Transamination steps

The kineties of nueleophilie substitution of the methoxy group in methoxy-butenone by the diethylamino group has been studied (91MIl).Thus, the reae-tions of 4-heterobut-3-en-2-ones with amines presented below often involve the transamination step. 

From a practical viewpoint they suffer from serious product inhibition and/or equilibrium constraints. One way of avoiding the latter issue is to couple the transamination step to a second enzymatic step which removes the coproduct In the example shown in Scheme 6.16 acetophenone undergoes TA-catalyzed transamination using L-alanine as the amine donor. The unfavorable equilibrium and... 

The two transamination steps in the pathways may be linked, as indicated in Fig. 17-5, to form a complete cycle that parallels the citric acid cycle but in which 2-oxoglutarate is oxidized to succinate via glutamate and y-aminobutyrate. No thiamin diphosphate is required, but 2-oxoglutarate is reductively aminated to glutamate. The cycle is sometimes called the y-aminobutyrate shunt, and it plays a significant role in the overall oxidative processes of brain tissue. 

Leucine is a branched chain-amino acid that is essential or required in the diet. Mitochondrial catabolism of excess leucine occurs by the pathway shown in Figure 20-3. The initial transamination step (removal of the amino group) is followed by a decarboxylation reaction to produce isovaleric acid. It is this decarboxylation of the a-keto analogs of the three... 

Mu, Chen, Li, Zhang, and Jiang (2009) also smdied the effect of medium composition on the production of PLA by lactic acid bacteria. Attempting to optimize a medium for the commercial production of PLA, the authors used a response surface methodology and the results showed that addition of phenylpyruvic acid (PPA) increased the yield of PLA. The authors suggested that because the transamination step is a bottleneck in the synthesis of PLA, the addition of PPA allowed for a shortcut that bypassed the transamination of phenylalanine to PPA, which is normally the first step when phenylalanine is used as the source for PLA. 

Direct evidence for the transamination step was the demonstration of the formation of glutamate from a-ketoglutarate during tyrosine oxidation and the accumulation of p-hydroxyphenylpyruvate under anaerobic conditions, or in the absence of ascorbic acid ( 07). The crowning step to this Ust of evidence is the isolation of a specific transaminase for tyrosine by Canellakis and Cohen ( 08). 

Accordingly, the Evans protocol, when applied to A-propionyl oxazolidinone 51 derived from ephedrine, leads to the predominant formation of the diastere-omeric syw-aldols, again with outstanding stereoselectivity. In this case, the enolate attacks the Re-hce of aldehydes with high preference. The procedure is illustrated in Scheme 4.48 for an aldol addition to a-benzyloxyacetaldehyde yielding the crude product 213 in a diastereomeric ratio of higher than 99 1. After recrystallization, the stereochemically homogeneous aldol adduct 213 was transformed into the Weinreb amide 214 in the course of a total synthesis of the macrolide antibiotic cytovaricin. In the transamination step, the chiral auxiliary 46 was recovered [111]. 

As a consequence of the enzyme block, the three a-keto acids accumulate in the tissues and body fluids. The transamination step is reversible, hence the concentrations of leucine and isoleucine in the body fluids rise to about 10 to 15 times normal and that of valine to four to five times normal. The a-keto acids also undergo other reactions, including reduction to the O-hydroxy acids, some of the products being excreted and giving the urine the characteristic odour resembling maple syrup. 

This chapter is concerned with the known disorders in the metabolism of the branched-chain amino acids after the initial transamination step, that lead to abnormal organic aciduria. Disorders of propionate and methylmalonate metabolism are discussed separately in Chapter 11. 

Branched-chain keto aciduria or maple syrup urine disease (McKusick 24 860) is an autosomal recessive disease first described by Menkes et al. (1954) in which, because of the reversible nature of the preceding transamination step, a characteristic branched-chain amino aciduria also occurs (Westall etal, 1957). In the classical form of the disease, the metabolism of all three branched-chain amino acids is affected, leading to accumulation of the three corresponding keto acids (Menkes, 1959 MacKenzie and Woolf, 1959 Dancis etaL, 1959), with the keto acid of isoleucine, 2-keto-3-methylvalerate, apparently being responsible for the characteristic maple syrup smell in the patients urine (Snyderman ra/., 1964). 

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