3-Phosphonopyruvate

This enzyme [EC S.4.2.9], also known as phosphoenolpyruvate phosphomutase, catalyzes the interconversion of phosphoenolpyruvate and 3-phosphonopyruvate. This enzyme participates in the biosynthesis of the C—P bond. However, the equilibrium greatly favors phosphoenolpyruvate. 

Fig. 6. Interconversion of phosphoenolpyruvate and 3-phosphonopyruvate. 1. Biosynthetic direction, in which the C—P bond is made. 2. Direction greatly favored at equilibrium.

Hydroxyalkylphosphonates have been prepared by reduction of the corresponding ketones. These include phosphonomalate esters by highly diastereose-lective reduction of 3-phosphonopyruvates with NHs.BHa and both 2-hydroxyalkyl-phosphonates, e.g. 178, and thiophosphonates by asymmetric hydrogenation using chiral ruthenium catalysts. An enantioselective synthesis, from 179, of both enantiomers of phosphonothrixin 180 and their absolute stereochemistry have been reported.The epoxide 179 was prepared from 2-methy -3-hydroxymethyl-1,3-butadiene via a Sharpless epoxidation. 

It is believed that 3-phosphonopyruvate may be the precursor of all naturally occurring phosphonates. It is obtained by the enzyme-catalysed reaction. 

Horiguchi, M. and Rosenberg, H., Phosphonopyruvic acid a probable precursor of phosphonic acids in cell-free preparations of Tetrahymena, Biochim. Biophys. Acta, 404, 333, 1975. 

In the framework of SFB380, two projects dealt extensively with acyloin-con-densing ThDP-dependent enzymes such as pyruvate decarboxylase (PDC), ben-zoylformate decarboxylase (BFD), or benzaldehyde lyase (BAL) (see Chapters 2.2.3 and 2.2.7). Another ThDP-dependent decarboxylase, phosphonopyruvate decarboxylase (PPD) from Streptomyces viridochromogenes, became available only recently and was studied in project B21. We wanted to find out whether this PDC-related enzyme could be a valuable tool in the provision of acyloin condensations involving C-P bonds (see Section 2.2.2.23). 

C-P bonds are present in a range of natural compounds, for example, antibiotics. Through a reaction of PEP mutase, phosphoenolpyruvate is converted to phosphonopyruvate, which is the precursor of all natural phosphono compounds. The ThDP-dependent enzyme phosphonopyruvate decarboxylase (PPD) has been discovered in several Streptomycetes and other bacteria [24] its reaction is depicted in Scheme 2.2.2.3. 

PPD from another bacterium was characterized by the Dunaway-Mariano group [26], Based on the PDC structure from Zymomonas mobilis and other ThDP enzymes [27], a hypothetical model for PPD was built. This model was then corroborated by site-directed mutagenesis of all the amino acid residues at the ThDP and phosphonopyruvate binding sites [25]. A hypothetical working model for the PPD active site is given in Fig. 2.2.2.2. 

Fig. 2.2.2.2 Postulated model of the active site of phosphonopyruvate decarboxylase. PPD from Str. viridochromogenes T0494 (based on the structure of PDC from Zymomonas mobilis [27] and data from analyis of site-directed mutants [25]). The model depicts the start of the catalytic reaction (deprotonation of the reactive C2 atom (yellow) on the thiazolium ring ofThDP...

Residues Glu224 and Asp263 are conserved among phosphonopyruvate and sulfopyruvate decarboxylases and are shaded in green. 

The malate, oxaloacetate, and fumarate analogues 3-arsonolactate (86), 3-arsonopyruvate (68), and CE)-3-arsonoacrylate (87,88) have been made Ali and Dixon (88) found that the fumarate and malate analogues were not substrates for fumarate hydratase, but competitive inhibitors, arsonoacrylate, H203As—CH=CH—COOH, with fumarate ( / 1.8) and arsonolactate, H203As—CH2—CHOH—COOH, with malate (KJKm 1.6). Incidentally, although phosphonopyruvate is a poor substrate for malate dehydrogenase (89,90), 3-(hydroxyphosphinoyl)pyru-vate, HO—P(H)(0)—CH2—CO—COOH, is much better (89). It proved impossible to show the reverse reaction with arsonolactate (89, 91). 

The lipids of some organisms, such as Tetrahymena, contain aminoethylphosphonate, a compound with a C-P bond (Chapter 8). There are also many other naturally occurring phosphono compounds and huge quantities of synthetic phosphonates, present in detergents, herbicides, and insecticides, are metabolized by bacteria 297 Here we will consider only one step in the biosynthesis of phosphonates, the conversion of PEP into phosphonopyruvate (Eq. 13-54), a reaction catalyzed by PEP mutase. The phospho group is moved... 

Because of the Perkow reaction, the above route for the production of ketophosphonates and phosphonopyruvates was abandoned. By coupling a-copperalkylphosphonates with acyl chlorides, we have been able to produce in one step ketophosphonate correctly functionalized as well as phosphonopyruvates in good yield and high purity (6). Rl... 

Phosphonopyruvate systems were the first candidates submitted to reductive amination. Because of the presence of the ester group, the a-ketoester carbonyl is less reactive than traditional oxoalkylphosphonates, and yields of isolated amino-esters never exceeded 55 %. The reaction is run at pH 7 in ethanol and it is general for ammonia and primary amines. Steric hindrance represents the second limiting factor since a-substituted or thiono-phosphonopyruvates react sluggishly thus secondary amines cannot be introduced. When the reductive amination process is effected the exclusive by-product is the a-hydroxyester which arises by reduction of the carbonyl group (7j-8). 

Nakashita, H., Watanabe, K., Hara, O., Hidaka, T., and Seto, H., Studies on the biosynthesis of bialaphos. Biochemical mechanism of C-P bond formation. Discovery of phosphonopyruvate decarboxylase which catalyzes the formation of phosphonoacetaldehyde from phosphonopyruvate, J. Antibiot., 50, 212, 1997. 

Feistauer, H., and Neidlein, R., Phosphonopyruvates. Syntheses, NMR investigations, and reactions, Helv. Chim. Acta, 78, 1806, 1995. 

Diethyl 2-pyrrolidinoalkenyIphosphonates, available from pyrrolidine and diethyl 1-formylalkylphosphonates, on low-temperature treatment with i-BuLi in THF, undergo metallation under kinetic control in the P-position to phosphorus. Acylation of the resulting oc-pyrrolidino anions with methyl or allyl chloroformate proceeds uneventfully to produce diethyl phosphonopyruvates in moderate to good yields after mild acid hydrolysis with oxalic acid on... 

Schwalbe, C.H., and Freeman, S., The crystal structure of the tri(cyclohexylammonium) salt of phosphonopyruvate. Theoretical calculations on the equilibrium constant for the rearrangement of phosphonopyruvate to phosphoenolpyruvate, 7. Chem. Soc., Chem. Commun., 251, 1990. 

Varlet, J.M., Colhgnon, N., and Savignac, P, Synthesis and reductive amination of phosphonopyruvates. Preparation of 2-amino-2-carboxyalkylphosphonic acids (P-phosphonoalanine), Can. J. Chem., 57, 3216, 1979. 

The equilibrium between phosphoenolpyruvate and phosphonopyruvate (19, Fig. 13-10) is catalyzed by a phosphomutase. The mechanism of the transformation of a phosphoryl into a phosphonoyl group has been studied with labeled and S-substituted analogs of the natural substrate ll53 158l... 

Sulphur and selenium-containing compounds-Jht enzyme, phosphoenolpyruvate phosphomutase, from Tetrahymena pyriformis, catalyses the tran.sformation of phosphoenolpyruvate (PEP) into its P-C bond-containing metabolite, phosphonopyruvate. 

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