Metabolic pathway

A catabolic pathway is a series of reactions that bring about a net release of energy in the form of a high energy phosphate bond formed with the energy carriers adenosine diphosphate (ADP) and guanosine diphosphate (GDP) to produce adenosine triphosphate (ATP) and guanosine triphosphate (GTP), respectively.[4]^: 91–93 The net reaction is, therefore, thermodynamically favorable, for it results in a lower free energy for the final products.[9]^{: 578–579} A catabolic pathway is an exergonic system that produces chemical energy in the form of ATP, GTP, NADH, NADPH, FADH2, etc. from energy containing sources such as carbohydrates, fats, and proteins. The end products are often carbon dioxide, water, and ammonia. Coupled with an endergonic reaction of anabolism, the cell can synthesize new macromolecules using the original precursors of the anabolic pathway.[10] An example of a coupled reaction is the phosphorylation of fructose-6-phosphate to form the intermediate fructose-1,6-bisphosphate by the enzyme phosphofructokinase accompanied by the hydrolysis of ATP in the pathway of glycolysis. The resulting chemical reaction within the metabolic pathway is highly thermodynamically favorable and, as a result, irreversible in the cell.

${\displaystyle {\ce {Fructose-6-Phosphate + ATP -> Fructose-1,6-Bisphosphate + ADP}}}$

A core set of energy-producing catabolic pathways occur within all living organisms in some form. These pathways transfer the energy released by breakdown of nutrients into ATP and other small molecules used for energy (e.g. GTP, NADPH, FADH₂). All cells can perform anaerobic respiration by glycolysis. Additionally, most organisms can perform more efficient aerobic respiration through the citric acid cycle and oxidative phosphorylation. Additionally plants, algae and cyanobacteria are able to use sunlight to anabolically synthesize compounds from non-living matter by photosynthesis.

Gluconeogenesis Mechanism

In contrast to catabolic pathways, anabolic pathways require an energy input to construct macromolecules such as polypeptides, nucleic acids, proteins, polysaccharides, and lipids. The isolated reaction of anabolism is unfavorable in a cell due to a positive Gibbs Free Energy (+ΔG). Thus, an input of chemical energy through a coupling with an exergonic reaction is necessary.[1]^: 25–27 The coupled reaction of the catabolic pathway affects the thermodynamics of the reaction by lowering the overall activation energy of an anabolic pathway and allowing the reaction to take place.[1]^: 25 Otherwise, an endergonic reaction is non-spontaneous.

An anabolic pathway is a biosynthetic pathway, meaning that it combines smaller molecules to form larger and more complex ones.[9]^: 570 An example is the reversed pathway of glycolysis, otherwise known as gluconeogenesis, which occurs in the liver and sometimes in the kidney to maintain proper glucose concentration in the blood and supply the brain and muscle tissues with adequate amount of glucose. Although gluconeogenesis is similar to the reverse pathway of glycolysis, it contains four distinct enzymes(pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, glucose 6-phosphatase) from glycolysis that allow the pathway to occur spontaneously.[11]

Amphibolic Properties of the Citric Acid Cycle

An amphibolic pathway is one that can be either catabolic or anabolic based on the availability of or the need for energy.[9]^: 570 The currency of energy in a biological cell is adenosine triphosphate (ATP), which stores its energy in the phosphoanhydride bonds. The energy is utilized to conduct biosynthesis, facilitate movement, and regulate active transport inside of the cell.[9]^: 571 Examples of amphibolic pathways are the citric acid cycle and the glyoxylate cycle. These sets of chemical reactions contain both energy producing and utilizing pathways.[5]^: 572 To the right is an illustration of the amphibolic properties of the TCA cycle.

The glyoxylate shunt pathway is an alternative to the tricarboxylic acid (TCA) cycle, for it redirects the pathway of TCA to prevent full oxidation of carbon compounds, and to preserve high energy carbon sources as future energy sources. This pathway occurs only in plants and bacteria and transpires in the absence of glucose molecules.[12]

Metabolic pathways can be targeted for clinically therapeutic uses. Within the mitochondrial metabolic network, for instance, there are various pathways that can be targeted by compounds to prevent cancer cell proliferation.[16] One such pathway is oxidative phosphorylation (OXPHOS) within the electron transport chain (ETC). Various inhibitors can downregulate the electrochemical reactions that take place at Complex I, II, III, and IV, thereby preventing the formation of an electrochemical gradient and downregulating the movement of electrons through the ETC. The substrate-level phosphorylation that occurs at ATP synthase can also be directly inhibited, preventing the formation of ATP that is necessary to supply energy for cancer cell proliferation.[17] Some of these inhibitors, such as lonidamine and atovaquone,[16] which inhibit Complex II and Complex III, respectively, are currently undergoing clinical trials for FDA-approval. Other non-FDA-approved inhibitors have still shown experimental success in vitro.

Heme, an important prosthetic group present in Complexes I, II, and IV can also be targeted, since heme biosynthesis and uptake have been correlated with increased cancer progression.[18] Various molecules can inhibit heme via different mechanisms. For instance, succinylacetone has been shown to decrease heme concentrations by inhibiting δ-aminolevulinic acid in murine erythroleukemia cells.[19] The primary structure of heme-sequestering peptides, such as HSP1 and HSP2, can be modified to downregulate heme concentrations and reduce proliferation of non-small lung cancer cells.[20]

The tricarboxylic acid cycle (TCA) and glutaminolysis can also be targeted for cancer treatment, since they are essential for the survival and proliferation of cancer cells. Ivosidenib and Enasidenib, two FDA-approved cancer treatments, can arrest the TCA cycle of cancer cells by inhibiting isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2), respectively.[16] Ivosidenib is specific to acute myeloma leukemia (AML) and cholangiocarcinoma, whereas Enasidenib is specific to just acute myeloma leukemia (AML).

In a clinical trial consisting of 185 adult patients with cholangiocarcinoma and an IDH-1 mutation, there was a statistically significant improvement (p<0.0001; HR: 0.37) in patients randomized to Ivosidenib. Still, some of the adverse side effects in these patients included fatigue, nausea, diarrhea, decreased appetite, ascites, and anemia.[21] In a clinical trial consisting of 199 adult patients with AML and an IDH2 mutation, 23% of patients experienced complete response (CR) or complete response with partial hematologic recovery (CRh) lasting a median of 8.2 months while on Enasidenib. Of the 157 patients who required transfusion at the beginning of the trial, 34% no longer required transfusions during the 56-day time period on Enasidenib. Of the 42% of patients who did not require transfusions at the beginning of the trial, 76% still did not require a transfusion by the end of the trial. Side effects of Enasidenib included nausea, diarrhea, elevated bilirubin and most notably, differentiation syndrome.[22]

Glutaminase (GLS), the enzyme responsible for converting glutamine to glutamate via hydrolytic deamidation during the first reaction of glutaminolysis, can also be targeted. In recent years, many small molecules, such as azaserine, acivicin, and CB-839 have been shown to inhibit glutaminase, thus reducing cancer cell viability and inducing apoptosis in cancer cells.[23] Due to its effective antitumor ability in several cancer types such as ovarian, breast and lung cancers, CB-839 is the only GLS inhibitor currently undergoing clinical studies for FDA-approval.