Pyruvate kinase
 Pyruvate kinase with three domains presented in different colors. | |||||||||
| Identifiers | |||||||||
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| EC number | 2.7.1.40 | ||||||||
| CAS number | 9001-59-6 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / EGO | ||||||||
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Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP, yielding one molecule of pyruvate and one molecule of ATP.
Reaction
The pyruvate kinase reaction:
This process also requires a magnesium ion. The enzyme is a 'transferase' under the international classification of enzymes.
This step is the final one in the glycolytic pathway, which produces pyruvate molecules, the final product of aerobic glycolysis. However, in anaerobic glycolysis, lactate dehydrogenase will utilize the NADH produced by glyceraldehyde phosphate dehydrogenase to reduce pyruvate to lactate. In humans, there are two pyruvate kinase isozymes: type M (muscle, SwissProt P14618) and type L,R (liver and erythrocyte, SwissProt P30613). The isozymes differ in primary structure and regulation.
Regulation
This reaction has a large negative free energy change, one of three in glycolysis. All three such steps regulate the overall activity of the pathway, and are, in general, irreversible under wild-type conditions.
Pyruvate kinase activity is regulated by
- Its own substrate PEP and fructose 1,6-bisphosphate, an intermediate in glycolysis, both of which enhance enzymatic activity. Thus, glycolysis is driven to operate faster when more substrate is present.
- ATP is a negative allosteric inhibitor. This accounts for parallel regulation with PFK 1.
- It is not known whether citrate plays a role in negative allosteric inhibition, however it is believed that acetyl-CoA does.
- Alanine, a negative allosteric modulator
This protein may use the morpheein model of allosteric regulation.[1]
Like PFK, pyruvate kinase is regulated both by allosteric effectors and by covalent modification (phosphorylation). Pyruvate kinase is activated by F-1,6-BP in the liver,[2] a second example of feedforward stimulation. ATP and alanine (a biosynthetic product of pyruvate) act as allosteric inhibitors of pyruvate kinase.
Liver pyruvate kinase is also regulated indirectly by epinephrine and glucagon, through protein kinase A. This protein kinase phosphorylates liver pyruvate kinase to deactivate it. Muscle pyruvate kinase is not inhibited by epinephrine activation of protein kinase A. Glucagon signals fasting (no glucose available). Thus, glycolysis is inhibited in the liver but unaffected in muscle when fasting. An increase in blood sugar leads to secretion of insulin, which activates phosphoprotein phosphatase I, leading to dephosphorylation and activation of pyruvate kinase. These controls prevent pyruvate kinase from being active at the same time as the enzymes that catalyze the reverse reaction (pyruvate carboxylase and phosphoenolpyruvate carboxykinase), preventing a futile cycle.
In fact, to say that the forward reaction and reverse reaction are not both active simultaneously may not be entirely accurate. Futile cycles, also known as substrate cycles, are known to fine-tune flux through metabolic pathways.
Deficiency
Genetic defects of this enzyme cause the disease known as pyruvate kinase deficiency. In this condition, a lack of pyruvate kinase slows down the process of glycolysis. This effect is especially devastating in cells that lack mitochondria, because these cells must use anaerobic glycolysis as their sole source of energy because the TCA cycle is not available.
One example is red blood cells, which in a state of pyruvate kinase deficiency rapidly become deficient in ATP and can undergo hemolysis. Therefore, pyruvate kinase deficiency can cause hemolytic anemia.
Role in gluconeogenesis
Pyruvate kinase also serves as a regulatory enzyme for gluconeogenesis, a biochemical pathway in which the liver generates glucose from pyruvate and other substrates. Gluconeogenesis utilizes noncarbohydrate sources to provide glucose to the brain and red blood cells in times of starvation when direct glucose reserves are exhausted.[3] During a fasting state, pyruvate kinase is phosphorylated by pyruvate carboxylase and inactivated, preventing phosphoenolpyruvate from being converted into pyruvate.[3] Instead, phosphoenolpyruvate is converted into glucose via a series of gluconeogenesis reactions. Although it utilizes similar enzymes, gluconeogenesis is not the reverse of glycolysis. It is instead a pathway that circumvents the irreversible steps of glycolysis. Furthermore, gluconeogenesis and glycolysis do not occur concurrently in the cell at any given moment as they are reciprocally regulated by cell signaling.[3] Once the gluconeogenesis pathway is complete, the glucose produced is expelled from the liver, proving energy for the vital tissues in the fasting state.
Alternatives
A reversible enzyme with a similar function, Pyruvate phosphate dikinase (PPDK), is found in some bacteria and has been transferred to a number of anaerobic eukaryote groups (for example, Streblomastix, Giardia, Entamoeba, and Trichomonas), it seems via horizontal gene transfer on two or more occasions. In some cases, the same organism will have both Pyruvate kinase and PPDK.[4]
See also
References
- ↑ T. Selwood and E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function.". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754.
- ↑ Ishwar, Arjun; Tang, Qingling; Fenton, Aron W. (2015). "Distinguishing the Interactions in the Fructose 1,6-Bisphosphate Binding Site of Human Liver Pyruvate Kinase That Contribute to Allostery". Biochemistry 54 (7): 1516–1524. doi:10.1021/bi501426w. ISSN 0006-2960.
- 1 2 3 Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.
- ↑ Liapounova, Na; Hampl, V; Gordon, Pm; Sensen, Cw; Gedamu, L; Dacks, Jb (Dec 2006), "Reconstructing the mosaic glycolytic pathway of the anaerobic eukaryote Monocercomonoides" (Free full text), Eukaryotic Cell 5 (12): 2138–46, doi:10.1128/EC.00258-06, ISSN 1535-9778, PMC 1694820, PMID 17071828
External links
- Pyruvate kinase at the US National Library of Medicine Medical Subject Headings (MeSH)
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