration of low energy molecules (GDP, ADP, NAD+, FAD) were to
[22]
accumulate then the reactions in the TCA cycle would increase .