Human pyruvate kinase, muscle, S437Y variant
Allali-Hassani, A., Hong, B., Dimov, S., Tempel, W., MacKenzie, F., Schapira, M., Arrowsmith, C.H., Edwards, A.M., Bountra, c., Weigelt, J., Bochkarev, A., Park, H., Vedadi, M.
(deposited on 30.Jan.09)
Datapack version: 1 (built on 25.Nov.09; last revised in 25.Nov.09)
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 subunits 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
less active dimer
. The balance between these two forms can be shifted and
tetramer formation. One of reported PKM2 SNPs,
, is located in the FBP-binding pocket, thereby resulting in poor interaction with the allosteric activator. We have determined the crystal structure of PKM2-S437Y variant. This structure will provide the basis for understanding the mechanism of PKM2 activity by FBP-induced allosteric regulation and addressing the underlying principles of PK-related human diseases by mutations.
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Jill D. Dombrauckas, Bernard D. Dantarsiero, and Andrew D. Mesecar. 2005. Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry. 44, 9417-9429.
Heather R. Christofk, Matthew G. Vander Heiden, Ning Wu, John M. Asara, and Lewis C. Cantley. 2008. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 452, 181-186
Sybille Mazurek, C. Bruce Boschek, Ferdinand Hugo, and Erich Eigenbrodt. 2005. Pyruvate kinase type M2 and its role in tumor growth and spreading. Seminars in Cancer Biology. 15, 300-308.
Sybile Mazurek. 2008. Pyruvate kinase type M2: A key regulator within the tumor metabolome and a tool for metabolic profiling of tumours. Ernst Schering Foundation Symposium Proceedings. 4, 99-124
Ashizawa K, Willingham MC, Liang CM, Cheng SY. 1991. In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediate via fructose 1,6-bisphosphate. Journal of Biological Chemistry. 266, 16842-16846.
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