Essential Role For Mevalonate Synthesis In DNA Replication(1)

This groundbreaking 1979 study investigated the connection between cholesterol production and cell division by examining a key enzyme called HMG CoA reductase, which produces a molecule called mevalonate as part of the cholesterol-making process. Scientists had noticed that rapidly growing tissues always have high levels of this enzyme, while slow-growing tissues have very low levels, suggesting an important link between cholesterol synthesis and cell growth.

The researchers used synchronized cell cultures to track exactly when DNA replication occurs during the cell cycle. They found that spikes in HMG CoA reductase activity consistently occurred right before or during the S-phase, when cells copy their DNA in preparation for division. When they blocked this enzyme with a drug called compactin, DNA synthesis completely stopped. Most surprisingly, when they added back mevalonate (the direct product of the enzyme), DNA synthesis immediately resumed within minutes. However, adding cholesterol itself had no effect.

This discovery revealed that mevalonate serves a critical function in DNA replication that's completely separate from its role in making cholesterol. The finding helps explain why rapidly dividing cells - whether they're healthy growing tissues, regenerating organs, or cancer cells - consistently show high cholesterol synthesis activity. It's not necessarily because they need more cholesterol for their membranes, but because they need mevalonate for the fundamental process of copying their genetic material.

In clinical practice, this research laid important groundwork for understanding how statin medications (which block the same HMG CoA reductase enzyme) might affect cell division and tissue repair. It also provides insight into why maintaining healthy cholesterol synthesis pathways may be important for tissue regeneration and overall metabolic function as we age.