Valine biosynthesis

Tang L, Zhang Y X, Hutchinson CR. Amino acid catabolism and antibiotic biosynthesis Valine is a source of piecursots for macrolide biosynthesis in Screpromjces ombo/ociens and StKptomycesfradiae. J Bactetiol 1994 176 6107-6119. 

Many kinds of amino acids (eg, L-lysine, L-omithine, t-phenylalanine, L-threonine, L-tyrosine, L-valine) are accumulated by auxotrophic mutant strains (which are altered to require some growth factors such as vitamins and amino acids) (Table 6, Primary mutation) (22). In these mutants, the formation of regulatory effector(s) on the amino acid biosynthesis is genetically blocked and the concentration of the effector(s) is kept low enough to release the regulation and iaduce the overproduction of the corresponding amino acid and its accumulation outside the cells (22). 

Fig. 5. Biosynthesis of penicillins when ACV is aminoadipoly cysteinyl valine and IPNS is isopenicillin N synthase and CgH CH2COSCoA represents benzyl coenzyme A. ACV synthetase is thought to catalyze the first step of this reaction sequence.

The building blocks for the biosynthesis of benzylpenicillin are three amino acids, a-aminoadipic acid, cysteine and valine, and PAA. The amino acids condense to a tripeptide, ring closure of which gives the penicillin ring structure with an cu-aminoadipyl side-chain, isopenicillin N. The side-chain is then displayed by a phenylacetyl group from PAA to give benzylpenicillin. 

The (5-lactam antibiotics are now so extensively described that we cannot attempt to summarize the literature. Since our emphasis is on sulfur, we note that the sulfur atoms of the thiazolidine or dihydrothiazine rings derive from a common tripeptide, 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine 1, ACV or Arnstein tripeptide . ACV is converted to a (5-lactam structure, isopenicillin N 2 and thereafter, the two pathways diverge, i.e. to benzylpenicillin 3 or to cephalosporin C 4 (Scheme 1). There have been extensive studies of the genes and enzymes involved in (5-lactam biosynthesis.18,19... 

Elimination reactions (Figure 5.7) often result in the formation of carbon-carbon double bonds, isomerizations involve intramolecular shifts of hydrogen atoms to change the position of a double bond, as in the aldose-ketose isomerization involving an enediolate anion intermediate, while rearrangements break and reform carbon-carbon bonds, as illustrated for the side-chain displacement involved in the biosynthesis of the branched chain amino acids valine and isoleucine. Finally, we have reactions that involve generation of resonance-stabilized nucleophilic carbanions (enolate anions), followed by their addition to an electrophilic carbon (such as the carbonyl carbon atoms... 

Figure 5.7 Examples of (a) elimination, (b) isomerization (aldose/ketose) and (c) a complex rearrangement of the pinacol-pinacolone type found in the biosynthesis of valine and isoleucine.

Valine, leucine, and isoleucine biosynthesis Lysine biosynthesis Lysine degradation Arginine and proline metabolism Histidine metabolism Tyrosine metabolism Phenylalanine metabolism Tryptophan metabolism Phenylalanine, tyrosine, and tryptophan biosynthesis Urea cycle and metabolism of amino groups... 

Capsaicinoids are synthesized by the condensation of vanillylamine with a short chain branched fatty acyl CoA. A schematic of this pathway is presented in Fig. 8.4. Evidence to support this pathway includes radiotracer studies, determination of enzyme activities, and the abundance of intermediates as a function of fruit development [51, 52, 57-63], Differential expression approaches have been used to isolate cDNA forms of biosynthetic genes [64-66], As this approach worked to corroborate several steps on the pathway, Mazourek et al. [67] used Arabidopsis sequences to design primers to clone the missing steps from a cDNA library. They have expanded the schema to include the biosynthesis of the key precursors phenylalanine and leucine, valine and isoleucine. Prior to this study it was not clear how the vanillin was produced, and thus the identification of candidate transcripts on the lignin pathway for the conversion of coumarate to feruloyl-CoA and the subsequent conversion to vanillin provide key tools to further test this proposed pathway. 

ACV is produced by the modular system for non-ribosomal peptide biosynthesis. The amino acid precursors are L-a-aminoadipic acid (an unusual amino acid derived by modification of L-lysine), L-cysteine, and L-valine during tripeptide formation, the L-valine is epimerized to o-valine (see Box 10.10). 

The enzymatic formation of 4 from isobutylamine, which is derived from valine, during the biosynthesis of valanimycin, was confirmed by high-resolution MS analysis The importance of the pathway shown in equation 5 is the notion that naturally occurring N—N bond products are likely to involve the condensation of HA and an amine to yield a hydrazine that is subsequently transformed to an azoxy moiety such as that occurring in valanimycin. 

Figure 9-4. Metabolism of the branched-chain amino acids. The first two reactions, transamination and oxidative decarboxylation, are catalyzed by the same enzyme in all cases. Details are provided only for isoleucine. Further metabolism of isoleucine and valine follows a common pathway to propionyl CoA. Subsequent steps in the leucine degradative pathway diverge to yield acetoacetate. An intermediate in the pathway is 3-hydroxy-3-methylglutaryl CoA (HMG-CoA), which is a precursor for cytosolic cholesterol biosynthesis.

Branched Chain Amino Acid Biosynthesis. The branched chain amino acids, leucine, isoleucine and valine, are produced by similar biosynthetic pathways (Figure 2.11). In one pathway, acetolactate is produced from pyruvate and in the other acetohydroxybutyrate is produced from threonine. Both reactions are catalysed by the same enzyme that is known as both acetolactate synthase (ALS) and acetohy-droxy acid synthase (AHAS). 

FIGURE 22-15 Biosynthesis of six essential amino acids from oxalo-acetate and pyruvate in bacteria methionine, threonine, lysine, isoleucine, valine, and leucine. Here, and in other multistep pathways, the enzymes are listed in the key. Note that L,L-a,e-diaminopimelate, the product of step (HI), is symmetric. The carbons derived from pyruvate (and the amino group derived from glutamate) are not traced beyond this point, because subsequent reactions may place them at either end of the lysine molecule. 

Examples biosynthesis of leucine and valine, xylose isomerase, glyoxalase)... 

Reaction type 6C (Table 10-1) occurs during the biosynthesis of leucine and valine (Fig. 24-17). The rearrangement is often compared with the nonenzy-matic acid-catalyzed pinacol-pinacolone rearrangement in which a similar shift of an alkyl group takes place (Eq. 13-57). The enzyme-catalyzed rearrangement... 

Figure 24-17 Biosynthesis of leucine, isoleucine, valine, and coenzyme A.

Isoleucine and Valine Biosynthesis Share Four Enzymes... 

The first step in valine biosynthesis is a condensation between pyruvate and active acetaldehyde (probably hy-droxyethyl thiamine pyrophosphate) to yield a-acetolactate. The enzyme acetohydroxy acid synthase usually has a requirement for FAD, which, in contrast to most flavopro-teins, is rather loosely bound to the protein. The very same enzyme transfers the acetaldehyde group to a-ketobutyrate to yield a-aceto-a-hydroxybutyrate, an isoleucine precursor. Unlike pyruvate, the a-ketobutyrate is not a key intermediate of the central metabolic routes rather it is produced for a highly specific purpose by the action of a deaminase on L-threonine as shown in figure 21.10. 

The biosynthesis of isoleucine and valine. The reactions leading to valine are catalyzed by the same enzymes that catalyze the corresponding reactions in isoleucine biosynthesis. Common enzymes are screened in yellow. 

Presumably the availability of valine inhibited an enzyme, such as acetohydroxy acid synthase, in the early stages of valine, isoleucine and leucine biosynthesis. 

As a side activity, many decarboxylases catalyze the formation of C-C bonds. In the reaction of two pyruvate molecules, catalyzed by pyruvate decarboxylase (PDC, E.C. 4.1.1.1), a-acetolactate is formed, an important intermediate of valine biosynthesis. In turn, a-acetolactale can be oxidatively decarboxylated by oxygen to diacetyl or enzymatically decarboxylated by acetolactate decarboxylase (ADC, E.C. 4.1.1.5) to (] )-acetoin (Figure 7.29). 

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