D-Hydroxyisovaleric acid

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...

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. ... 

Amidomycin, C,BHtllN,t011 mol wt 796,98. C 60.28%, H 8.60%, N 7.03%, O 24,09%. Antibiotic substance produced by an unidentified Streptomyces culture (PRL 1642). Composed of 4 moles each of D-(—)-valine and D-(—)- -hydroxyisovaleric acid, linked alternately by ester and amide bonds to form a 24-membered ring Vining. 

Fig. 1 Chemical structure of valinomycin (left). D-Val and L-Val are the D- and L-enantiomers of valine. D-Hyi is D-hydroxyisovaleric acid, and L-Lac is L-lactic acid. A solid-state structure of the potassium complex is shown on the right. (View this art in color at...

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... 

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. 

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. 

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.]... 

The enniatins are composed of three N-methyl-L-amino acid residues linked in an alternating fashion with three residues of D-2-hydroxyisovaleric acid to form an 18-membered cyclic structure 1, in which the R groups may be Pr, Bus, or Bu1. They are usually isolated as complexes which may contain enniatin A (1 R1=R2=R3=Bus),... 

Acid hydrolysis of the crystallized enniatin complex supported the spectroscopic data, affording as expected, D-2-hydroxyisovaleric acid and a mixture of N-methylisoleucine, N-methylleucine, and N-methylvaline, in which N-methylisoleucine was the predominant amino acid, and the other two were minor products. 

Formic acid Propionic acid D-dt-hydroxyisovaleric acid a-n-hexyl-/S,y-dihydroxypentanoic acid... 

Fig. 3.22. GC separation of keto and hydroxy acids from the urine of a patient with maple syrup urine disease. Top chromatogram, the patient before dietary treatment middle chromatogram, the same patient after two days on a diet bottom chromatogram, a mixture of reference compounds. Peaks 1, lactic acid 2, 2-hydroxyisobutyric acid 3, 2-hydroxybutyric acid 4, pyruvic acid 5, 3-hydroxyisobutyric acid 6, 3-hydroxybutyric acid 7, 2-hydroxyisovaleric acid 8, 2-ketobutyric acid 9, malonic acid (internal standard) 10, 2-methyl-3-hydroxybutyric acid 11, 2-hydroxy-n-valeric acid 12. methylmalonic acid 13, 3-hydroxyisovaleric acid 14a and b, 2-ketoisovaleric acid IS, acetoacetic add 16, 2-hydroxyisocaproic acid 17, 2-hydroxy-3-methylvaleric acid 18a, L-2-keto-3-methylvaleric add 18b, D-2-keto-3-methyl-valeric acid 19, 2-ketoisocaproic acid. Reproduced from [386],...

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. 

D Hydroxy acids, like D-2-hydroxyisovaleric acid, the corresponding building unit of peptolide SDZ 214-103, and D-lactic acid, the isosteric compound to D-Ala, are not incorporated into position 8 by cyclosporin synthetase (62). Thus, cyclosporin synthetase is not capable of introducing an ester linkage between positions 7 and 8, as does pep-toiide SDZ 214-103 synthetase. 

AIB aminoisobutyric acid DAB (x,y-diaminobutyric acid DAP diaminopropionic acid DHA 2,6-diamino-7-hydroxyazelaic acid HIV D-2-hydroxyisovaleric acid ISER isoserine LAC L-lactic acid MO A 6-methyloctane acid (isopelargonic acid) MVAL iV-methyl-L-valine SP spermidine BTYR / -tyrosine mod, modified... 

VaUnomycin, 1, is obtained from Streptomyces fulvis-simus and several other Streptomyces strains and is made np of D- and L-valine (Val), o-hydroxyisovaleric acid (Hyv). 

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 . 

---