PK is activated by fructose 1,6-bisphosphate, which is the product of the PFK-1 reaction. This unique form of regulation, called feedforward regulation, connects the two kinase activities. When PFK-1 activity increases, it leads to higher levels of fructose 1,6-bisphosphate, which in turn activates PK. It is important to note that ATP inhibits PK.

In the liver, covalent regulation occurs through phosphorylation by cAMP-dependent PKA, resulting in the inactivation of the hepatic isozyme of PK. This process is triggered by elevated glucagon levels when blood glucose levels are low. Glucagon increases the intracellular concentration of cAMP, leading to the phosphorylation and inactivation of PK specifically in the liver. Consequently, PEP cannot proceed in glycolysis and instead enters the gluconeogenesis pathway. This mechanism partially explains why hepatic glycolysis is inhibited and gluconeogenesis is stimulated by glucagon. The dephosphorylation of PK by a phosphatase enzyme reactivates the enzyme.

Pyruvate kinase deficiency affects red blood cells (RBC). As RBC lack mitochondria, they rely solely on glycolysis for ATP production. ATP is crucial for meeting the metabolic needs of RBC and fueling the ion pumps necessary for maintaining their flexible, biconcave shape, which allows them to pass through narrow capillaries. In glycolytic enzyme deficiencies, the reduced rate of glycolysis leads to decreased ATP production through substrate-level phosphorylation. Consequently, the RBC membrane undergoes alterations, resulting in changes in cell shape and eventual phagocytosis by cells of the mononuclear phagocyte system, particularly splenic macrophages. The premature death and breakdown of RBC cause mild-to-severe nonspherocytic hemolytic anemia, with severe cases requiring regular transfusions. PK deficiency is the most common glycolytic enzyme deficiency, and the severity depends on the degree of enzyme deficiency (typically 5%–35% of normal levels) and the compensatory synthesis of increased levels of 2,3-BPG. Individuals with PK deficiency usually possess a mutant enzyme with altered kinetics or decreased stability. Interestingly, individuals heterozygous for PK deficiency exhibit resistance to the most severe forms of malaria.

The tissue-specific expression of PK in RBC and the liver is a result of the gene encoding the enzyme utilizing different start sites during transcription.

Pyruvate is converted to lactate by LDH, marking the final product of anaerobic glycolysis in eukaryotic cells. This reduction to lactate is the primary fate of pyruvate in poorly vascularized tissues (such as the lens and cornea of the eye and the kidney medulla) and in RBC lacking mitochondria.
Feedforward regulation: PK is activated by fructose 1,6-bisphosphate, the product of the PFK-1 reaction. This feedforward (instead of the more usual feedback) regulation has the effect of linking the two kinase activities: increased PFK-1 activity results in elevated levels of fructose 1,6-bisphosphate, which activates PK. [Note: PK is inhibited by ATP.] 2.
Covalent regulation in the liver: Phosphorylation by cAMP-dependent PKA leads to inactivation of the hepatic isozyme of PK (Fig. 8.19). When blood glucose levels are low, elevated glucagon increases the intracellular level of cAMP, which causes the phosphorylation and inactivation of PK in the liver only. Therefore, PEP is unable to continue in glycolysis and, instead, enters the gluconeogenesis pathway. This partly explains the observed inhibition of hepatic glycolysis and stimulation of gluconeogenesis by glucagon. Dephosphorylation of PK by a phosphatase results in reactivation of the enzyme.
diphosphate.
3. Pyruvate kinase deficiency: Because mature RBC lack mitochondria, they are completely dependent on glycolysis for ATP production. ATP is required to meet the metabolic needs of RBC and to fuel the ion pumps necessary for the maintenance of the flexible, biconcave shape that allows them to squeeze through narrow capillaries. The anemia observed in glycolytic enzyme deficiencies is a consequence of the reduced rate of glycolysis, leading to decreased ATP production by substrate-level phosphorylation. The resulting alterations in the RBC membrane lead to changes in cell shape and, ultimately, to phagocytosis by cells of the mononuclear phagocyte system, particularly splenic macrophages. The premature death and lysis of RBC result in mild-to-severe nonspherocytic hemolytic anemia, with the severe form requiring regular transfusions. Among patients with rare genetic defects of glycolytic enzymes, the majority has a deficiency in PK. [Note: Liver PK is encoded by the same gene as the RBC isozyme. However, liver cells show no effect because they can synthesize more PK and can also generate ATP by oxidative phosphorylation.] Severity depends both on the degree of enzyme deficiency (generally 5%–35% of normal levels) and on the extent to which RBC compensate by synthesizing increased levels of 2,3-BPG (see p. 31). Almost all individuals with PK deficiency have a mutant enzyme that shows altered kinetics or decreased stability (Fig. 8.20). Individuals heterozygous for PK deficiency have resistance to the most severe forms of malaria.
The tissue-specific expression of PK in RBC and the liver results from the use of different start sites in transcription (see p. 473) of the gene that encodes the enzyme.
K. Pyruvate reduction to lactate
Lactate, formed from pyruvate by LDH, is the final product of anaerobic glycolysis in eukaryotic cells (Fig. 8.21). Reduction to lactate is the major fate for pyruvate in tissues that are poorly vascularized (for example, the lens and cornea of the eye and the kidney medulla) or in RBC that lack mitochondria.
1.