Structure and mechanism of enzymes involved in biosynthesis and breakdown of the phosphonates fosfomycin, dehydrophos, and phosphinothricin

Abstract

Recent years have seen a rapid increase in the mechanistic and structural information on enzymes that are involved in the biosynthesis and breakdown of naturally occurring phosphonates. This review focuses on these recent developments with an emphasis on those enzymes that have been characterized crystallographically in the past five years, including proteins involved in the biosynthesis of phosphinothricin, fosfomycin, and dehydrophos and proteins involved in resistance mechanisms.

The Streptomyces-Produced Antibiotic Fosfomycin Is a Promiscuous Substrate for Archaeal Isopentenyl Phosphate Kinase

“…Bacterial resistance to fosfomycin is achieved by mutations in MurA and by alterations in the glycerophosphate transporter (39, 40). Fosfomycin is inactivated by hydrolysis of its epoxide moiety by the thiol transferases FosA and FosB, and the homologous hydratase enzyme FosX (12–15, 41). Two additional enzymes, FomA and FomB, alter the antibiotic by two consecutive phosphorylation steps resulting in a product unable to alkylate the relevant cysteine residue in MurA.…”

Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases

“…These enzymes possess a vicinal oxygen chelate fold that is unrelated to the DSBH fold, do not require 2OG, and carry out oxidative decarboxylation of the 2-oxo acid moiety of the substrate to generate the ferryl intermediate that is used in subsequent chemistry (81). Furthermore, three Fe(II)-dependent oxygenases possess the DSBH fold, but act independent of 2OG; isopenicillin N synthase converts the tripeptide ␦-(L-␣-aminoadipoyl)-L-cysteinyl-D-valine to isopenicillin N (20, 82), 1-aminocyclopropane-1-carboxylate oxygenase catalyzes the synthesis of ethylene (83), and the epoxide-forming enzyme HppE catalyzes the formation of fosfomycin from (2S)-hydroxypropylphosphonate (84,85). New members of the of Fe(II)/2OG-dependent oxygenase superfamily are certain to be discovered, and it is likely they too will utilize a ferryl intermediate to catalyze their novel oxidative transformations.…”

Synthesis and Biological Applications of Phosphinates and Derivatives

“…phosphonates or phosphinates) are rarely encountered in living organisms and they still represent an underused functional group for the development of bioactive compounds [3,4]. The last few years have seen the revival of the work, originally started early in the 1970s, relating to the growing information on the genomic and metabolic pathways of bacteria [5,6]. Interestingly, the few synthetic or naturally occurring molecules which contain a phosphinate function play key roles in many different areas of life science.…”