PKM2: A Key Enzyme in Cancer and Cell Metabolism

Pyruvate Kinase M2, or PKM2, is a protein that functions as an enzyme, a substance that accelerates chemical reactions necessary for life. PKM2 is one of four types, or isoforms, of the pyruvate kinase enzyme. Its presence is most notable in cells that are rapidly multiplying, such as those found during development, in adult stem cells, or in certain disease states. The primary function of PKM2 is to act as a regulator of how cells process and use energy.

PKM2: A Key Player in How Cells Make Energy

The body’s cells rely on a fundamental process called glycolysis to convert sugar, specifically glucose, into energy. This multi-step pathway breaks down glucose molecules to produce a substance called ATP, which is the main energy currency of the cell. PKM2 plays a part in this sequence by catalyzing the very last reaction. In this final step, a molecule named phosphoenolpyruvate (PEP) is converted into pyruvate, which generates a molecule of ATP in the process.

This function places PKM2 at a control point in a cell’s energy production line. The rate at which PKM2 works can influence the overall flow of glucose through the glycolytic pathway. Different tissues in the body have different energy needs, and this is met in part by having different versions, or isoforms, of the pyruvate kinase enzyme.

The Switching Enzyme: How PKM2 Changes its Shape and Job

A distinctive feature of PKM2 is its ability to change its structure, which in turn alters its function. The enzyme can exist in two primary forms: a highly active tetramer and a less active dimer. The tetrameric form consists of four PKM2 protein units bound together, while the dimeric form is composed of just two units. This structural flexibility allows cells to dynamically regulate their metabolic activity.

When PKM2 is in its tetrameric state, it has a high affinity for its substrate, PEP, and efficiently drives the final step of glycolysis. This state maximizes the production of ATP, providing a rapid source of energy for the cell.

Conversely, the dimeric form of PKM2 is less efficient at converting PEP to pyruvate. This slowdown in the final glycolytic step causes a buildup of earlier molecules in the pathway. These accumulated glycolytic intermediates can then be diverted into other biosynthetic pathways that produce components for new cells, such as the building blocks for proteins, lipids, and DNA.

The switch between the tetrameric and dimeric states is controlled by various factors within the cell. The presence of upstream glycolytic metabolites, like fructose-1,6-bisphosphate (FBP), can stabilize its active tetrameric configuration. Other signals, including certain amino acids or modifications to the enzyme itself, can favor the formation of the less active dimer, redirecting metabolic flow toward biosynthesis.

PKM2’s Role in Cancer Cell Metabolism

The ability of PKM2 to switch between its two forms is exploited by cancer cells to support their rapid growth. Many types of cancer cells show elevated levels of PKM2 and predominantly favor the less active, dimeric form of the enzyme. This metabolic adaptation is a phenomenon known as the Warburg effect, or aerobic glycolysis.

The Warburg effect describes how cancer cells consume large amounts of glucose but, unlike healthy cells, process it inefficiently. By maintaining PKM2 in its dimeric state, cancer cells deliberately slow down the final step of glycolysis. This leads to the accumulation of glucose intermediates, which are then rerouted into pathways that produce the raw materials needed for building new cancer cells, such as nucleotides for DNA replication and lipids for cell membranes.

This metabolic reprogramming gives cancer cells a distinct advantage. While it produces less energy per glucose molecule compared to full breakdown, the high rate of glucose uptake compensates for this inefficiency. The dimeric PKM2 acts as a gatekeeper, directing cellular resources away from pure energy production and toward expansion.

More Than an Energy Regulator: PKM2’s Surprising Other Functions

Beyond its role in glycolysis, PKM2 has other functions inside the cell. These non-metabolic, or “moonlighting,” roles demonstrate the protein’s versatility. One of its capabilities is to act as a protein kinase, adding phosphate groups to other proteins to alter their activity or location.

When PKM2 is in its dimeric form, it can travel from the cell’s cytoplasm into the nucleus. Inside the nucleus, it can influence which genes are turned on or off, a process known as gene expression. It achieves this by acting as a transcriptional coactivator, interacting with proteins like HIF-1α and β-catenin to regulate genes involved in cell progression and survival.

These non-glycolytic functions are directly linked to its structural state. The dimeric form enables nuclear entry and protein kinase activity, while the tetrameric form remains in the cytoplasm to perform its metabolic duties. For example, PKM2’s interaction with these factors can help tumor cells adapt to low-oxygen environments or promote genes that drive cell growth.

PKM2 as a Target for New Medical Treatments

The discovery of PKM2’s multifaceted roles, particularly its support of cancer cell growth, has made it an attractive target for the development of new medical therapies. Because many tumors rely on the functions of the dimeric form of PKM2, researchers are actively exploring ways to manipulate the enzyme’s activity with drugs. The goal is to disrupt the metabolic advantages that cancer cells gain from this protein.

One major therapeutic strategy involves developing small-molecule drugs that act as PKM2 activators. These compounds are designed to force PKM2 into its highly active tetrameric state. By locking the enzyme in this form, the drugs aim to restore normal glycolytic activity, thereby preventing the buildup of biosynthetic precursors and starving cancer cells of the building blocks they need.

Another approach focuses on inhibiting the non-metabolic functions of PKM2. This could involve creating drugs that block its ability to enter the nucleus or prevent it from interacting with other proteins that control gene expression. By targeting these specific activities, scientists hope to curb tumor growth and even reverse resistance to existing chemotherapy drugs. These targeted strategies offer a promising avenue for future treatments for cancer and potentially other diseases where cellular metabolism is dysregulated.