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PubMed1979

Synthesis of ceramides and cerebrosides containing both alpha-hydroxy and nonhydroxy fatty acids from lignoceroyl-CoA by rat brain microsomes.

The conversion of [1-14C]lignoceroyl-CoA to nonhydroxy- and alpha-hydroxyceramides and cerebrosides by brain microsomes of developing rat in the presence of NADPH was investigated. A new technique of thin layer chromatography for the separation of these lipids and unreacted substrate was developed for this assay. The synthesis of nonhydroxy- and hydroxyceramides was significantly stimulated by the addition of heat-stable factor, a factor which is essential in the alpha-hydroxylation of free lignoceric acid (I. Singh and Y. Kishimoto, manuscript in preparation). The addition of sphingosine also stimulated the ceramide synthesis to a great extent. When the microsomes or heat-stable factor were crude, the ceramides formed were further converted to cerebrosides, apparently by UDP-galactose contamination. The purification of these subcellular components resulted in the formation of only ceramides which, in turn, were converted to cerebrosides by the addition of UDP-galactose. These observations indicate that hydroxyceramide is the precursor of hydroxycerebroside and is formed by alpha-hydroxylation of lignoceroyl-CoA and N-acylation of sphingosine. However, lignoceroyl-CoA, like free lignoceric acid, does not appear to be the immediate substrate of the alpha-hydroxylation.

Acyl Coenzyme A↗
PubMed1994

Hepatic total 3 alpha-hydroxy bile acids concentration and enzyme activities in prednisone-treated dogs.

High serum alkaline phosphatase (ALP) activity is considered a sensitive marker of cholestasis in most mammalian species, including dogs. Induction of high serum ALP activity in association with cholestasis is dependent on high hepatic bile acids concentrations. Treatment of dogs with glucocorticoids also results in high serum ALP activity. The possible causal relation between serum ALP activity and bile acids concentration was investigated in dogs treated with glucocorticoids. The relation of glucocorticoid treatment to changes in the activity of individual ALP isoenzymes, alanine transaminase (ALT) and gamma-glutamyltransferase (GGT) also was investigated. Eight conditioned dogs were given 4 mg of prednisone/kg of body weight, i.m., daily for 10 days. Blood samples were taken prior to treatment and on treatment days 3, 5, 7, and 10. Liver tissue was then taken from each dog. Serum total ALP activity was significantly (P < 0.05) high at day 3 in prednisone-treated dogs. Isoenzyme analysis indicated that this increase was attributable to an increase in the liver ALP isoenzyme (LALP). Significant increases in serum corticosteroid-induced ALP (CALP) and bone ALP were first observed on days 7 and 10, respectively. Serum ALT and GGT activities were significantly increased by day 5. Increased serum or hepatic tissue bile acids concentrations were not observed in prednisone-treated dogs, compared with values in 8 clinically normal (control) dogs, but were high in 3 dogs with complete bile duct ligation. Hepatic activities of LALP, CALP, and GGT were higher in prednisone-treated dogs than values in controls, indicating probable increased hepatic synthesis of these enzymes. Hepatic ALT activity was not increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1998

Simultaneous analysis of plasma free fatty acids and their 3-hydroxy analogs in fatty acid beta-oxidation disorders.

We present a new derivatization procedure for the simultaneous gas chromatographic-mass spectrometric analysis of free fatty acids and 3-hydroxyfatty acids in plasma. Derivatization of target compounds involved trifluoroacetylation of hydroxyl groups and tert-butyldimethylsilylation of the carboxyl groups. This new derivatization procedure had the advantage of allowing the complete baseline separation of free fatty acids and 3-hydroxyfatty acids while the superior gas chromatographic and mass spectrometric properties of tert-butyldimethylsilyl derivatives remained unchanged, permitting a sensitive analysis of the target compounds. Thirty-nine plasma samples from control subjects and patients with known defects of mitochondrial fatty acid beta-oxidation were analyzed. A characteristic increase of long-chain 3-hydroxyfatty acids was observed for all of the long-chain 3-hydroxyacyl-CoA dehydrogenase-deficient and mitochondrial trifunctional protein-deficient plasma samples. For medium-chain acyl-CoA dehydrogenase deficiency and very-long-chain acyl-CoA dehydrogenase deficiency, decenoic and tetradecenoic acids, respectively, were the main abnormal fatty acids, whereas the multiple acyl-CoA dehydrogenase-deficient patients showed variable increases of these unusual intermediates. The results showed that this selective and sensitive method is a powerful tool in the diagnosis and monitoring of mitochondrial fatty acid beta-oxidation disorders.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1998

13-hydroxy octadecadienoic acid (13-HODE) inhibits triacylglycerol-rich lipoprotein secretion by CaCo-2 cells.

Oxidized lipids present in atherogenic lipoproteins are derived, in part, from the diet. To address the effects of an oxidized lipid on intestinal lipoprotein assembly and secretion, CaCo-2 cells were incubated with 13-HODE or its native fatty acid, linoleic acid, and triacylglycerol-rich lipoprotein synthesis and secretion were investigated. 13-HODE was readily taken up by cells and esterified to lipids. Although both fatty acids were largely esterified to neutral lipids, in comparison to neutral lipids containing linoleic acid, a greater proportion of cellular neutral lipids containing 13-HODE and/or its metabolites was secreted. Compared to linoleic acid, however, 13-HODE caused less triacylglycerol, derived from de novo synthesis, and less triacylglycerol mass to be secreted. Cells incubated with both linoleic acid and 13-HODE together secreted less triacylglycerol mass than did cells incubated with linoleic acid alone. Less newly synthesized apoB and apoB mass were secreted by cells incubated with 13-HODE without altering the abundance of apoB mRNA. The fraction of newly synthesized apoB translocated into the secretory pathway of cells exposed to 13-HODE was significantly less than that observed in cells incubated with linolenic acid, suggesting that 13-HODE interfered with the assembly and secretion of triacylglycerol-rich lipoprotein particles.

Apolipoproteins B↗
PubMed1977

The crystal structure of 3-hydroxy-3-isobutyl-2-pyrrolidone-5-carboxylic acid, lactam of 4-hydroxy-4-isobutylglutamic acid from Reseda odorata L.

The relative configuration of 3-hydroxy-3-isobutyl-2-pyrrolidone-5-carboxylic acid has been determined by an X-ray crystal structure analysis. The compound crystallized in space group P212121 with two molecules in the asymmetric unit. a=16.023(3) A, b=19.349(7) A, c=6.9053(16) A. The structure was solved by direct methods using MULTAN and refined by full-matrix least-squares technique to an R of 0.137 for 645 diffractometer-collected intensities. The absolute configurations of the title compounds were deduced; the configuration of the amino acid and the lactam are 2(S), 4(S) and 3(S), 5(S), respectively.

Chemical Phenomena↗
PubMed1990

Bioactivation mechanism of cytotoxic homocysteine S-conjugates.

S-(1,2-Dichlorovinyl)-L-homocysteine is a much more potent nephrotoxin than the corresponding cysteine S-conjugate S-(1,2-dichlorovinyl)-L-cysteine (A. A. Elfarra, L. H. Lash, and M. W. Anders (1986) Proc. Natl. Acad. Sci. USA 83, 2667-2671). The objective of the present experiments was to test the hypothesis that the increased toxicity of homocysteine S-conjugates may be associated with the formation of the reactive metabolite 2-oxo-3-butenoic acid, which may arise via a nonenzymatic retro-Michael elimination reaction from the 2-oxo acid metabolites of homocysteine S-conjugates. S-(2-Benzothiazolyl)-L-homocysteine, which was a substrate for purified bovine kidney cysteine conjugate beta-lyase (glutamine transaminase K) and whose metabolism was dependent on the presence of a 2-oxo acid, was cytotoxic in isolated rat kidney cells and was toxic to rat renal mitochondria, whereas the cysteine S-conjugate S-(2-benzothiazolyl)-L-cysteine had little effect. L-Methionine sulfoximine, L-canavanine, and the Michael acceptor methyl vinyl ketone were cytotoxic. The 2-hydroxy acid analogs of S-(1,2-dichlorovinyl)-L-homocysteine and 2-oxo-3-butenoic acid, S-(1,2-dichlorovinyl)-2-hydroxy-4-mercaptobutanoic acid and 2-hydroxy-3-butenoic acid, respectively, which are expected to be metabolized by rat renal L-2-hydroxy (L-amino) acid oxidase to yield 2-oxo-3-butenoic acid, were also cytotoxic. To obtain evidence for the formation of 2-oxo-3-butenoic acid as a product of the metabolism of L-homocysteine S-conjugates and analogs, trapping experiments were conducted. S-(2-Benzothiazolyl)-L-homocysteine, S-(1,2-dichlorovinyl)-L-homocysteine, L-methionine sulfoximine, and L-canavanine were converted by snake venom L-amino acid oxidase to 2-oxo-3-butenoic acid, which was trapped by the nucleophile methanethiol to yield 4-methylthio-2-oxobutanoic acid; the trapped product was derivatized with 2,4-dinitrophenylhydrazine and was identified by its electronic absorption spectrum and by high-performance liquid chromatography. Similar trapping experiments conducted with kidney homogenates and purified beta-lyase were not successful. The data indicate that the bioactivation of homocysteine S-conjugates and analogs involves the enzymatic formation of the corresponding 2-oxo acids followed by a nonenzymatic retro-Michael elimination reaction to yield the Michael acceptor 2-oxo-3-butenoic acid, which may contribute to the observed cytotoxicity of homocysteine S-conjugates.

Animals↗
PubMed2001

Effects of hydrogen-bond deletion on peptide helices: structural characterization of depsipeptides containing lactic acid.

The insertion of alpha-hydroxy acids into peptide chains provides a convenient means for investigating the effects of hydrogen bond deletion on polypeptide secondary structures. The crystal structures of three oligopeptides containing L-lactic acid (Lac) residue have been determined. Peptide 1, Boc-Val-Ala-Leu-Aib-Val-Lac-Leu-Aib-Val-Ala-Leu-OMe (Boc: tert-butyloxycarbonyl; Aib: alpha- aminoisobutyric acid; OMe: methyl ester), and peptide 2, Boc-Val-Ala-Leu-Aib-Val-Lac-Leu-Aib-Val-Leu-OMe, adopt completely helical conformations in the crystalline state with the Lac(6) residue comfortably accommodated in the center of a helix. The distance between the O atoms of Leu(3) CO group and the Lac(6) O (ester) in both the structures is 3.1-3.3 A. The NMR and CD studies of peptide 1 and its all-amide analogue 4, Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-OMe, provide firm evidence for a continuous helical conformation in solution in both the cases. In a 14-residue peptide 3, Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Val-Ala-Leu-Aib-Val-Lac-Leu-OMe, residues Val(1)-Leu(10) adopt a helical conformation. Aib(11) is the site of chiral reversal resulting in helix termination by formation of a Schellman motif. Residues 12-14 adopt nonhelical conformations. The loss of the hydrogen bond near the C-terminus appears to facilitate the chiral reversal at Aib(11). Published 2001 John Wiley & Sons, Inc. Biopolymers 59: 276-289, 2001

Amino Acid Sequence↗
PubMed1996

A clinical and histologic evaluation of two medium-depth peels. Glycolic acid versus Jessner's trichloroacetic acid.

BACKGROUND: Chemical peels using alpha hydroxy acids have become one of the most frequently requested dermatologic procedures. The use of glycolic acid in superficial chemical peels is now well established. However, the role of glycolic acid in medium-depth chemical peels has yet to be elucidated. OBJECTIVE: We performed a clinical and histologic comparison of 70% glycolic acid versus Jessner's solution as part of a medium-depth chemical peel using 35% trichloroacetic acid (TCA). METHODS: Thirteen patients with actinic keratoses, solar lentigines and fine wrinkling were evaluated prospectively. Each patient was treated with 70% glycolic acid plus 35% TCA (GA-TCA) to the right face and Jessner's solution plus 35% TCA (JS-TCA) to the left face. Clinical and histologic changes were evaluated at 7, 30, and 60 days postoperatively. RESULTS: Clinically, the GA-TCA peel was effective in treating photodamaged skin. The GA-TCA peel was slightly more efficacious in removing actinic keratoses (clinical response score = 1.5) than the JS-TCA peel (clinical response score = 1.0). Histologically, the GA-TCA peel caused the formation of a slightly thicker Grenz zone (mean = 0.053 mm) 60 days postpeel than the JS-TCA peel (mean = 0.048 mm) (not statistically significant). The GA-TCA peel caused more neoelastogenesis than the JS-TCA peel, while the JS-TCA peel resulted in more papillary dermal fibrosis and neovascularization than the GA-TCA peel. CONCLUSION: The GA-TCA peel is a new medium-depth chemical peel that is effective in treating photodamaged skin.

Chemexfoliation↗
PubMed2005

Pharmacology of RALGA, a mixture of retinaldehyde and glycolic acid.

BACKGROUND: Retinoids and alpha-hydroxy acids (AHAs) are major compounds in topical therapy. They exert distinct but potentially complementary activities. However, their association is limited by their respective irritating potential. Recently, the first association between a retinoid and an AHA has been achieved; this formulation (RALGA) associates retinaldehyde (RAL)--a precursor of retinoic acid (RA)--and glycolic acid (GA)--an AHA. OBJECTIVE: To study the pharmacological properties of RALGA. METHODS: The bioavailability of RAL into the skin after topical RALGA was studied by HPLC, and its bioconversion to RA was analysed by measuring the enzyme activity of retinaldehyde dehydrogenase and the RA content in the epidermis and dermis. The retinoid activity of RALGA was studied on the modulation of Hhb4 keratin mRNA on the tail of C57BL/6 mice, and its comedolytic properties on the size and density of dermal cysts and the morphology of sebaceous glands in hairless mice. RESULTS: Epidermal and dermal concentrations of RAL and RA were higher after RALGA treatment, as compared to both RAL 0.1% alone and RA 0.05% alone; this indicates that the presence of GA favours the bioavailability and biotransformation of RAL into RA. The retinoid activity of RALGA (suppression of Hhb4 mRNA keratin) was similar to that of RAL alone, indicating that the presence of GA does not interfere with specific retinoid activity; GA alone had no effect in this test, which confirms the specificity of Hhb4 mRNA keratin modulation for retinoid activity. The diameter and the density of dermal cysts as well as the size of sebaceous glands were significantly decreased by RALGA. CONCLUSION: These observations indicate that the addition of an AHA such as GA to a retinoid such as RAL results in a better bioavailability of the retinoid, thus a higher delivery of RA, which potentiates the biological activities of the retinoid. This combination allows a delivery of high amounts of RA in the skin while preventing the side-effects usually observed with high concentrations of topical RA.

Aldehyde Oxidoreductases↗
PubMed1992

Optimization of a process for the production of (R)-2-hydroxy-4-phenylbutyric acid--an intermediate for inhibitors of angiotensin converting enzyme.

(R)-2-Hydroxy-4-phenylbutyric acid, an intermediate in the manufacture of inhibitors of angiotensin converting enzyme, can be produced continuously in an enzyme membrane reactor by enzymatic reduction of its corresponding alpha-keto acid. D-Lactate dehydrogenase (D-LDH) from Staphylococcus epidermidis was chosen as the most appropriate enzyme to carry out the NADH-dependent reduction. Formate dehydrogenase (FDH) was used for NADH regeneration. Detailed kinetic measurements and a mathematical model for the coupled enzyme reactions were applied to calculate the optimal conditions for continuous production of the alpha-hydroxy acid. A mass of 1 kg [corrected] (R)-2-hydroxy-4-phenylbutyric acid was synthesized in a 220 ml enzyme membrane reactor over a period of 4 weeks. A mean space-time-yield of 165 g l-1 d-1 was achieved at low enzyme consumptions of 150 U kg-1 alpha-hydroxy acid for FDH and D-LDH.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

Intermolecular hydrogen transfer catalyzed by a flavodehydrogenase, bakers' yeast flavocytochrome b2.

Bakers' yeast flavocytochrome b2 is a flavin-dependent L-2-hydroxy acid dehydrogenase which also exhibits transhydrogenase activity. When a reaction takes place between [2-3H]lactate and a halogenopyruvate, tritium is found in water and at the halogenolactate C2 position. When the halogenopyruvate undergoes halide ion elimination, tritium is also found at the C3 position of the resulting pyruvate. The amount tau of this intermolecular tritium transfer depends on the initial keto acid-acceptor concentration. At infinite acceptor concentration, extrapolation yields a maximal transfer of 97 +/- 11%. This indicates that the hydroxy acid-derived hydrogen resides transiently on enzyme monoprotic heteroatoms and that exchange with bulk solvent occurs only at the level of free reduced enzyme. Using a minimal kinetic scheme, the rate constant for hydrogen exchange between Ered and solvent is calculated to be on the order of 10(2) M-1 S-1, which leads to an estimated pK approximately equal to 15 for the ionization of the substrate-derived proton while on the enzyme. It is suggested that this hydrogen could be shared between the active site base and Flred N5 anion. It is furthermore shown that some tritium is incorporated into the products when the transhydrogenation is carried out in tritiated water. Finally, with [2-2H]lactate-reduced enzyme, a deuterium isotope effect is observed on the rate of bromopyruvate disappearance. Extrapolation to infinite bromopyruvate concentration yields DV = 4.4. An apparent inverse isotope effect is determined for bromide ion elimination. These results strengthen the idea that oxidoreduction and elimination pathways involve a common carbanionic intermediate.

Hydroxy Acids↗
PubMed2005

Free radical oxidation of coriolic acid (13-(S)-hydroxy-9Z,11E-octadecadienoic acid).

The reaction of (13S,9Z,11E)-13-hydroxy-9,11-octadecadienoic acid (1a), one of the major peroxidation products of linoleic acid and an important physiological mediator, with the Fenton reagent (Fe(2+)/EDTA/H(2)O(2)) was investigated. In phosphate buffer, pH 7.4, the reaction proceeded with >80% substrate consumption after 4h to give a defined pattern of products, the major of which were isolated as methyl esters and were subjected to complete spectral characterization. The less polar product was identified as (9Z,11E)-13-oxo-9,11-octadecadienoate (2) methyl ester (40% yield). Based on 2D NMR analysis the other two major products were formulated as (11E)-9,10-epoxy-13-hydroxy-11-octadecenoate (3) methyl ester (15% yield) and (10E)-9-hydroxy-13-oxo-10-octadecenoate (4) methyl ester (10% yield). Mechanistic experiments, including deuterium labeling, were consistent with a free radical oxidation pathway involving as the primary event H-atom abstraction at C-13, as inferred from loss of the original S configuration in the reaction products. Overall, these results provide the first insight into the products formed by oxidation of 1a with the Fenton reagent, and hint at novel formation pathways of the hydroxyepoxide 3 and hydroxyketone 4 of potential (patho)physiological relevance in settings of oxidative stress.

Fatty Acids, Unsaturated↗