Structural Biochemistry/Carbon-Phosphorus Bond

Natural products with carbon-phosphorus bond

Phosphonic and phosphinic acid are similar to phosphate ester and anhydrides with instead of carbon oxygen bond have the C-P-C bond. They are stable and can withstand harsh chemical treatments.

The first naturally produced phosphonate compound was 2-aminoethylphosphonate (AEP). AEP was found in phosphonolipids. Phosphonolipids are present in many protozoa, plants, bacteria and even humans. It was found they are formed through ingestion and not made by the body. These phosphonolipids have a fatty acid chain and different phosphonate headgroups. Studies have shown that phosphonates can affect metabolism although the effects and causes are not well understood. The synthesis of AEP from phosphonoenolpyruvate (PEP) is the shortest known pathway to produce natural phosphonates. This pathway requires only three enzymes: PEP mutase, phosphonopyruvate decarboxylase, and AEP transaminase

Fosfomycin aka: (1R,2S)-Epoxypropylphosphonic acid It is used for the treatment of acute cystitis (urinary tract infections) and gastrointestinal infections. It has activity against methicillin- vancomycin-resistant organisms. Fosfomycin works by inhibiting the activation of necessary enzyme, UDP-N-acetylglucosamine- 3-O-enolpyruvyltransferase (MurA) is needed for catalyzing the first step of cell wall synthesis. This is done by alkylation of the active site cysteine.

Major Points

• Phosphonates and phosphinates have similar function to phosphate esters or anhydrides or carboxylate groups in enzyme substrates.

• Reactions involved in the biosynthesis of fosfomycin, phosphinothricin, and FR900098 is highly studied in this field

• Phosphoenolpyruvate (PEP) mutase catalyzes the C-P bond-forming step in all naturally occurring phosphonates. Therefore, degenerate primers for PEPM can be used for the discovery of new phosphonate encoding gene clusters and hence new natural products.

• Given the current commercial use of phosphonates and phosphinates in medicine and agriculture, discovery of new naturally occurring compounds beyond the twenty or so currently known structures may provide an important untapped source of new products for human use.

Reference

Metcalf, William W., and Wilfred A. Van Der Donk. "Biosynthesis of Phosphonic and Phosphinic Acid Natural Products." Annual Review of Biochemistry 78.1 (2009): 65-94.