Heptulosonic synthesis

Glyphosate also inhibits the activity of a form of 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase (13), however, this inhibition is relatively weak. Effects of glyphosate on the enzymes of aromatic amino acid synthesis have been described in more detail in recent reviews (14-17). 

Deoxy-araWno-heptulosonic acid 7-phosphate (10) is a metabolic intermediate before shikimic acid in the biosynthetic pathway to aromatic amino-acids in bacteria and plants. While (10) is formed enzymically from erythrose 4-phosphate (11) and phosphoenol pyruvate, a one-step chemical synthesis from (11) and oxalacetate has now been published.36 The synthesis takes place at room temperature and neutral pH... 

Deoxy-D-araZu o-heptulosonate-7-phosphate synthetase (DAHPS) is the initial enzyme in the pathway responsible for the synthesis of aromatic compounds in microorganisms and plants. It catalyses the reaction shown in Equation (4) ... 

The efficiency of this strategy for the synthesis of 3-deoxy-D-arajblno-2-heptulosonates is outlined in Scheme 12 (51). ... 

J. Frost and J. R. Knowles, 3-Deoxy-D-arabino-heptulosonic acid 7-phosphate Chemical synthesis and isolation from Escherichia coli auxotrophs, Biochemistry 23 4465 (1984). 

R. Ramage, A. M. MacLeod, and G. W. Rose, Dioxolanes as synthetic intermediates. Part 6. Synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO), 3-deoxy-D-araMiio-2-heptulosonic acid (DAH) and 2-keto-3-deoxy-D-gluconic acid (KDG), Tetrahedron 47 5625 (1991). 

The six-carbon chain of ManNAc 6-P can be extended by three carbon atoms using an aldol-type condensation with a three-carbon fragment from PEP (Eq. 20-7, step c) to give N-acetylneuraminic acid (sialic acid).48 Tire nine-carbon chain of this molecule can cyclize to form a pair of anomers with 6-membered rings as shown in Eq. 20-7. In a similar manner, arabi-nose 5-P is converted to the 8-carbon 3-deoxy-D-manno-octulosonic acid (KDO) (Fig. 4-15), a component of the lipopolysaccharide of gram-negative bacteria (Fig. 8-30), and D-Erythrose 4-P is converted to 3-deoxy-D-arafrmo-heptulosonate 7-P, the first metabolite in the shikimate pathway of aromatic synthesis (Fig. 25-1).48a The arabinose-P used for KDO synthesis is formed by isomerization of D-ribulose 5-P from the pentose phosphate pathway, and erythrose 4-P arises from the same pathway. 

Scheme 5. Combined enzymatic synthesis of 3-deoxy-D-arahmo-heptulosonic acid 7-phosphate...

Fourthly, biotransformations have been used for the synthesis of 3-deoxy-2-glyculosonic acids, using whole cells or purified enzymes. For instance, 3-deoxy-D-araZu rao-heptulosonic acid (DAH) and its 7-phosphate (DAHP, 122) have been produced directly from D-glucose by mutants of E. coli JB-5, that lack dehydroquinate synthase, the enzyme that converts DAHP into the cyclic intermediate dehydroquinic acid (DHQ, Scheme 14). Both DAH and DAHP are secreted into the medium. The dephosphorylated product could be generated in vivo by a phosphatase acting on DAHP.312... 

D. B. Sprinson, J. Rothschild, and M. Sprecher, The synthesis of 3-deoxy-D-arabino-heptulosonic acid 7-phosphate, J. Biol. Chem., 238 (1963) 3170-3175. 

F. Trigalo, M. Level, and L. Szabo, Phosphorylated sugars. Part XVII. Synthesis of 3-deoxy-D-araWrco-[l-14C]heptulosonic acid 7-(dihydrogen phosphate), J. Chem. Soc., Perkin Trans. I, (1975) 600-602. 

J. Mlynarski and A. Banaszek, A novel chemical synthesis of a 3-deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP) derivative and its 2-deoxy analogue, Carbohydr. Res., 295 (1996) 69-75. 

The view that such a reaction is the initial one in the conversion of enolpyruvate phosphate plus D-erythrose 4-phosphate to shikimate, was supported by fractionation of the crude, bacterial extracts and by the chemical synthesis of 3-deoxy-D-ara6mo-heptulosonic acid 7-phosphate. The steps in... 

Fig. 5.—Chemical Synthesis of 3-Deoxy-D-aro6ino-heptulosonic Acid 7-Phosphate. (Ph denotes phenyl, and Tr, triphenylmethyl.)...

What may be called the 3-deoxy-D-om6mo-heptulosonic acid 7-phosphate pathway is used in E. coli for the synthesis of (a) the aromatic amino acids of proteins and (b) p-aminobenzoate. In Neurospora this pathway is also used for the synthesis of niacin ( > since these organisms convert tryptophan to niacin by a pathway first observed in mammals, but E. coli synthesizes niacin by a different pathway. jt is clear at present, even on the basis of limited evidence, that plants use the 3-deoxy-D-oroWno-heptulosonic acid 7-phosphate pathway for the synthesis of a much more extensive series of products. 

The biologically active monosaccharide 3-deoxy-D-ura6//io-heptulosonic acid 7-phosphate (8 DAMP) is an important intermediate in the biosynthesis of aromatic amino acids in plants (the shikimate pathway). As shown in Scheme 2, this compound has been produced in a combined chemical and enzymatic synthesis from racemic V-acetylaspartate 3-semialdehyde (4) and DHAP (1). The four-step synthesis proceeds in an overall yield of 13% (37% for the aldolase reaction). The enzymatic step generates the required, enantiomerically pure, syn aldol adduct compound (5). In view of the broad range of substrates tolerated by FDP aldolase, this method may be applicable to the production of analogs of DAMP. 

The 3-deoxy-D-ara6mo-2-heptulosonic acid 7-phosphate (DAHP) synthetase (EC 4.1.2.15) is an enzyme involved in the shikimic pathway of aromatic amino acids biosynthesis in bacteria and plants, where catalyzes the construction of 3-deoxy-D-ara6/ o-2-heptulosonic acid 7-phosphate from phosphoenolpyruvate and D-erythrose 4-phosphate [6]. Although 3-deoxy-D-ara6/H0-2-heptulosonic acid 7-phosphate (DAHP) synthetase has not been widely investigated it has been employed for the DAHP synthesis on preparative scale from D-fructose in multienzyme system [68], This one-pot synthesis was subsequently even more simplified by the results of further studies which indicated that it was more efficient and economical to use the whole cells containing a DAHP synthetase plasmid [69]. 

Much effort towards stereoselective synthesis of 3-deoxy-2-ulosonic acids resulted in the development of several strategies based on the diverse building units. Among them aldol reaction between D-arabinose derivative 50 and methyl dichloroacetate (51) deserves some attention [78] (Scheme 14). The condensation product isolated as oxirane derivative 52 reacted smoothly with Mgk to give the intermediate 53, easily convertible into 3-deoxy-D-ara6mo-2-heptulosonic acid methyl ester 56 in high yield. 

This strategy was also used in the stereoselective synthesis of L-xylo-heptulosonic acid [79] as well as D-ma/wooctulosonic acid (KDO) [80]. It is worth to note that the mannose derivative when used in hemiacetal form, failed to react with methyl dihaloacetate [80b]. 

The synthesis via Barton esters succeeded when the thiopirydyl adduct was created from 2,3 4,5-di-0-isporopylidene ribonic acid as a substrate [109c]. Treatment of this adduct with aqueous NaHCC>3 gave an epimeric mixture of ethyl 4,5 6,7-di-0-isopropylidene-3-deoxy-D-ara6/no- and D-r/6o-2-heptulosonates (3 1, respectively), the first one was further converted into DAH ethyl ester by use of Dowex (H+) resin in aqueous EtOH. 

This ketene dithioacetal protocol was employed to deliver all the isomeric 3-deoxy-heptulosonic and heptulosaric acids, as well as their 2-deoxy counterparts [130]. Further, by this route the synthesis of KDO and 2-deoxy-KDO was accomplished [133]. This methodology was also utilized for direct construction of naturally occurring KDO disaccharides [134]. 

Enzyme assisted aldol condensation was the key step of the synthesis of 3-deoxy-D-ara mo-heptulosonic acid 7-phosphate (Scheme 63) [154], In the four steps synthesis of DAHP Whitesides started from A-acetyl -D/L-aspartate P-semialdehyde and dihydroxyacetone phosphate. The required threo stereochemistry was generated by using commercial rabbit muscle aldolase as catalyst. 

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