*4.2.1 Glycolysis*

Once glucose enters the cells through glucose transporters (GLUT), it is rapidly catabolized to pyruvate in a sequential enzymatic process generating a variety of macromolecules needed for different biosynthetic pathways (PPP, *de novo* FAS and amino acid (AA) Hypoxia synthesis pathways) as well as for maintaining cellular redox equilibrium (nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrogen, NAD+/NADH), thereby supporting anabolic growth. Pyruvate either gets reduced to lactate (*via* lactate dehydrogenase, LDH) by engaging in cytosolic aerobic glycolysis (Warburg effect) in the presence of oxygen, generating 4 molecules of adenosine triphosphate (ATP)/unit of glucose or can enter the mitochondrial matrix (through citrate-pyruvate shuttle system) where it gets oxidized and decarboxylated to acetyl- coenzyme A (CoA) (*via* pyruvate dehydrogenase, PDH) to enter into Kreb's cycle and undergo mitochondrial OXPHOS generating NADH/ reduced flavin adenine dinucleotide (FADH2) and a total of 36 molecules of ATP/unit of glucose. Though ATP generation via glycolysis is far less as compared to OXPHOS, activated and effector immune cells rely on glycolysis because of its 100 times faster rate of ATP production, its proficiency to generate a range of biosynthetic intermediates needed for cell growth, as well as its ability to provide both these facilities in oxygen-poor conditions [43]. The mitochondrial enzyme PDH, a key bifurcation enzyme in the choice between glycolytic and mitochondrial oxidative metabolism, in its active dephosphorylated form catalyzes the movement of pyruvate from the cytoplasm to mitochondria for Kreb's cycle. Because of its crucial bifurcating function, PDH is under tight regulation of PDH kinases (PDHKs) that inactivate PDH via phosphorylation, and PDH phosphatases (PDHPs) that dephosphorylate and activate phosphorylated-PDH.
