Role of cholesterogenesis and isoprenoid synthesis in DNA replication and cell growth.

In summary, there is now ample evidence that cell growth, as well as DNA replication, is closely linked to cholesterogenesis in a manner that has only recently been appreciated. Mevalonic acid, the product of HMG-CoA reductase, the rate-limiting enzyme of cholesterogenesis, is now known to serve at least two functions in the cell cycle. First, mevalonate acts as a precursor of the cholesterol that is needed for cell membrane synthesis, and second, independent of cholesterogenesis, mevalonate has been shown to serve a rapid and essential initiator function in DNA replication. These findings, coupled with the fact that loss of the cholesterol feedback control of mevalonic acid represents the most consistent biochemical defect so far identified in the malignant and premalignant states, suggests the possibility that uncontrolled synthesis of mevalonate may play a role in deranged DNA synthesis and malignant transformation.