Bile acid chemistry. 3. Stepwise side-chain shortening by way of sodium per-iodate oxidation of alpha-hydroxy bile acids into corresponding aldehydes.
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Anhydrides↗
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Physiology and molecular genetics of poly(beta-hydroxy-alkanoic acid) synthesis in Alcaligenes eutrophus.
The Alcaligenes eutrophus genes for beta-ketothiolase, NADPH-dependent acetoacetyl-CoA reductase and poly(beta-hydroxybutyric acid) synthase (PHB synthase) which comprise the three-step PHB-biosynthetic pathway, were cloned. Molecular studies revealed that these genes are organized in a single operon. The A. eutrophus PHB-biosynthetic genes are readily expressed in other bacteria, and DNA fragments harbouring the operon can be used as a cartridge to confer to other bacteria the ability to synthesize PHB from acetyl-CoA. The biochemical and physiological capabilities of A. eutrophus for the synthesis of a wide variety of polyhydroxyalkanoates are discussed.
Acetyl-CoA C-Acyltransferase↗
The sustainability of interactions between the orexin-1 receptor and beta-arrestin-2 is defined by a single C-terminal cluster of hydroxy amino acids and modulates the kinetics of ERK MAPK regulation.
The orexin-1 receptor interacts with beta-arrestin-2 in an agonist-dependent manner. In HEK-293T cells, these two proteins became co-internalized into acidic endosomes. Truncations from the C-terminal tail did not prevent agonist-induced internalization of the orexin-1 receptor or alter the pathway of internalization, although such mutants failed to interact with beta-arrestin-2 in a sustained manner or produce its co-internalization. Mutation of a cluster of three threonine and one serine residue at the extreme C-terminus of the receptor greatly reduced interaction and abolished co-internalization of beta-arrestin-2-GFP (green fluorescent protein). Despite the weak interactions of this C-terminally mutated form of the receptor with beta-arrestin-2, studies in wild-type and beta-arrestin-deficient mouse embryo fibroblasts confirmed that agonist-induced internalization of this mutant required expression of a beta-arrestin. Although without effect on agonist-mediated elevation of intracellular Ca2+ levels, the C-terminally mutated form of the orexin-1 receptor was unable to sustain phosphorylation of the MAPKs (mitogen-activated protein kinases) ERK1 and ERK2 (extracellular-signal-regulated kinases 1 and 2) to the same extent as the wild-type receptor. These studies indicate that a single cluster of hydroxy amino acids within the C-terminal seven amino acids of the orexin-1 receptor determine the sustainability of interaction with beta-arrestin-2, and indicate an important role of beta-arrestin scaffolding in defining the kinetics of orexin-1 receptor-mediated ERK MAPK activation.
Amino Acid Sequence↗
The inhibition of PB125I formation in calf thyroid caused by 14-iodo-15-hydroxy-eicosatrienoic acid is due to decreased H2O2 availability.
Previous work from our laboratory has shown that 14-iodo-15-hydroxy-5,8,11-eicosatrienoic acid (I-HO-A) is a potent inhibitor of iodine organification in calf thyroid slices. The present studies were performed in order to clarify the mechanism of this action. Incubation of thyroid slices with 10(-4)M I-HO-A caused a 47 and 53% decrease in PB125I formation after 30 and 60 min incubation, respectively. In a series of experiments an inverse relationship between the degree of inhibition caused by I-HO-A and total iodine content and basal iodoprotein formation was observed. Chromatographic analysis of the labeled compounds showed a significant decrease in 125I incorporation into MIT, DIT, T3 and total iodolipid. The site of the inhibitory effect of I-HO-A was then sought. TPO was measured by three different methods. When TPO was solubilized from I-HO-A treated slices, no change in enzymatic activity was observed. Moreover, the same lack of action was found when solubilized TPO was incubated with I-HO-A. The production and release of H2O2 into the incubation medium was measured by chemiluminiscence technique. In control slices the values increased during the first 10 min and reached a plateau. Pretreatment of the slices with 10(-4)M KI caused a 51% inhibition, while the same concentration of I-HO-A produced a 59% inhibition. The possibility that I-HO-A might exert its action through a putative protein inhibitor was also explored. Incubation of slices with 10(-5)M I-HO-A caused a 46% decrease in PB125I formation and addition of actinomycin D or puromycin failed to alter this effect.(ABSTRACT TRUNCATED AT 250 WORDS)
8,11,14-Eicosatrienoic Acid↗
Mass spectrometric identification of 2-hydroxy-sebacic acid in the urines of patients with neonatal adrenoleukodystrophy and Zellweger syndrome.
The urines of children with neonatal adrenoleukodystrophy and Zellweger syndrome contained an excess of unusual even- and odd-numbered dicarboxylic acids with a chain length of from 5 to 15 carbon atoms, as well as 2-hydroxy-compounds, including 2-hydroxy-isocaproate, 2-hydroxy-glutarate and 2-hydroxy-sebacate. The latter product, not previously found in metabolic diseases, appears as an additional useful marker of these peroxisomal disorders.
Adrenal Gland Diseases↗
Structure of aureobasidin A.
Aureobasidin A, a new antifungal antibiotic, was isolated from the culture medium of Aureobasidium pullulans R106. Aureobasidin A was a cyclic depsipeptide consisting of eight alpha-amino acid units and one hydroxy acid unit. The structures of the units were found by acid hydrolysis of the antibiotic to be 2(R)-hydroxy-3(R)-methylpentanoic acid, beta-hydroxy-N-methyl-L-valine, N-methyl-L-valine, L-proline, allo-L-isoleucine, N-methyl-L-phenylalanine, L-leucine, and L-phenyl-alanine. The sequence of the units was identified by NMR and FAB-MS of the products from the alkaline hydrolysis of aureobasidin A.
Amino Acid Sequence↗
Precursor directed biosynthesis of aureobasidins.
The antifungal antibiotic aureobasidin A (AbA) is a cyclic depsipeptide composed of eight amino acids and a hydroxy acid. New Ab analogs were produced by feeding various amino acids to Aureobasidium pullulans R 106 c-712 in a chemically-defined medium containing glucose and ammonium sulfate. The constituent amino acids of AbA at positions 3 (L-phenylalanine), 4 (N-methyl-L-phenylalanine), 5 (L-proline), 6 (L-allo-isoleucine) and 8 (L-leucine) were replaced by respective analogous amino acids such as o-fluoro-L-phenylalanine, 4-hydroxy-L-proline, L-norleucine and L-norvaline, resulting in the production of eight new Ab analogs. This is the first paper to describe amino acid replacements at positions 3, 5 and 8. L-[1-13C]-Valine exogenously added was incorporated into the three valine-related moieties of AbA at positions 2, 7 (both N-methyl-L-valine) and 9 (beta-hydroxy-N-methyl-L-valine), but these moieties were never replaced by exogenous amino acid analogs. The comparative antifungal activities of AbA and the eight new Ab analogs were determined.
Amino Acid Sequence↗
A gas-liquid-chromatographic procedure for separating a wide range of metabolites occuring in urine or tissue extracts.
1. A gas-liquid-chromatographic procedure is described which permits separation and identification on the same chromatogram of a wide range of substances occurring in urine or tissue extracts. The method uses hydrogen flame ionization, which detects organic compounds whether free or conjugated with no requirement for specific reactive groups. 2. For chromatography, carboxyl groups are quantitatively converted into methyl esters or trimethylsilyl esters. Phenolic, alcoholic and potential enolic groups are converted into trimethylsilyl ethers. Separations are carried out on a 6ft. column of either 10% F-60 (a polysiloxane) or 1% F-60, temperature programming at 2 degrees /min. being used over such part of the temperature range 30 degrees -260 degrees as is required. Propionyl derivatives of hydroxy compounds can also be used, but only on a non-quantitative basis. Derivatives and columns have been selected for optimum range of usefulness when large numbers of samples are examined by using automated gas chromatography. 3. The method is applicable to: fatty acids above butyric acid; di- and tri-carboxylic acids; hydroxy acids and keto acids; polyhydroxy and alicyclic compounds such as glycerol, inositol, quinic acid, shikimic acid, ascorbic acid and sugar alcohols; aromatic hydroxy and acidic compounds, both benzenoid and indolic; sesquiterpenes; steroids; glycine conjugates; mercapturic acids; glucuronides. It is not satisfactory for sulphate conjugates, iminazoles or polypeptides. 4. Methylene units provide an accurate and reproducible parameter for characterizing peak position. Methylene unit values are reported for a large variety of substances occurring in, or related to those occurring in, urine and tissue extracts. 5. The nature of derivatives was confirmed by combining gas chromatography with mass spectrometry. Combined gas chromatography-mass spectrometry gives a diagnostic tool of great power in the evaluation of metabolic patterns, and various uses are discussed.
Journal Article↗
The origin of urinary aromatic compounds excreted by ruminants. 2. The metabolism of phenolic cinnamic acids to benzoic acid.
1. The extent to which phenolic derivatives of benzoic acid (seven); of phenylacetic acid (one); of 3-phenylpropionic acid (one) and of cinnamic acid (six) served as precursors of the urinary benzoic acid excreted by sheep was determined after administration as continuous drips via rumen or abomasal cannulas. 2. Phenolic derivatives of benzoic or of phenylacetic acid were not dehydroxylated to yield aromatic acids following administration via either route. 3. Rumen infusion of phenolic derivatives of both 3-phenylpropionic and cinnamic acids gave enhanced rumen concentrations of 3-phenylpropionic acid with negligible amounts of benzoic acid. Between 63 and 106% of the 2-, 3- or 4-hydroxy acids, of the 3,4-dihydroxy acids or of the 3-methoxy, 4-hydroxy acids infused were excreted in the urine as benzoic acid and a variable proportion, characteristic of the individual animal, of up to 20% of the dose as cinnamic acid. 4. Abomasal infusion of monohydroxy 3-phenylpropionic and cinnamic acids did not yield urinary benzoic acid increments. However, between 11 and 34% of abomasally-infused disubstituted phenolic cinnamic acids infused were excreted in the urine as benzoic acid due, it is postulated, to entero-hepatic circulation and microbial metabolism of the infused acids in the large intestine. 5. It is concluded that rumen microbial metabolism of dietary phenolic cinnamic acids to 3-phenylpropionic acid followed by its absorption and oxidation in the body tissues is responsible for the greater part of the benzoic and cinnamic acids found in ruminant urine.
Abomasum↗
Synthesis and some pharmacological properties of [4-threonine, 7-glycine]oxytocin, [1-(L-2-hydroxy-3-mercaptopropanoic acid), 4-threonine, 7-glycine]oxytocin (hydroxy[Thr4, Gly7]oxytocin), and [7-Glycine]oxytocin, peptides with high oxytocic-antidiuretic selectivity.
[4-Threonine, 7-glycine]oxytocin and [1-(L-2-hydroxy-3-mercaptopropanoic acid), 4-threonine, 7-glycine]oxytocin (hydroxy[Thr4, Gly7]oxytocin) were synthesized by a combination of solid-phase and classical methods of peptide synthesis. A protected octapeptide was synthesized by the solid-phase method and following ammonolysis and purification 1 + 8 couplings in solution were employed to furnish the required key nonapeptide and acyl octapeptide intermediates, respectively. [7-Glycine]oxytocin was prepared from a sample of the protected nonapeptide intermediate used in the original synthesis of this peptide. [7-Glycine]oxytocin has an oxytocic potency (O) of 93 +/- 4 units/mg and an antidiuretic potency (A) of 0.0056 +/- 0.0003 units/mg. It has an O/A ratio of 16 000. [4-Threonine, 7-glycine]oxytocin has an oxytocic potency of 166 +/- 4 units/mg and an antidiuretic potency of 0.002 +/- 0.0004 units/mg. Its O/A ratio is 83 000. Threonine substitution has thus brought about a substantial enhancement in oxytocic activity and a fivefold enhancement in O/A selectivity. Hydroxy [Thr4, Gly7]oxytocin has an oxytocic potency of 218 +/- 8 units/mg and antidiuretic potency of 0.0040 +/- 0.0005 units/mg. Its O/A ratio is thus 54 500. All three 7-glycine-substituted analogues exhibit a marked sensitivity to Mg2+ on the rat uterus assay ststem and in the presence of 0.5 mM Mg2+ had oxytocic potencies in the range of 900-1000 units/mg. Should these peptides exhibit enhanced oxytocic selectivity in humans, they might offer a greater margin of safety than oxytocin in those clinical stiuations in which the latter is currently employed.
Amino Acids, Sulfur↗
Malaria-parasitized erythrocytes and hemozoin nonenzymatically generate large amounts of hydroxy fatty acids that inhibit monocyte functions.
Plasmodium falciparum digests up to 75% of erythrocyte (red blood cell [RBC]) hemoglobin and forms hemozoin. Phagocytosed hemozoin and trophozoites inhibit important monocyte functions. Delipidized trophozoites and hemozoin were remarkably less toxic to monocytes. Parasitized RBCs and hemozoin contained large amounts of mostly esterified monohydroxy derivatives (OH-PUFAs), the stable end products of peroxidation of polyenoic fatty acids. The concentrations of OH-PUFA were 1.8 micromoles per liter RBCs in nonparasitized RBCs, 11.1 micromoles per liter RBCs in rings, 35 micromoles per liter RBCs in trophozoites; and approximately 90 micromoles per liter RBC equivalents in hemozoin. In parasitized RBCs and hemozoin a complex mixture of monohydroxy derivatives of arachidonic (HETEs) and linoleic (HODEs) acid was determined. Respectively, 13- and 9-HODE and 9- and 12-HETE were predominant in hemozoin and parasitized RBCs. The estimated concentrations of all HETE isomers were 33 and 39 micromoles per liter RBCs or RBC equivalents in trophozoites and hemozoin, respectively. No evidence of lipoxygenase activity was found, whereas the large number of positional and optical isomers, the racemic structure, and their generation by incubation of arachidonic acid with hemozoin indicated nonenzymatic origin via heme-catalysis. Sub/low micromolar concentrations of 12- and 15-HETE were toxic to monocytes, whereas HODE isomers were ineffective. Low micromolar concentrations of HETE isomers were estimated to be similarly present in monocytes after phagocytosis of trophozoites or hemozoin. Thus, specific products of heme-catalyzed lipid peroxidation appear to contribute to hemozoin toxicity to phagocytes and may thus play a role in increased cytoadherence, vascular permeability, and chemotaxis, as well as in immunodepression in malaria.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Biosynthesis of prostaglandins and hydroxy fatty acids in primary squamous carcinomas of head and neck in humans.
The metabolism of [14C]arachidonic acid into cyclooxygenase and lipoxygenase products by homogenates of primary squamous carcinomas of head and neck in 12 patients was studied in vitro. The lipoxygenase pathway was predominant in all samples. The major metabolites were 12-hydroxy-5,8,11-14-eicosatetraenoic acid, (12-HETE) and 15-HETE. 5-HETE, 5,12-diHETE, 8-HETE and 9-HETE were also detected. The cyclooxygenase products detected were in the following order: PGE2 greater than PGF2 alpha greater than TxB2 greater than 15-keto-PGE2 greater than 6-keto-PGF1 alpha greater than PGD2. Literature review of the biological activities of these oxygenated metabolites of arachidonic acid suggest important modulatory roles in the pathophysiology of head and neck cancer.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Efficacy and pharmacokinetics of simvastatin in heart transplant recipients.
OBJECTIVE: To evaluate the efficacy and safety of simvastatin administered to a group of heart transplant patients receiving triple-drug immunosuppressive therapy. We also assessed the potential pharmacokinetic interaction between simvastatin and cyclosporine by comparing mean plasma concentrations of simvastatin beta-hydroxy acid, the major metabolite of the drug, in a group of heart transplant patients treated with cyclosporine and in a control group of patients who had not received heart transplants. Both groups received long-term (> 6 wk) simvastatin therapy. DESIGN: We monitored hyperlipidemia in 20 hypercholesterolemic heart transplant patients receiving simvastatin 10 mg/d and triple-drug immunosuppressive therapy. Changes in laboratory results before and after 4 months of simvastatin therapy were considered. The same laboratory data were monitored in a control group of 20 nonhypercholesterolemic heart transplant patients who were not treated with simvastatin but were receiving triple-drug immunosuppressive therapy. Plasma concentrations of simvastatin beta-hydroxy acid were measured in 14 hypercholesterolemic patients, 7 of whom had received heart transplants and 7 who had not. SETTING: The Division of Cardiology and the First Medical Clinic for the clinical study, as well as the Department of Pharmacology for the pharmacokinetic analysis. PARTICIPANTS: Forty heart transplant patients and 7 hypercholesterolemic nontransplant patients. MAIN OUTCOME MEASURES: Effectiveness of simvastatin was determined by comparing cholesterol and lipoprotein plasma concentrations in 20 patients who underwent heart transplant and were treated with simvastatin for 4 months. The safety of the drug was determined by analyzing changes in laboratory results in the treated group and in the control group, both those who had received heart transplants and those who had received immunosuppressive therapy. RESULTS: After 4 months of simvastatin therapy, total cholesterol decreased by 12.5% and low-density lipoprotein cholesterol decreased by 21.3%. The only statistically significant laboratory change was an increase of 28.7% in the alanine aminotransferase concentrations. Plasma concentrations of simvastatin beta-hydroxy acid were higher in heart transplant patients than in those who had not received heart transplants, the control group. CONCLUSIONS: Low-dosage simvastatin treatment seems to be safe and sufficiently effective to decrease cholesterol concentrations. Concomitant treatment with immunosuppressive therapy (primarily cyclosporine) in heart transplant patients appeared to cause a reduced metabolic clearance of simvastatin from the plasma. More extensive studies on the interaction between simvastatin and cyclosporine are needed to understand the marked variability found in the response to simvastatin.
Adult↗
Biotransformation of lovastatin. I. Structure elucidation of in vitro and in vivo metabolites in the rat and mouse.
Structures of in vitro microsomal and in vivo metabolites of lovastatin, a new cholesterol-lowering drug, were elucidated with the combined application of HPLC, UV, fast atom bombardment-MS, and NMR spectroscopy. Liver microsomes from rats and mice catalyzed the biotransformation of lovastatin, primarily at the 6'-position of the molecule, to form 6'-hydroxy-lovastatin and a novel 6'-exomethylene derivative. Hydroxylation at the 6'-position occurred stereoselectively, giving 6'-beta-hydroxy-lovastatin. Stereoselective hydroxylation at the 3"-position of the methylbutyryl side chain and hydrolysis of the lactone group to the corresponding hydroxy acid were the other two pathways of microsomal metabolism. 3'-Hydroxy-iso-delta 4',5'-lovastatin was isolated, but is not believed to be a direct metabolite since 6'-beta-hydroxy-lovastatin rearranges to this compound under mildly acidic conditions. The major metabolites excreted in bile of rats treated with the hydroxy acid form of the drug were identified as the 3'-hydroxy analog and a taurine conjugate of a beta-oxidation product of lovastatin. The pentanoic acid derivative of lovastatin, formed by beta-oxidation of the heptanoic acid moiety, was a major metabolite in livers of mice dosed with the hydroxy acid form of lovastatin. The microsomal metabolites, in their hydroxy acid forms, were active inhibitors of HMG-CoA reductase. The relative enzyme inhibitory activities of hydroxy acid forms of lovastatin, 6'-beta-hydroxy-, 6'-exomethylene-, and 3"-hydroxy-lovastatin were 1, 0.6, 0.5, and 0.15, respectively.
Animals↗
The van urk-Salkowski reagent--a sensitive and specific chromogenic reagent for silica gel thin-layer chromatographic detection and identification of indole derivatives.
The chromogenic reagent described has been tested with seventy-nine indole derivatives and found to be very sensitive and indole-specific. The lower limit of detection on silica gel thin-layer plates was between 25 and 50 ng for most indoles. Phenols and hydroxy-, and amino-benzoic acids, hydroxy-, and methoxy-cinnamic acids did not yield chromophores with the exception of p-amino-benzoic acid and p-hydroxy-cinnamic acid which gave yellow and pink chromophores at concentrations greater than 1 and 2 mug. Although many of the C-3 substituted indoles such as indole-3-acetic acid and tryptamine had colors in the reddish-violet-blue color region, most exhibited sufficient color differentiation to allow their identification by thin-layer chromatography. The procedure was simple and required only 10 min from the time of spraying the thin-layer plate until full color development was reached. The colors had a wide spectral range from yellow of the indole-3-glyoxylamide chromophore to blue of the melatonin chromophore, and were extremely stable.
Benzaldehydes↗
Enantioselective reduction of carbonyl compounds by whole-cell biotransformation, combining a formate dehydrogenase and a (R)-specific alcohol dehydrogenase.
A whole-cell biotransformation system for the reduction of prochiral carbonyl compounds, such as methyl acetoacetate, to chiral hydroxy acid derivatives [methyl (R)-3-hydroxy butanoate] was developed in Escherichia coli by construction of a recombinant oxidation/reduction cycle. Alcohol dehydrogenase from Lactobacillus brevis catalyzes a highly regioselective and enantioselective reduction of several ketones or keto acid derivatives to chiral alcohols or hydroxy acid esters. The adh gene encoding for the alcohol dehydrogenase of L. brevis was expressed in E. coli. As expected, whole cells of the recombinant strain produced only low quantities of methyl (R)-3-hydroxy butanoate from the substrate methyl acetoacetate. Therefore, the fdh gene from Mycobacterium vaccae N10, encoding NAD+-dependent formate dehydrogenase, was functionally coexpressed. The resulting two-fold recombinant strain exhibited an in vitro catalytic alcohol dehydrogenase activity of 6.5 units mg-1 protein in reducing methyl acetoacetate to methyl (R)-3-hydroxy butanoate with NADPH as the cofactor and 0.7 units mg-1 protein with NADH. The in vitro formate dehydrogenase activity was 1.3 units mg-1 protein. Whole resting cells of this strain catalyzed the formation of 40 mM methyl (R)-3-hydroxy butanoate from methyl acetoacetate. The product yield was 100 mol% at a productivity of 200 micromol g-1 (cell dry weight) min-1. In the presence of formate, the intracellular [NADH]/[NAD+] ratio of the cells increased seven-fold. Thus, the functional overexpression of alcohol dehydrogenase in the presence of formate dehydrogenase was sufficient to enable and sustain the desired reduction reaction via the relatively low specific activity of alcohol dehydrogenase with NADH, instead of NADPH, as a cofactor.
Acetoacetates↗
Efficient intramolecular asymmetric reductions of alpha-, beta-, and gamma-keto acids with diisopinocampheylborane.
[figure: see text] alpha-, beta-, and gamma-Keto acids are reduced with diisopinocampheylborane at room temperature to the corresponding hydroxy acids with predictable stereochemistry in very high ee. The gamma-hydroxy acids produced were conveniently cyclized to the corresponding lactones. This provides a simple synthesis of 4-hexanolide, a component of the pheromone secreted by the female dermestid beetle Trogoderma glabrum.
Animals↗
High molecular weight lipids from the trilaminar outer wall (TLS)-containing microalgae Chlorella emersonii, Scenedesmus conmmunis and Tetraedron minimum.
High molecular weight lipids were isolated from Chlorella emersonii, Scenedesmus communis and Tetraedron minimum, thin trilaminar outer wall (TLS)-containing freshwater microalgae producing an insoluble non-hydrolysable biopolymer (i.e. algaenan). Molecular weight determination by gel permeation chromatography indicated that their molecular weights range from ca. 400 to 2000 Da. Flash pyrolysis with in situ methylation using tetramethylammonium hydroxide (TMAH) and alkaline hydrolysis showed that the high molecular weight lipids isolated from C. emersonii and S. communis are mainly composed of saturated n-C26 and n-C28 fatty acids and alcohols and of saturated n-C30 and n-C32 alpha,omega-diols and omega-hydroxy acids. In contrast the high molecular weight lipids isolated from T. minimum are predominantly composed of long-chain fatty acids and omega-hydroxy acids. Aromatic moieties were also identified in small amounts in the thermochemolysate and in the hydrolysate. Chemical structural models containing long-chain mono- and polyesters were proposed for the high molecular weight lipids isolated from the three microalgae in agreement with analytical and spectroscopic data. Structural similarity between the outer cell wall of these microalgae and the cuticular membrane of higher plants is suggested.
Cell Wall↗