Biosynthesis of phosphonic and phosphinic acid natural products

Abstract

Natural products containing carbon-phosphorus bonds (phosphonic and phosphinic acids) have found widespread use in medicine and agriculture. Recent years have seen a renewed interest in the biochemistry and biology of these compounds with the cloning of the biosynthetic gene clusters for several family members. This review discusses the commonalities and differences in the molecular logic that lie behind the biosynthesis of these compounds. The current knowledge regarding the metabolic pathways and enzymes involved in the production of a number of natural products, including the approved antibiotic fosfomycin, the widely used herbicide phosphinothricin (PT), and the clinical candidate for treatment of malaria FR-900098, is presented. Many of the enzymes involved in the biosynthesis of these compounds catalyze chemically and biologically unprecedented transformations, and a wealth of new biochemistry has been revealed through their study. These investigations have also suggested new strategies for natural product discovery.

Figure 1

Structures of naturally occurring small molecule phosphonates and phosphonates. The P-C bonds are highlighted in red. The inset shows for a representative sampling the resemblance between the phosphonate/phosphonate and the substrate of the enzyme they target.

Figure 2

A. Biosynthetic pathway for AEP. B. Originally proposed mechanism for PEP mutase involving nucleophilic catalysis. C. Most recent proposed mechanism, involving a dissociative process with a metaphosphate intermediate.

Figure 3

Originally proposed biosynthetic pathway for fosfomycin biosynthesis (dashed arrow) and more recent revised pathway involving FomC and 2-HEP.

Figure 4

A. Proposed mechanism of methyl transfer to HEP catalyzed by Fom3. B. Proposed mechanisms for conversion of 2-HPP to fosfomycin by HppE (Fom4).

Figure 5

The most recent proposed biosynthetic pathway for the biosynthesis of phosphinothricin. Three highly unusual transformations are highlighted in blue, and the steps with similarities with glycolytic transformations are depicted in red. For comparison, the corresponding reactions in glycolysis are shown in the box.

Figure 6

Proposed mechanism for the conversion of HEP to HMP by HEPD. Half-filled circles indicate oxygen atoms derived from O₂ that have exchanged with solvent.

Figure 7

Proposed mechanisms for P-methyltransferase. A. Heterolytic pathway transferring a methyl group from MeCbl as a methyl cation equivalent. B. Homolytic pathway transferring the methyl group as a radical.

Figure 8

Proposed biosynthetic pathway of FR900098 based on gene homologies and in vitro biochemistry.

Figure 9

Overview of currently known biosynthetic pathways of phosphonates and phosphonates starting from PEP. The steps resembling TCA cycle reactions for phosphonates (red) and phosphinates (blue) are compared with the reactions in the TCA cycle (inset).