Geranylgeranyl pyrophosphate

Geranylgeranyl pyrophosphate (GGPP) is a key isoprenoid intermediate in the biosynthesis of many important biological molecules, including carotenoids, quinones, sterols, and terpenes. It is a 20-carbon molecule that serves as a building block for the synthesis of larger isoprenoid compounds through the process of prenylation, which is critical for the proper localization and function of various proteins within the cell.

Biosynthesis

Geranylgeranyl pyrophosphate is synthesized from isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) through a series of enzymatic reactions. Initially, IPP and DMAPP undergo a head-to-tail condensation catalyzed by the enzyme geranyl pyrophosphate synthase to form geranyl pyrophosphate (GPP). Subsequently, GPP is further condensed with another molecule of IPP by farnesyl pyrophosphate synthase to produce farnesyl pyrophosphate (FPP). Finally, FPP is converted into GGPP by the enzyme geranylgeranyl pyrophosphate synthase.

Function

Geranylgeranyl pyrophosphate plays a crucial role in the post-translational modification of proteins, a process known as prenylation. During prenylation, GGPP is attached to the cysteine residues of specific proteins, which facilitates their attachment to cell membranes and influences their function and interaction with other cellular components. This modification is essential for the activity of a variety of proteins, including members of the Ras superfamily of GTPases, which are involved in signal transduction pathways that regulate cell growth, differentiation, and survival.

GGPP is also a precursor in the biosynthesis of various biologically significant compounds. For example, it is involved in the production of dolichols, which are essential for the glycosylation of proteins and lipids, and ubiquinones (coenzyme Q), which are crucial for mitochondrial electron transport and ATP synthesis. Additionally, GGPP is a precursor for the synthesis of vitamin K and certain diterpenes, which have various biological activities.

Clinical Significance

Alterations in the biosynthesis or utilization of GGPP can have significant clinical implications. For instance, inhibitors of the enzymes involved in the synthesis of GGPP, such as statins (which inhibit HMG-CoA reductase) and bisphosphonates (which inhibit farnesyl pyrophosphate synthase), are used in the treatment of hypercholesterolemia and osteoporosis, respectively. These inhibitors can affect the levels of GGPP in cells, potentially impacting the prenylation and function of proteins.

Furthermore, aberrant prenylation of proteins due to mutations in the enzymes responsible for attaching GGPP to target proteins has been implicated in various diseases, including certain forms of cancer and developmental disorders. Research into the role of GGPP in disease pathogenesis and the development of therapeutic agents targeting GGPP biosynthesis or utilization is ongoing.

See Also

• Isoprenoid
• Prenylation
• Farnesyl pyrophosphate
• Terpenes