Keto acids formation

KCl, dissolution process, 39 416 Ketab, synthesis, 30 263 Ketenimine complexes with iron, 12 245 KetiminoberyIlium halides, preparation and properties of, 14 307-308 a-Keto acid, formation, 43 427-428... 

Pyridoxal phosphate is the coenzyme in a large number of amino acid reactions. At this point it is convenient to consider together 1,he mechanism of those pyridoxal-dependent reactions concerned with aromatic amino acids. The reactions concerned are (1) keto acid formation (e.g., from kynurenine, above), 2) decarboxylation (e.g., of 5-hydroxytrypto-phan to 5-hydroxytryptamine, p. 106), (3) scission of the side claain (e.g., 3-tyrosinase, p. 78 tryptophanase, p. 110 and kynureninase, above), and 4) synthesis (e.g., of tryptophan from indole and serine, p. 40). Many workers have considered the mechanism of one or more of these reactions (e.g., 24, 216, 361, 595), but a unified theory is primarily due to Snell and his colleagues (summarized in 593). Snell s experiments have been carried out largely in vitro, and it should be emphasized that in vivo it is the enzyme protein which probably directs the electromeric changes. 

The complex may then split in various ways. If splitting occurs at aa, keto acid formation can occur by way of the following prototropic changes ... 

B. /3-Keto Acid Formation List of Abbreviations References... 

This is the first a-keto acid formation by nonenzymatic CO2 fixation to thioesters as a model of RC(0)SCoA. The mechanism of the reactions [Eqs. (19) and (20)] is of interest from the viewpoint of the introduction of CO2 to the positively polarized carbonyl carbon of a thioester. 

Scheme 7. Proposed catalitic cycle for a-keto acid formation.

Figure 17-4. Synthesis of D-amino acids from a-keto acid, formate, NAD+, D-alanine, and ammonia by coupling of u-alanine dehydrogenase (AlaDH), formate dehydrogenase (FDH), alanine racemase (AlaR), and D-amino acid aminotransferase (d-ATA).

The mechanism for the a-keto acid formation was proposed as shown in Scheme 4, which is reminiscent of those for a-keto amide and ester formation.Benzoyl(hydroxy-carbonyOpalladium complex was assumed as a key intermediate, which undergoes reductive elimination to form a-keto acid. Decarboxylation of this intermediate giving a benzoylpalladium hydride species followed by reductive elimination was proposed to give benzaldehyde as by-product. 

Until recently, the amino acid oxidase reaction has been studied only in the direction of ammonia and a-keto acid formation. In the presence of air the reaction proceeds to completion and is essentially irreversible because of the reoxidation of the reduced flavoprotein by molecular oxygen [reaction (5)]. Meister and his associates 11, 12) have provided a clear demonstration of the reversibility of the amino acid oxidase reaction with D-amino acid oxidase (from sheep kidney) and L-amino acid oxidase (from snake venom). When an amino acid, ammonia, and the a-keto acid analog of a second amino acid are incubated with either amino acid oxidase under anaerobic conditions, the formation of the second amino acid is observed ... 

Both isomers of both serine and threonine are deaminated by Neuro-spora extracts 225-228). The enzymes involved have been purified by Yanofsky and his associates 225-228). A specific D-serine and D-threonine dehydrase has been purified thirty-five- to fortyfold from this mold 2f ). An absolute requirement for pyridoxal phosphate was demonstrated. No requirement for AMP or glutathione could be demonstrated. Some indication of a metal requirement was observed. The preparation was not active with the li-isomers of serine and threonine or DL-homoserine and DL-homo-cysteine. The rate of deamination of D-threonine is very slow compared to that with L-serine. Activity was observed with D-glutamic acid and D-as-partic acid. Since other D-amino acids were not deaminated by the preparation, these results could not be due to a contamination with D-amino acid oxidase. Furthermore, when either of these amino acids was incubated in the presence of D-serine, the keto acid production was a summation of that for each substrate alone. Pyridoxal phosphate had no effect on keto acid formation from the dicarboxylic amino acids. It is of interest that D-amino acid oxidase of Neurospora does not attack D-serine or D-threonine (77). 

The dehydrase enzyme, named dihydroxy acid dehydrase was found to have a pH optimum at 8-9. It is inhibited by fluoride and the equilibrium of the reaction appears to be far toward keto acid formation. 

The carbon-carbon bond forming potential inherent m the Claisen and Dieckmann reac tions has been extensively exploited m organic synthesis Subsequent transformations of the p keto ester products permit the synthesis of other functional groups One of these transformations converts p keto esters to ketones it is based on the fact that p keto acids (not esters ) undergo decarboxylation readily (Section 19 17) Indeed p keto acids and their corresponding carboxylate anions as well lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation... 

Although the nature of the general polar effect suggested by Kamernitzsky and Akhrem " to account for axial attack in unhindered ketones is not clear, several groups have reported electrostatic interactions affect the course of borohydride reductions. Thus the keto acid (5a) is not reduced by boro-hydride but its ester (5b) is reduced rapidly further, the reduction of the ester (6b) takes place much more rapidly than that of the acid (6a). Spectroscopic data eliminate the possibility that in (5a) there is an interaction between the acid and ketone groups (e.g. formation of a lactol). The results have been attributed to a direct repulsion by the carboxylate ion as the borohydride ion approaches. " By contrast, House and co-workers observed no electrostatic effect on the stereochemistry of reduction of the keto acid (7). However, in this compound the acid group may occupy conformations in which it does not shield the ketone. Henbest reported that substituting chlorine... 

FIGURE 18.18 Thiamine pyrophosphate participates in (a) the decarboxylation of n-keto acids and (b) the formation and cleavage of n-hydroxyketones. 

The second line of circumstantial evidence quoted in support of this hypothesis is the ready formation of l,2,3,4-tetrahydro-/3-carboline derivatives under pseudo-physiological conditions of temperature, pH, and concentration. Tryptamine and aldehydes, trypt-amine and a-keto acids, and tryptophan and aldehydes condense at room temperature in a Pictet-Spengler type intramolecular Mannich reaction in the pH range 5.2-8.0 (cf. Section III, A, 1, a). It was argued that experiments of this type serve as models for biochemical reactions and may be used in evidence. 

Decarboxylation is not a general reaction of carboxylic acids. Rather, it is unique to compounds that have a second carbonyl group two atoms away from the —COoH. That is, only substituted malonic acids and /3-keto acids undergo loss of CC>2 on heating. The decarboxylation reaction occurs by a cyclic mechanism and involves initial formation of an enol, thereby accounting for the need to have a second carbonyl group appropriately positioned. 

Yet a third method for the synthesis of a-amino acids is by reductive amination of an a-keto acid with ammonia and a reducing agent. Alanine, for instance, is prepared by treatment of pyruvic acid with ammonia in the presence of NaBH As described in Section 24.6, the reaction proceeds through formation of an intermediate imine that is then reduced. 

A clever new method of peptide synthesis involves formation of an amide bond by reaction of an cv-keto acid with an N-alkylhydroxylamine ... 

TPP-dependent enzymes are involved in oxidative decarboxylation of a-keto acids, making them available for energy metabolism. Transketolase is involved in the formation of NADPH and pentose in the pentose phosphate pathway. This reaction is important for several other synthetic pathways. It is furthermore assumed that the above-mentioned enzymes are involved in the function of neurotransmitters and nerve conduction, though the exact mechanisms remain unclear. 

---