Pyruvate kinase (PK, EC 126.96.36.199) catalyzes the last step of glycolysis, where the phosphoryl group of phosphoenolpyruvate (PEP) is transferred to ADP to form pyruvate and ATP, and thus participates in the primary intersections of the energy methabolism. Lately, the enzyme was linked to other diseases related to both glucose and oxygen utilization, such as diabetes, blood and brain phenylketonuria, and angiogenesis. Different isoenzymes of pyruvate kinase are expressed depending upon the metabolic responsibilities of the various cells and tissues. Pyruvate kinase type L (PK-L) is the characteristic pyruvate kinase isoenzyme of tissues with gluconeogenesis such as liver and kidney. Erythrocytes express the pyruvate kinase isoenzyme type R (PK-R). Pyruvate kinase type M1 (PKM1) is present in tissues in which large amount of energy have to be rapidly provided such as in muscle and brain. Pyruvate kinase type M2 (PKM2) is characteristic of lung tissues as well as all cells with high rates of nucleic acid synthesis, including all proliferating cells such as embryonic cells and especially tumor cells. During tumor formation, a shift in the isoenzyme composition of pyruvate kinase always takes places in such a manner that the tissue specific isoenzyme, such as PKM1 in brain or PK-L in the liver, disappears and PKM2 is expressed.
Of these isoforms, M2, L and R isozymes are regarded as allosterically regulated via feed-forward activation by fructose-1,6-bisphosphate (FBP), the product of the phosphofructokinase reaction. The architecture of PK is evolutionally highly conserved and is organized as a homotetramer with four distinct domains in each subunit. The activity of the enzyme is a combination of domain and subunit rotations coupled to active site geometry. Residues, located in the domain interfaces, play a crucial role in function and communication between the subunits of the PK.
There are two major forms of PKM2 in cells, a highly active tetramer and a less active dimer. The balance between these two forms can be shifted and FBP induces tetramer formation. The structures of PKM2 in the presence of various activators and inhibitors are needed to understand the nature of allosteric modulation of the subunits. These structures will provide the basis for understanding the mechanism of PKM2 activity and addressing the underlying principles of PK-related human diseases.