2- Hydroxyisovaleric acid/2-Hydroxyisovalerate

Hydroxy-3-methylbutyric (a-hydroxyisovaleric) acid [600-37-3] M 118.1, m 86°, pK, -3.9. Crystd from ether/pentane. 

Other cyclic tetrapeptides have also been isolated by Japanese workers and AM toxins I, II, and III, isolated from Alternaria mail., are extremely toxic to certain plant species (9.10). These are constructed of L- i-hydroxyisovaleric acid, L-alanine, c-amino-acrylic acid and, in AM toxin I, L-6(-amino- -( .-methoxyphenyl)-valeric acid. The phenyl residue in AM toxin II is L-t(-amino-S-phenylvaleric acid, while in AM toxin III, it is L-ol-amino-( .-hydroxyphenyl)valeric acid (Figure 2), All the AM toxins produce leaf spot, or necrosis, in apple but as might he expected slight change in substitution (R-group) on the phenyl ring radically alters the specific activity of the molecule. Both AM toxin I and III induce interveinal necrosis in the "Indo" apple cultivar, which is also highly susceptible to A. mail. at concentrations as low as 0.1 pph within 18 h after treatment. In contrast, the resistant apple cultivar "Jonathan" is only affected by 1 ppm of AM toxin I and 10 ppm of AM toxin III. 

An example of an ionophore that is a cage carrier is valinomycin (9.56). This cyclic peptide lactone consists of three molecules each of L-valine, D-a-hydroxyisovaleric acid, and L-lactate. The six highly polarized lactone carbonyl oxygens line the inside of the ring, whereas the nonpolar alkyl groups point to the outside of the molecule. Thus... 

To elucidate the role of one of the two carboxyl groups of TA in the adsorbed state on the catalyst, a study was conducted on the effect of the cation which was used for the pH adjustment of the modifying solution on the EDA of MRNi (29). As shown in Fig. 23, the EDA of TA-MRNi was strongly affected by the kind of cation used, and sodium was found to be the most favorable one, although the EDA of (S)-2-hydroxyisovaleric acid-MRNi was not affected, as shown in Table XXII. From this finding it can be deduced that one of the carboxyl groups of TA participates in the adsorption, while the other must exist as a carboxyl anion and that the counter cation must be present near the carboxyl ion. 

Enniatins belong to the class of A-mcthylatcd cyclopeptides which are produced by various strains of the genus Fusarium [12], As shown in Figure 1, enniatins consist of alternating residues of D-2-hydroxyisovaleric acid (D-Hiv) and a branched chain A-methyl-L-amino acid, linked by peptide and ester bonds. In the case of beauvericin the branched chain L-amino acid is substituted by L-phenylalanine (Fig. 1). 

Figure 2 Order and organization of enniatin synthetase and cyclosporin synthetase as deduced from gene sequence and biochemical characterization. Symbols in the adenylateforming modules (black boxes) indicate the corresponding activated amino acids. M stands for A -methyltransferase domain. Condensation domains are represented by white boxes. (A) Top Structure of enniatin synthetase. EA represents the D-Hiv-activating module EB represents the L-valine-activating module D-Ehv is D-2-hydroxyisovaleric acid. Bottom Structural features of the wild-type A -methyltransferase domain M of esynl. The black boxes indicate conserved motifs which can be found within methyltransferases and A -methyltransferase domains of peptide synthetases (see also Fig. 3). The numbers indicate the amino acid position in the sequence of Esyn. (B) Structure of cyclosporin synthetase. Abu = L-a-aminobutyric acid Bmt = (4A)-4-[(E)-2-butenyl]-4-methyl-L-threonine.

The cyclic depsipeptides destruxin C and D 103 and bassianolid 104 23I), which contain a-hydroxyisovaleric acid, N-methylvaline, or N-methylleucine, act as insecticides. 

Figure 20.20 Pathways of branched-chain amino acid metabolism. A, B, C, D, E, and F indicate defects in valinemia, maple syrup urine disease, isovaleric acidemia, /3-hydroxyisovaleric aciduria, a-methyl-j3-hydroxybutyric aciduria, and methylmalonic aciduria, respectively.

Urinary organic acid analysis is useful for differentiating isolated carboxylase deficiencies from the biotin-responsive multiple carboxylase deficiencies. P-Hydroxyisovalerate is the most common urinary metabolite observed in isolated P-methylcrotonyl-CoA carboxylase deficiency, biotinidase deficiency, biotin holo-carboxylase synthetase deficiency, and acquired biotin deficiency. In addition to P-hydroxy-isovalerate, elevated concentrations of urinary lactate, methylcitrate, and P-hydroxypropionate are indicative of multiple carboxylase deficiency. 

Figure 3-3 Structures of the K+ salts of (a) [p-hydroxyisovaleric acid-/V-methyl-L-valine]3 or enniatin B and (b) nonactin.

Holocarboxylase synthetase deficiency can be diagnosed prenatally by assessing the response of carboxylase activity in cultured amniocytes (obtained by amniocentesis) to the addition of biotin, or by the detection of methylcitric and hydroxyisovaleric acids in the amniotic fluid. Prenatal therapy, by giving the mother 10 mg of biotin per day, results in sufficiently elevated fetal blood concentrations of biotin to prevent the development of organic acidemia at birth. 

Mock NI, Malik MI, Stumbo PJ, Bishop WP, and Mock DM (1997) Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased biotin status in experimental biotin deficiency. American Journal of Clinical Nutrition 65, 951-8. 

A halo acid, p-(/S-bromoethyl)-benzoic acid (87%), a hydroxy acid, yS-hydroxyisovaleric acid (9%), and an acetylated amino acid, p-(/3-acetyl-aminoethyl)4>enzoic acid (78%), have been made by this method. Attempts to prepare 3-nitro- and 4-hydroxy-benzoic acids from the corresponding acetophenones have failed. Oxidation of the methylene group of 2-acetylfluorene occurs during the reaction to give fluorenone-2-car-boxylic acid (60%). ... 

Fig. 10. Structures of nonribosomally synthesized peptides of bacterial origin (1-6) and fungal origin (7-9). Me, N-methylated peptide boni Orn, ornithine 4-MHA, 4-methyl-3-hydroxyanthranilic acid Aad, aminoadipic acid Aeo, 2-amino-9,10-epoxy-8-oxodecanoic acid D-Hiv, D-hydroxyisovaleric acid Bmt, (4i )-4-[( )-2-butenyl]-4-methyl-L-threonine Abu, a-aminoisobutyric acid Sar, sarcosine. The boxes signify gene products for peptide synthetases composed of modules which activate and process the indicated amino acids...

Silyl ethers of hydroxy amino acids have been employed in both solid-phase and solution peptide synthesis. Since the TBDMS and TBDPS ether groups are stable to piperidine and other basic reagents, these derivatives of Ser and Thr (Tables 8 and 9) can be used in the Fmoc strategy.Homodetic peptides and depsipeptides have also been synthesized using TBDMS hydroxy protection for phenyllactic acid and hydroxyisovaleric acid, respectively. 

The use of unprotected a-hydroxy acids may also be compatible with the preparation of depsipeptides. However, attempts to couple L-a-hydroxyisovaleric acid and benzyl phenyl-alaninate using TBTU resulted in the formation of considerable amounts of the hy-droxycarbamoylated compound,in contrast to the smooth reaction mediated by PyBOP. Transfer of the dimethylcarbamoyl moiety of uroniuno/guanidinium salts appears to be restricted to a-hydroxy acids and has not been observed in coupling reactions between Fmoc-Ser-OH, Fmoc-Thr-OH, or L-3-hydroxybutyric acid and H-Phe-OBzl in the presence of TBTU/NMM in... 

Valinomycin is a depsipeptide which contains ester linkages as well as amide linkages. The antibiotic is made up of d- and L-valine, L-lactic acid, and D-hydroxyisovaleric acid. When incorporated info an artificial membrane bathed in a K+-containing medium, valinomycin increases the conductance greatly and when it is added to a suspension of Streptococcus faecalis cells the high ratio of [K+]j / [K ] falls rapidly. The loss of K+ from cells probably explains fhe antibiotic activify. However, under suitable conditions, with a high external [K ], the bacteria will continue to grow and reproduce in the presence of the antibiotic. ... 

Valinomycin is a cyclic structure containing three molecules of L-valine, three molecules of D-valine, three molecules of L-lactic acid, and three molecules of D-hydroxyisovalerate. These four components are linked in an ordered fashion such that there is an alternating sequence of ester and amide Unking bonds around the cyclic structure. This is achieved by the presence of a lactic or hydroxyvaleric acid unit between each of the six vahne units. Further ordering can be observed by noting that the L and D portions of valine alternate around the cycle, as do the lactate and hydroxyisovalerate units. 

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