Phosphoglycerate kinase (PGK) is an enzyme found in all living organisms. As a transferase, it facilitates the movement of a phosphate group from one molecule to another. PGK is important for cellular energy generation and various other functions.
Phosphoglycerate Kinase in Energy Production
Phosphoglycerate kinase plays a primary role in glycolysis, a metabolic pathway where glucose is broken down to produce energy. This process occurs in the cytoplasm and involves ten enzymatic reactions. PGK participates in the seventh step, in the energy pay-off phase.
During this step, PGK catalyzes the transfer of a phosphate group from 1,3-bisphosphoglycerate (1,3-BPG) to adenosine diphosphate (ADP). This reaction yields 3-phosphoglycerate (3-PG) and adenosine triphosphate (ATP). This ATP production is known as substrate-level phosphorylation, a direct way cells generate energy without oxygen. The enzyme requires magnesium ions (Mg²⁺) as a cofactor for substrate binding and stabilization. The reaction is highly exergonic, releasing significant energy that helps drive preceding glycolysis steps. While its main function is in glycolysis, PGK can also catalyze the reverse reaction, converting 3-phosphoglycerate and ATP back to 1,3-bisphosphoglycerate and ADP, a process in gluconeogenesis (glucose synthesis).
Beyond Energy: Diverse Roles of Phosphoglycerate Kinase
Beyond its role in energy production, phosphoglycerate kinase (PGK) performs other “moonlighting” activities. One role involves DNA replication and repair, observed within the nuclei of mammalian cells.
PGK’s involvement extends to viral replication, where certain viruses, like the tomato bushy stunt virus (TBSV), co-opt it. PGK helps provide a local ATP supply within the viral replication compartment, fueling molecular chaperones for assembling new viral components. PGK can also act as a chaperone protein, interacting with proteins like heat shock protein 90 (Hsp90) to regulate their activity.
When Phosphoglycerate Kinase Malfunctions
When phosphoglycerate kinase malfunctions due to genetic mutations in the PGK1 gene, it leads to a rare inherited disorder known as PGK deficiency. This condition impairs the body’s ability to break down glucose for energy, as the enzyme’s activity is reduced. About 30 affected families have been reported, indicating its rarity.
PGK deficiency can manifest with a range of symptoms, commonly affecting red blood cells and the nervous system. Individuals may experience chronic hemolytic anemia, where red blood cells are prematurely destroyed, leading to symptoms such as:
- Pale skin
- Yellowing of the eyes and skin (jaundice)
- Fatigue
- Shortness of breath
- Rapid heart rate
Neurological problems can also occur, including:
- Intellectual disability
- Seizures
- Hemiplegic migraines
- Ataxia
- Tremors
Muscle-related issues (myopathy) are also seen, characterized by:
- Exercise intolerance
- Muscle weakness
- Cramping
- Muscle pain
PGK deficiency is an X-linked recessive disorder, meaning the PGK1 gene is on the X chromosome, and it primarily affects males.
Targeting Phosphoglycerate Kinase in Medicine
Current research explores phosphoglycerate kinase (PGK) as a target for medical interventions, particularly in cancer and parasitic infections. PGK1 overexpression has been linked to various cancers, including gastric, breast, ovarian, and brain cancers like glioblastoma. It is associated with tumor growth, migration, and chemotherapy resistance. Scientists are investigating ways to inhibit PGK activity in cancer cells to disrupt their energy metabolism and potentially limit tumor progression.
PGK also presents a target in parasitic diseases, such as malaria, caused by Plasmodium falciparum. The parasite relies on glycolysis for energy, making its PGK enzyme a potential weakness. Developing drugs that specifically inhibit the parasite’s PGK, without significantly affecting human PGK, could offer new therapeutic strategies against these infections.