A-Hydroxyisovaleric acid

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

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... 

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. 

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... 

Structure of valinomycin (a) and its complex with K" " (b). Valinomycin, which consists of three identical fragments of D-valyl-L-lactyl-L-valyl-D-a-hydroxyisovaleric acid (D-Val-L-Lac-L-Val-D-Hyi), is a mobile or channel-forming ionophore and an uncoupler of oxidative phosphorylation. Note the hydrophobic exterior and the hydrophilic interior of the complex. [Structure (b) is reproduced, with permission, from B. C. Pressman Biological application of ionophores. Amu. Rev. Biochem. 45,501 (1976). 1976 by Annual Reviews Inc.]... 

Fukuda and coworkers have described one of the first applications of the enantioselective hydrolysis of nitriles (Scheme 12.1-6). Using a whole cell biocatalyst optically pure a-hydroxy acids (L-a-hydroxyisovaleric acid and L-a-hydroxyisocaproic acid) have been prepared from the racemates of the corresponding a-hydroxyni-... 

Enniatin family, cyclic depsipeptides produced by strains of Fusarium. Members are enniatin A, cyclo-(-D-Hiv-Me-Ile-)3, enniatin B, cyclo-(-D-Hiv-MeVal-)3, and enniatin C, cyclo-(-D-Hiv-MeLeu-)3, enniatin D, cyclo-(-D-Hiv-MeLeu-D-Hiv-MeVal-D-Hyv-MeVal-), enniatin E, cyclo-(-D-Hiv-MelLe-D-Hiv-MeLeu-D-Hiv-MeVal-), and enniatin F, cyclo-(-D-Hiv-MeLeu-MeIle-D-Hiv-Melle-) which all contain D-a-hydroxyisovaleric acid (o-Hiv) besides various L-methylamino acids. Enniatins act as ionophores to form complexes with K+ ions which allow their transport across membranes. 

In 1955, H. Brockmann and Schmidt-Kastner [15] isolated an antibiotic substance from extracts of Streptomyces fulvissimus. They named it valinomycin after valine having been found as the only amino acid in the acid-hydrolyzate. Since no amino group nor carboxyl group could be detected in the substance which was almost insoluble in water, a cyclic structure had to be assumed. Valinomycin has a macrocyclic molecular structure consisting of three identical tetradepsipeptide fragments with alternating peptide and ester bonds between D-a-hydroxyisovaleric acid, D-valine, L-lactic add, L-valyl residues (Fig. 10). 

A soln. of D-valyl-D-a-hydroxyisovaleryl-D-valyl-D-a-hydroxyisovaleric acid in aq. 50%-alcohol refluxed 20 hrs. D-a-hydroxyisovaleryl-D-valyl-D-a-hydroxy-isovaleric acid. Y 69%. F. e. s. M. M. Shemyakin et al., 34, 1782 (1964) G. A. 61, 10774d. 

Abbreviations AcAib, acetyl aminoisobutyric acid pheol, phenyl-alaninol Lac, L-lactic acid D-HIV, D- a - hydroxyisovaleric acid L-MeVal, N-methyl-L-valine Me, methyl. 

It was interesting in the case of valinomycin, that addition of unlabelled a-ketoisovalerate to protoplasts of Streptomyces tsusi-maensis reduced the incorporation of "4c-valine into valinomycin. We suppose that a-ketoisovalerate serves as the precursor of valine as has been established for other organisms. However, more experiments will be required to prove that a-ketoisovalerate is also the precursor of D-a-hydroxyisovaleric acid. 

Sporidesmolides cyclic depsipeptides om the fungus Pithomyces charumtm. Sporidesmolide I is c -clo-(-Hyv-D-Val-D-Leu-Hyv-Val-MeLeu-) sporidesmolide II contains D-allo-isoleucine in place of D-va-line, while sporidesmolide III contains L-leucine in place of L-Al-methylleucine. (Hyv represents a residue of a-hydroxyisovaleric acid). 

Valinomycin cyclo-(-D-Val-Lac-Val-D-Hyv-)j, an antibiotic, cyclic depsipeptide, especially active against Mycobacterium tuberculosis. In addition to valine, it contains the heterocomponents, L-lactic acid (Lac) and n-a-hydroxyisovaleric acid (o-Hyv). It is an lonophore (see), which selectively transports potassium ions across membranes. 

Amidomycin contains 4 residues of D-a-hydroxyisovaleric acid and 4 of D-valine while valinomycin contains 2 units of D-a-hydroxyisovaleryl-D-valine and 2 of L-lactyl-L-valine . 

A soln. of N-nitroso-N-methyl-L-isoleucyl-D-a-hydroxyisovaleric acid in abs. ether stirred 20 min. at 0° with PCI5, filtered, evaporated in vacuo at 30°, the residue dissolved in abs. ether, added dropwise with vigorous stirring at —10° during 15 min. to a soln. of p-nitrobenzyl N-methyl-L-isoleucyl-D-a-hydroxyiso-valerate and triethylamine in abs. ether, allowed to warm to room temp., and the product isolated after 2 hrs. p-nitrobenzyl N-nitroso-N-methyl-L-isoleucyl-D-a-hydroxyisovaleryl-N-methyl-L-isoleucyl-D- -hydroxyisovalerate. Y 93%. F. e. s. P. Quitt, P. O. Studer, and K. Vogler, Helv. 47, 166 (1964). 

On can conclude that L-vahne was used efficiently as a precursor of the L-valyl and D-valyl parts of vahnomycin, and less efficiently as a precursor of the D-a-hydroxyisovaleryl portion of the molecule. MacDonald (i960) considered it unlikely that the D-a-hydroxyisovaleryl-D-valyl portions of the molecule were derived from D-valyl-D-vahne, for if such were the case one would expect the D-a-hydroxyisovaleric acid and D-vahne obtained on hydrolysis of vahnomycin to have the same specific activity. It is apparent that much more work will have to be done to explain how vahnomycin is synthesized from its components. 

Alternaramide is a cyclic depsipentapeptide isolated from Altemaria sp. collected on a shore line sediment in Masan Bay, Korea. The ester bond comes from a L-a-hydroxyisovaleric acid, and i-proline and two D-phenyl-alanines are present (Kim et al, 2009). 

Landaas, S. and Jakobs, C. (1977), The occurrence of a-hydroxyisovaleric acid in patients with lactic acidosis and ketoacidosis. Clin. Chim. Acta, 78,489. 

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