|Topic:||Pyruvate Kinase .|
The final reaction of aerobic glycolysis is catalyzed by the highly regulated enzyme pyruvate kinase (PK). In this strongly exergonic reaction, the high-energy phosphate of PEP is conserved as ATP. The loss of phosphate by PEP leads to the production of pyruvate in an unstable enol form, which spontaneously tautomerizes to the more stable, keto form of pyruvate. This reaction contributes a large proportion of the free energy of hydrolysis of PEP.
There are two distinct genes encoding pyruvate kinase activity. One PK gene, identified as the PKLR gene, is located on chromosome 1q22 and is composed of 12 exons. The PKLR gene generates two distinct mRNAs, one of which encodes the liver (PKL or L-PK) pyruvate kinase and one that encodes the erythrocyte (PLR or R-PK) pyruvate kinase. These tissue specific PK encoding mRNAs result from the use of alternative promoters. Of the 12 exons in the PKLR gene, exons 3-12 encode identical portions of both the liver and erythrocyte mRNAs. The erythrocyte PK mRNA also includes exon 1, whereas exon 2 is included in the liver PK mRNA. Activation of promoter used in erythroid cells is driven by both basal promoter elements and a strong erythroid specific enhancer. The PKR mRNA encodes the larger of the two PK isoforms which is a 574 amino acid protein. The PKL mRNA contains an alternate 5' exon, relative to the PKR mRNA, and the resultant encoded protein is shorter at 543 amino acids. Deficiencies in expression of the PKLR gene in erythrocytes are the cause of the most common form of inherited non-spherocytic anemia which is also the second most common cause of inherited hemolytic anemia.
The other PK gene (identified as the PKM gene) is located on chromosome 15q23 and is composed of 16 exons that generate eight alternatively spliced mRNAs. The major protein products resulting from this complex alternative splicing of the PKM precursor mRNA are identified as PKM1 (also identified as isoform b) and PKM2 (also identified as isoform a). The designation PKM reflects the fact that the enzyme was originally thought to be muscle specific in its expression. Most tissues express either the PKM1 or the PKM2 isoform. PKM1 is found in numerous normal differentiated tissues, whereas, PKM2 is expressed in most proliferating cells. All cancers that have been examined for PK expression pattern show expression of the PKM2 isoform. The state of methylation of the PKM gene is a major mechanism for the control of expression of the PKM2 isoform. Elevated expression of the PKM2 isoform has been correlated, in numerous cancers, to a hypomethylated state in intron 1 of the PKM gene. The heightened expression of PKM2 allows for a unique pathway of enhanced glucose oxidation to lactate in cancer cells and constitute what is referred to as the Warburg effect
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