Valine, synthesis

Figure 2.23 Chromatogram of sample from L-valine synthesis. Chromatography conditions column, Nucleosil 120-5Ci8 mobile phase, 2 mM copper(II) acetate/4 mM l-DPA/1 mM TEA (pH 5.1). (Reprinted from Ref. 108 with permission.)...

Diacetyl, and its reduction products, acetoin and 2,3-butanediol, are also derived from acetaldehyde (Fig 8D.7), providing additional NADH oxidation steps. Diacetyl, which is formed by the decarboxylation of a-acetolactate, is regulated by valine and threonine availability (Dufour 1989). When assimilable nitrogen is low, valine synthesis is activated. This leads to the formation of a-acetolactate, which can be then transformed into diacetyl via spontaneous oxidative decarboxylation. Because valine uptake is suppressed by threonine, sufficient nitrogen availability represses the formation of diacetyl. Moreover, the final concentration of diacetyl is determined by its possible stepwise reduction to acetoin and 2,3-butanediol, both steps being dependent on NADH availability. Branched-chain aldehydes are formed via the Ehrlich pathway (Fig 8D.7) from precursors formed by combination of acetaldehyde with pyruvic acid and a-ketobutyrate (Fig 8D.7). 

The syntheses of valine, leucine, and isoleucine from pyruvate are illustrated in Figure 14.9. Valine and isoleucine are synthesized in parallel pathways with the same four enzymes. Valine synthesis begins with the condensation of pyruvate with hydroxyethyl-TPP (a decarboxylation product of a pyruvate-thiamine pyrophosphate intermediate) catalyzed by acetohydroxy acid synthase. The a-acetolactate product is then reduced to form a,/3-dihydroxyisovalerate followed by a dehydration to a-ketoisovalerate. Valine is produced in a subsequent transamination reaction. (a-Ketoisovalerate is also a precursor of leucine.) Isoleucine synthesis also involves hydroxyethyl-TPP, which condenses with a-ketobutyrate to form a-aceto-a-hydroxybutyrate. (a-Ketobutyrate is derived from L-threonine in a deamination reaction catalyzed by threonine deaminase.) a,/3-Dihydroxy-/3-methylvalerate, the reduced product of a-aceto-a-hydroxybutyrate, subsequently loses an HzO molecule, thus forming a-keto-/kmethylvalerate. Isoleucine is then produced during a transamination reaction. In the first step of leucine biosynthesis from a-ketoisovalerate, acetyl-CoA donates a two-carbon unit. Leucine is formed after isomerization, reduction, and transamination. 

The valine and isoleucine biosynthetic pathways share four enzymes. Isoleucine synthesis begins with the reaction of a-ketobutyrate (a derivative of threonine) with pyruvate. In valine synthesis the condensation of two pyruvate molecules is the first step. Leucine is produced by a series of reactions that begin with a-ketoisovalerate, an intermediate in valine synthesis. 

Branched chain amino acid synthesis has been extensively studied (, Figure 3). In branched chain amino acid biosynthesis ALS Is the second enzyme of Isoleuclne biosynthetic pathway and the first enzyme of valine synthesis. Commonly the first enzyme of a synthetic pathway is Inhibited by the end-product thus preventing waste of carbon skeletons and energy. Two ALS Isozymes exist In... 

Brat D, Weber C, Lorenzen W, Bode HB, Boles E. (2012). Cytosolic re-localization and optimization of valine synthesis and catabolism enables increased isobutanol production with the yeast Saccharomyces cerevisiae. Biotechnol Biofuels, 5, 65. 

The valine synthesis just presented utilized lactam intermediates. A quite different lactam driven synthesis reacted imide 6.150 with isobutenylmagnesium chloride to give 6.151. Catalytic hydrogenation gave 6.152 along with 18% of... 

Work on the mechanism of the biosynthesis of isoleucine and valine began with the isolation of a mutant strain of Neurospora which required both isoleucine and valine for growth. Bonner suggested that the double requirement was due to the accumulation of an isoleucine precursor which then inhibited the conversion of an analogous intermediate in the scheme of valine synthesis. This explanation has been shown not to be true, as will be pointed out below. The steps in scheme for the biosynthesis of isoleucine and valine in microorganisms are given in Fig. 3. 

Strassman et al. (144), on the basis of the equal incorporation of lactate C-2 into valine C-2 and C-3, suggested that valine synthesis was initiated by the condensation of two pyruvate molecules, similar to the known condensation of pyruvate and acetaldehyde to yield acetolactic acid (162). The methyl group of pyruvate was indicated to be the precursor of the valine methyl groups. To explain this required a migration of the methyl group as in the pinacol rearrangement. 

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