A-keto acid precursors

Conversion of the acetohydroxy acids to the a,/3-dihydroxyacid precursors of valine and isoleucine is catalyzed by acetohydroxy acid isomeroreductase. The a,/3-dihydroxy acids are both converted to the a-keto acid precursors of valine and isoleucine by a dihydroxy acid dehydrase. Finally, the two amino acids are formed in trans-... 

Dihydroxyacid dehydratase is involved in the biosynthesis of valine and isoleucine. L-a,/3-dihydroxyisovaleric acid and L-aj3-dihydroxy-/3-methylvaleric acid are dehydrated to form the a-keto acid precursors of valine and isoleucine. 

Some general reactions that involve degradation or interconversion of amino acids provide for the synthesis of nonessential amino acids from a-keto acid precursors derived from carbohydrate intermediates. 

Because transamination reactions are reversible, it is theoretically possible for all amino acids to be synthesized by transamination. However, experimental evidence indicates that there is no net synthesis of an amino acid if its a-keto acid precursor is not independently synthesized by the organism. For example, alanine, aspartate, and glutamate are nonessential for animals because their a-keto acid precursors (i.e., pyruvate, oxaloacetate, and a-ketoglutarate) are readily available metabolic intermediates. Because the reaction pathways for synthesizing molecules such as phenylpyruvate, a-keto-/Thydroxybutyrate, and imidazolepyruvate do not occur in animal cells, phenylalanine, threonine, and histidine must be provided in the diet. (Reaction pathways that synthesize amino acids from metabolic intermediates, not only by transamination, are referred to as de novo pathways.)... 

Fig. 8.7. Proposed mechanism for hydroxylation of phenyl ring with a-keto acid precursor.

A rather limited collection of simple precursor molecules is sufficient to provide for the biosynthesis of virtually any cellular constituent, be it protein, nucleic acid, lipid, or polysaccharide. All of these substances are constructed from appropriate building blocks via the pathways of anabolism. In turn, the building blocks (amino acids, nucleotides, sugars, and fatty acids) can be generated from metabolites in the cell. For example, amino acids can be formed by amination of the corresponding a-keto acid carbon skeletons, and pyruvate can be converted to hexoses for polysaccharide biosynthesis. 

Biochemical reactions include several types of decarboxylation reactions as shown in Eqs. (1)-(5), because the final product of aerobic metabolism is carbon dioxide. Amino acids result in amines, pyruvic acid and other a-keto acids form the corresponding aldehydes and carboxylic acids, depending on the cooperating coenzymes. Malonyl-CoA and its derivatives are decarboxylated to acyl-CoA. -Keto carboxylic acids, and their precursors (for example, the corresponding hydroxy acids) also liberate carbon dioxide under mild reaction conditions. 

A pH-dependent chemoselective catalytic reductive amination of a-keto acids, affording a-amino acids with HCOONH4 in water, was achieved using the complex 31 or its precursor 28 as the catalyst [51]. The formation rates of alanine and lactic acid from pyruvic acid exhibited a maximum value around pH 5 and pH 3, respectively, and therefore, alanine was obtained quite selectively (96%) with a small amount of lactic acid (4%) at pH 5 (Scheme 5.18). A variety of nonpolar, uncharged polar and charged polar amino acids were also synthesized in high yields. 

These results confirmed that branched-chain amino acid catabolism via the BCDH reaction provides the fatty acid precursors for natural avermectin biosynthesis in S. avermitilis. In contrast, B. subtilis appears to possess two mechanisms for branched-chain precursor supply. The dual substrate pyruvate/branched-chain a-keto acid dehydrogenase (aceA) and an a-keto acid dehydrogenase (bfmB), which also has some ability to metabolize pyruvate, appears to be primarily involved in supplying the branched-chain initiators of long, branched-chain fatty acid biosynthesis [32,42], Two mutations are therefore required to generate the bkd phenotype in B. subtilis [31,42],... 

CWC Hu, KS Lau, TA Griffin, JL Chuang, CW Fisher, RP Cox, DT Chuang. Isolation and sequencing of a cDNA encoding the decarboxylase (El)-a precursor of bovine branched-chain a-keto acid dehydrogenase complex expression of El-a mRNA and subunit in maple-syrup-urine-disease and 3T3-L1 cells. J Biol Chem... 

The a-keto acid decarboxylases such as pyruvate (E.C. 4.1.1.1) and benzoyl formate (E.C. 4.1.1.7) decarboxylases are a thiamine pyrophosphate (TPP)-dependent group of enzymes, which in addition to nonoxidatively decarboxylating their substrates, catalyze a carboligation reaction forming a C-C bond leading to the formation of a-hydroxy ketones.269-270 The hydroxy ketone (R)-phenylacetylcarbinol (55), a precursor to L-ephedrine (56), has been synthesized with pyruvate decarboxylase (Scheme 19.35). BASF scientists have made mutations in the pyruvate decarboxylase from Zymomonas mobilis to make the enzyme more resistant than the wild-type enzyme to inactivation by acetaldehyde for the preparation of chiral phenylacetylcarbinols.271... 

The enantioselective synthesis of 1 has also been achieved by a number of methods including enzymatic resolution of a keto ester precursor to the racemate followed by conversion of the ester to an amino group, enzymatic resolution of an amino azide precursor followed by reduction, enzymatic resolution through 0-acylation of a racemic A -benzylcarbamate derivative of and the resolution via the formation of an amide with a homochiral amino acid. Bioconversion of in-... 

Numerous asymmetric catalytic hydrogenations of carbon-nitrogen double bonds have been carried out. Some of the substrates used are oximes and hydrazones, but most of the reactions were carried out using Schiff s bases of ketones. a-Keto acids are precursors of a-amino acids in biosynthesis, and therefore a-keto acids have been used for the asymmetric syntheses of a-amino acids. ... 

The addition of lithium and Grignard reagents to isocyanides which do not contain a-hydrogens proceeds by an a-addition to produce a metalloaldimine (7, an acyl anion equivalent). The lithium aldimines are versatile reagents which can be used as precursors for the preparation of aldehydes, ketones, a-hy-droxy ketones, a-keto acids, a- and 3-hydroxy acids, silyl ketones and a-amino acids (Scheme 5). - ... 

Identify the amino acid that is a catabolic precursor of each of the following a-keto acids ... 

Resistance to vancomycin is via a sensor histidine kinase (VanS) and a response regulator (VanR). VanH encodes a D-lactate dehydrogenase/a-keto acid reductase and generates D-lactate, which is the substrate for VanA, a D-Ala-D-Lac ligase. The result is cell wall precursors terminating in D-Ala-D-... 

In contrast to the oxidative generation of radicals described above, redactions of alkyl iodides nsing tris(trimethylsilyl)silane also produces alkyl radicals under conditions suitable for Minisci-type substitution. Carboxylic acids (a-keto acids) are also useful precursors for alkyC° and/or acyC radicals via silver-catalysed peroxide oxidation, or from their l-hydroxypyridine-2-thione derivatives, the latter in non-aqueous conditions. 

There is one major disadvantage to most of the transamination technology as presented above because the transamination reaction involves an amino acid reacting with a 2-keto acid to generate products which consist of a 2-keto acid and an amino acid, the equilibrium constant is often close to unity. As a result, the net conversion of substrates to products is thermodynamically limited. The key to the development of an efficient transamination technology lies in overcoming the problem of incomplete conversion of the 2-keto acid precursor to the desired amino acid product. 

There is a relatively rare genetic disease in which the three branched-chain a-keto acids (as well as their precursor amino acids, especially leucine) accumulate in the blood and spill over into the urine. This condition, called maple syrup urine disease because of the characteristic odor imparted to the urine by the a-keto acids, results from a defective branched-chain a-keto acid dehydrogenase complex. Untreated, the disease results in abnormal development of the brain, mental retardation, and death in early infancy. Treatment entails rigid control of the diet, limiting the intake of valine, isoleucine, and leucine to the minimum required to permit normal growth. ... 

The biosynthetic pathway which is indicated by the above results is illustrated in Scheme 11 norlaudanosoline (70) had previously been shown to be a morphine (71) precursor. The implication of a keto-acid rather than an aldehyde in benzyliso-quinoline formation accords with observations on the biosynthesis of simpler isoquinolines and stands in contrast with the utilization of an aldehyde, sec-ologanin, in a similar reaction in the biosynthesis of terpenoid indole alkaloids. ... 

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