Valine pathway

Capsaicin is a bioactive molecule synthesized by enzymatic (putative capsaicin synthase) condensation of vanillylamine, a phenyl propanoid intermediate with 8-methyl-nonenoic acid, a fatty acid derivative from the leucine/valine pathway. Analysis of levels of 8-methyl-nonenoic acid and phenyl propanoid intermediates in high-, medium- and low-pungent Capsicum genotypes revealed that the 8-methyl-nonenoic acid pool plays a crucial role in determining the efficacy of capsaicin levels. Cerulenin-mediated inhibition of 8-methyl-nonenoic... 

The branched-chain amino adds (BCAAs) are leucine, isoleucLne, and valine. Pathways for the breakdown cif leucine and isoleudnc appear in Figures 8,5 and... 

Demain A.L., Jackson M. and Trenner N.R. (1967) Thiamine-dependent accumulation of tetramethylpyrazine accompanying a mutation in the isoleucine-valine pathway. J. Bacteriol. 94, 323-6. 

In leucine biosynthesis, the intermediate 218 on the valine pathway reacts with acetyl-CoA to yield a-isopropylmalate 225 whose configuration has been shown to be S by X-ray crystallography (200). This reaction is analogous to that catalyzed by citrate synthase, and indeed the subsequent reaction, dehydration/rehydration giving ) -isopropylmalate 226, is analogous to the conversion of citrate to isocitrate. The configuration of / -isopropylmalate 226 had been shown to be 2i ,3S (201), and so the stereochemistry of the citrate and isopropylmalate reactions was identical. j -Isopropylmalate 226 was finally converted to leucine 205 by a 4-pro-R NADH specific dehydrogenase (EC 1.1.1.85) (202) and transamination (Scheme 61). 

Fig. 9. Postulated pathway of tetramethylpyrazine formation in a mutant of C. glutamicum blocked in the isoleucine-valine pathway. The actual oizyme deficiency is not known but presumed to be the leductoisomerase...

If the chromosomal ilv fragment was derived from the K-12 strain of E, coli, it would have to contain an ilvO mutation so that ilvG would be expressed. See Figure 1.) Such a plasmid would be even more effective if the Inserted DNA carried an ilvA lesion, l.e., was threonine deaminase negative. Overproduction of valine would be expected, since the valine pathway derives its carbon exclusively from a key intermediate in the central metabolic route, pyruvate. Flow into the pathway would then never be restricted as long as ample carbon source was present. 

An example of the second type (b) is the mutation leading to loss of the keto-acid reductoisomerase (EC 1.1.1.86) in the parallel pathways leading to valine and isoleucine. This enzyme catalyses an isomerization coupled to a reduction, producing 2,3-dihy-droxyisovalerate in the valine pathway, or 2,3-dihy-droxy-3-methylvalerate in the leucine pathway. A single mutation of the gene for this enzyme produces val /ile doubly auxotrophic organisms. 

In the metabolism of L-leucine, the isovaleryl-CoA produced by the oxidative decarboxylation step is further metabolized by a series of enzyme-catalysed steps to acetoacetate and acetyl-CoA and thence into the tricarboxylic acid cycle. Specific enzyme deficiencies at every stage of this metabolic pathway are known and are described in Section 10.3. In contrast, only one disorder of L-isoleucine metabolism subsequent to the oxidative decarboxylation step has been recognized (Section 10.4), and no disorders of the L-valine pathway from isobutyryl-CoA have been described. This may be due to their relative rarity but possibly also to greater difficulty in their detection. The metabolism of valine and leucine is, however, of particular interest in the organic acidurias, since both are major precursors of propionyl-CoA and methylmalonyl-CoA, defects in the metabolism of which lead to propionic acidaemia and methylmalonic aciduria (Chapter 11). 

Herbicides also inhibit 5- (9/-pymvylshikiniate synthase, a susceptible en2yme in the pathway to the aromatic amino acids, phenylalanine, tyrosine and tryptophan, and to the phenylpropanes. Acetolactate synthase, or acetohydroxy acid synthase, a key en2yme in the synthesis of the branched-chain amino acids isoleucine and valine, is also sensitive to some herbicides. Glyphosate (26), the sulfonylureas (136), and the imida2oles (137) all inhibit specific en2ymes in amino acid synthesis pathways. 

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

Penicillins and cephalosporins are products of biosynthetic pathways that have many identical enzymatic steps. It is generally accepted that the tripeptide, 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine (LLD-ACV), is the direct precursor to both penicillin and cephalosporin C. 

Similar methodology has been applied in the syntheses of 2-amino-3-hydroxycarboxylic acids in high diastereomeric and enantiomeric purity. Two separate pathways give either the antt- or. WM-products. The first strategy relies on haloacetate precursors derived either from (S )-valine 17"- oi or from norephedrine 18102, which are converted into the boron enolates103 and subsequently reacted with aldehydes to deliver. ym-adducts99 102. The diastereomeric ratio, defined as the ratio of the desired diastereomer/the sum of all others, is 50 1 for the former and about 95 5 for the latter adducts. 

Interest in JAK2 inhibitors for the treatment of MPN was bolstered by the discovery of a point mutation in JAK2 at position 617 (valine to phenylalanine, V617F) in the majority of patients with MPN [2,3]. This mutation occurs in the JH2 pseudokinase domain and relieves an autoinhibitory function of this domain, constitutively activating the catalytic function of the kinase via a cytokine-independent mechanism. Although this is the predominant mutation in the disease, additional mutations in the enzyme, its receptor, or within other levels of the network have also been identified that result in JAK2-STAT pathway activation [5-9] (Figure 1). 

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... 

Valine A branched-chain essential amino add that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]... 

Valine, methionine, isoleucine, and threonine are all metabolized through the propionic acid pathway (also used for odd-carbon fatty acids). Defidency of either enzyme results in neonatal ketoacidosis from failure to metabolize ketoacids produced from these four amino adds. The defidendes may be distinguished based on whether meth)dmalonic adduria is present. A diet low in protein or a semisynthetic diet with low amounts of valine, methionine, isoleudne, and threonine is used to treat both deficiencies. 

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. 

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.

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