PKM2 - Human Pyruvate Kinase, Muscle
Choe, J., Atanassova, A., Schapira, M., Arrowsmith, C., Edwards, A., Sundstrom, M., Bochkarev, A., Park, H.
Datapack version: 1 (built on 10.Mar.08)
Pyruvate kinase (PK, EC 220.127.116.11) has been extensively studied since the mid 1960s, as the enzyme's deficiency in human erythrocytes is the most common cause of hemolytic anemia. More than 150 mutations in the gene coding PK in erythrocytes, designated as RPK, have been identified so far. The enzyme 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.
Cations, such as H+, K+, Mg2+ and/or Mn2+, modulate the activity of PKs. Mono- or biphosphorylated sugars as well as PEP activate the enzyme and alter its properties. Phenylalanine is known as a physiological inhibitor of the enzyme. Indeed, we obtained well diffracting crystals when PKM2 was crystallized in presence of phenylalanine, Mg2+ and ADP. However, these ligands and Mg2+ were not located in the structure of PKM2, suggesting that they acted as additives for the crystallization of PMK2. 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.
The architecture of PK is evolutionally highly conserved and is organized as a
four distinct domains
. Residues, located in the domain interfaces, play a crucial role in function and communication between the subunits of the PK. The activity of the enzyme is a combination of domain and subunits rotations coupled to active site geometry.
Superimposition with a different PKM2 crystal structure,
, elucidates the locations of the catalytic site as well as the binding site of the allosteric activator,
contains the Mg2+ and K+ cofactors, as well as the inhibitor, oxalate. Phenylalanine inhibits PKM2 by binding to an allosteric site different from the FBP binding site. In this allosteric site, there is competitive binding between alanine and phenylalanine. However, alanine does not trigger the same allosteric response as phenylalanine.
Superimposition with another PKM2 crystal structure,
, reveals the location of this
Much progress has been made in the understanding of the structure and property for RPK, which is expressed in erythrocytes and liver. Less is known about the two other iso-forms, PKM1 and PKM2, which are expressed in muscle, kidney and lung, and are the products of alternative splicing of the same mRNA.
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Dombrauckas, J.D., Santarsiero, B.D., Mesecar, A.D. (2005). Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry, 44(27), 9417-9429.
Williams, R., Holyoak, T., McDonald, G., Gui, C., Fenton, A.W. (2006). Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase. Biochemistry, 45(17), 5421-5429.
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