A-Hydroxy-isovaleric acid

Fig. 8. Stmcture of (a) valinomycin and (J3) and enniatins and beauvericin. Hov = a-hydroxy-isovaleric acid and Lac = lactic acid. The /V-methylamino acid for enniatin A is isoleucine enniatin B, valine enniatin C, leucine and beauvericin, phenylalanine.

The carbodiimide method has been employed in several syntheses of depsipeptides. However, direct application of DCC for the formation of the ester bond between the amino acid and hydroxy acid components under the usual conditions of amide coupling affords the desired depsipeptides in acceptable yields only in the case of unhindered co-hydroxy units [54] or an active hydroxy group, such as in TV-benzoyl-u-hydroxyglycine benzyl ester. For example, Ravdel et al.[55 have performed the esterification of various benzyloxycarbonyl- and phthalylamino acids with /V-benzoyl-a-hydroxyglycine benzyl ester with DCC in 50-65% yield. On the other hand, Shemyakin et all21 failed to obtain the expected depsipeptide products on condensation of bulky benzyloxycarbonyl- or phthalylvaline with a-hydroxy-isovaleric acid benzyl ester. The main product was acylurea in the first case and phthalylvaline anhydride in the second. Thus, the classical carbodiimide procedure could not be applied in practical depsipeptide preparation. 

Diazonamide A is a potently antimitotic natural product and its penultimate step involves the coupling of macrocyclic amine 104 with (5)-a-hydroxy isovaleric acid and DEPC in 90% yield.46-41... 

Several fungal metabolites have been found which enhance the passive uptake of potassium. Some, like nonactin and monactin 14.6), are macro-tetrolides others, like valinomycin, are depsipeptides. Valinomycin 14.7) (from Streptomycesfulvissimus) is a macrocycle composed of three residues of each of L-valine, D-valine, L-lactic acid, and D-a-hydroxy-isovaleric acid, linked alternatively by ester and amide bonds to form a 36-membered ring (Shemyakin... 

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. 

Biotin deficiency in experimental animals is teratogenic, and a number of the resultant birth defects resemble human birth defects. Up to half of pregnant women have elevated excretion of 3-hydroxy-isovaleric acid (Section 11.4), which responds to supplements of biotin, in the first trimester, suggesting that marginal stams may be common in early pregnancy and may be a factor in the etiology of some birth defects. This may be the result of increased catabolism of biotin as a result of steroid induction of biotin catabolic enzymes there is increased excretion of bisnorbiotin and biotin sulfoxide (Zempleni and Mock, 2000a Mock et al., 2002). 

Onchidin is cyclo(Meval-Amo-Val-Hiv-Hiv-MevabAmo-VabHiv-Hiv). It is the first example of a dimeric depsipeptide isolated from a mollusk. Meval is N-methylvaline and Hiv is 2-hydroxy-isovaleric acid. 

Further enzymological studies on the condition have been provided by Bartlett et al. (1980), who described a 4-year-old girl with mild metabolic acidosis and who excreted grossly increased concentrations of 3-hydroxy-isovaleric acid and 3-methylcrotonylglycine in her urine. She was responsive to biotin therapy (oral, 5 mg day ) and studies on her cultured skin fibroblasts showed deficient activities of propionyl-CoA carboxylase and of 3-methyl-crotonyl-CoA carboxylase. Studies in vivo showed that the latter enzyme was stimulated by biotin supplementation of the medium to a much greater degree than the other mitochondrial carboxylase enzymes. 

Tanaka, K., Orr, J.C. and Isselbacher, K.J. (1968), Identification of j8-hydroxy-isovaleric acid in the urine of a patient with isovaleric acidemia. Biochim. Biophys. Acta, 152, 638. 

Metabolism of the 2,S -isomers proceeds sequentially hydroxylation at the phenoxy group, hydrolysis of the cyano group, and cleavage of the ester linkage (Coats et al. 1989). Fenvalerate and the IS-isomers yield two ester metabolites in feces from hydroxylation at the 4 - and 2 -phenoxy positions. Other significant metabolites were 3-phenoxybenzoic acid and its hydroxy derivatives from the alcohol moiety, 3-(4-chlorophenyl) isovaleric acid and its hydroxy derivatives from the acid moiety, and thiocyanate and carbon dioxide from the cyano moiety (Ohkawa et al. 1979). A slow elimination rate characterizes fenvalerate and other a-cyano pyrethroids when compared with... 

The kutzneride cluster encodes three multidomain NRPS proteins, KtzE, KtzG, and KtzH, that make up the six required modules. KtzE activates o-MecPG and catalyzes its condensation with the hydroxy acid, which is activated by the A domain of KtzG. KtzG adenylates 2-keto-isovaleric acid and, after in situ reduction of the keto function by the KR domain, a methyltransferase forms the t-butyl group. Whether the... 

Isolated from the species Lyngbya semiplena collected at a shallow depth (1-3 m) in Wewak Bay, Papua New Guinea, the wewakpeptins A-D are cytotoxic depsipeptides which contain many nonribosomal amino acids such as 2,2-dimethyl-3-hydroxy-octanoic acid (Dhoaa) and 2,2-dimethyl-3-hydroxy-octynoic (Dhoya), as well as N-methy-lated amino adds such as N-methylvahne and N-methyl-alanine. A second lactone implies 2-hydroxy-isovaleric add (Hiva) for wewakpeptins A and B, and phenyllactic add (Pla) for wewakpeptins C and D. Wewakpeptins A and B are approximately tenfold more cytotoxic towards the lung cancer NCI-H460 than are wewakpeptins C and D (Han et al, 2005b). 

Fig. 10.1 Metabolites in the urine of an untreated patient with branched-chain keto aciduria (maple syrup urine disease). Extracted using ethyl acetate and separated as their trimethylsilyl-oxime derivatives on a 25 m SE-30 capillary column, using temperature programming from 80°C to 110°C at 0.5°C min and an injection split ratio 1 12 at a temperature of 250°C. The peaks marked R are due to solvent and reagents. Peak identifications are 1, lactic 2, 2-hydroxyisobutyric 3, 2-hydroxybutyric 4, pyruvic 5, 3-hydroxybutyric 6, 2-hydroxyisovaleric 7, 2-oxobutyric 8, 2-methyl-3-hydroxy-isovaleric 10, a and b, 2-oxoisovaleric 11, acetoacetic 12, 2-hydroxyisocaproic 13, 2-hydroxy-3-methyl- -valeric 14, 2-oxo-3-methyl-/i-valeric (14a L- 14b D-) 15, 2-oxoisocaproic acids. The internal standard was malonic acid. (Redrawn with modifications from Jellum etal., 1976)...

Fig. 3.2.5 Profiles of acylcarnitines as their butyl esters in plasma (precursor of m/z 85 scan) of a normal control (a) and patients with various organic acidemias. Propionylcarnitine (C> m/z 274 peak 3) is the primary marker for both propionic acidemia (b) and methylmalonic acidemias (c). Note that an elevation of methylmalonylcarnitine (C4-UC m/z 374) is not typically found in patients with methylmalonic acidemias. In the three cases of ethylmalonic encephalopathy (d) analyzed in our laboratory, elevations of ,- (m/z 288 peak 4) and C5-acylcarnitine (m/z 302 peak 5) species were noted. Isolated C5-acylcarnitine elevations are encountered in patients with isovaleric acidemia (e), where it represents isovalerylcarnitine. Cs-Acylcarnitine is also elevated in patients with short/branched chain acyl-CoA dehydrogenase deficiency, where it represents 2-methylbutyrylcarnitine (see Fig. 3.2.4), and in patients treated with antibiotics that contain pivalic acid, where it represents pivaloylcarnitine [20, 59, 60]. Patients with /3-ketothio-lase deficiency (f) present with elevations of tiglylcarnitine (C5 i m/z 300 peak 6) and C5-OH acylcarnitine (m/z 318 peak 7). In most cases of 3-methylcrotonyl-CoA carboxylase deficiency (g) Cs-OH acylcarnitine is the only abnormal acylcarnitine species present. The differential diagnosis of C5-OH acylcarnitine elevations includes eight different conditions (Table 3.2.1). Also note that C5-OH acylcarnitine represents 3-hydroxy isovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase deficiency (g), and 2-methyl 3-hydroxy butyrylcarnitine in / -ketothiolase deficiency...

Ethyl sorbate Ethyl undecanoate Ethyl vanillin Formic acid Furfuryl thioacetate Geranium maculatum oil a-D-Glucose pentaacetate Guaiol acetate Heptyl crotonate Heptyl isobutyrate Heptyl valerate Hexanal propylene glycol acetal cis-3-Hexenyl anthranilate cis-3-Hexenyl benzoate cis-3-Hexenyl crotonate cis-3-Hexenyl hexanoate 3-Hexenyl isovalerate cis-3-Hexenyl phenylacetate cis-3-Hexenyl senecioate Hexenyl-cis-3-valerate Hexyl alcohol Hexyl 2-furoate Hexyl lactate Hexyl nicotinate Hexyl phenylacetate Hexyl valerate Hydroxycitronellal residue Hydroxylamine sulfate 5-Hydroxy-4-octanone y-lonone... 

The roots of Echinacea angustifolia usually contain only ca. 0.1% essential oil [5, 14, 15]. Bischoff [16], who reported an essential oil content of 1.25-1.5%, must have used the roots of . pallida for his studies. The main components of the essential oil of . angustifolia are compounds such as dodeca-2,4-diene-l-yl-isovalerate, as well as palmitic and linoleic acids [14]. One other major constituent (44% of the oil) has been identified as pentadeca-l,8Z-diene, a minor one as 1-pentadecene [17]. A further volatile compound, ( )-10-hydroxy-4,10-dimethyl-4,ll-dodecadiene-2-one ( Echinolon ), published as a constituent of "Echinacea angustifolia roots [18], is probably from the adulterant . pallida. Pentadeca-8Z-en-2-one, already reported by Schulte et al. [19] as a major constituent of "Echinacea angustifolia"", is presumably derived from . pallida, since Heinzer et al. [14] found it as one of the main components only in the root oil of . pallida. It is also very probable that this compound is identical with the substance reported by Verelis [20] as geranyl-isobutyrate, because Heinzer et al. [14] failed to detect geranyl-isobutyrate... 

Inhibition of these enzymes is achieved with various diazoacetylamino acid esters, which apparently react with carboxyl groups on the active site, and with pepstatin. The latter is isolated from various Streptomycetes as a peptide mixture with the general formula (R isovaleric or n-caproic acid AHMHA 4-amino-3-hydroxy-6-methyl heptanoic acid) ... 

Important components of hard cheeses (Gouda type) include some carboxylic acid esters (ethyl butanoate, ethyl hexanoate), as well as carboxylic acids (acetic, butyric, isobutyric, valeric, isovaleric, 2-methylbutyric and caproic acids). Cheeses manufactured using bacteria of the genus Propionibacterium (such as Emmental and Gruyere) contain propionic acid and other lower fatty acids, methyl thioacetate, some oxocarboxylic acids, various alcohols, esters (such as ethyl butanoate), lactones (such as 8-decalactone), amines and other basic compounds (also skatole in addition to aliphatic amines), alkylpyrazines (e.g. 2-sec-butyl-3-methoxypyrazine), 4-hydroxy-2,5-dimethyl-2H-furan-3-one (furaneol), 2-ethyl-4-hydroxy-5-methyl-2H-furan-3-one (homofuraneol) and a range of other compounds. 

Brucein A (49a), B (50) and C (51), isolated in 1967 from Brucea amarissima, were the first C-15 esters of bruceolide (48) to have their structures determined 82). These quassinoids differ in the nature of the ester group at C-15. They are esters of isovaleric, acetic and 3,4-dimethyl-4-hydroxy-2-pentenoic acid, respectively. 

---