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PubMed1996

Treatment of photoaged skin. Efficacy, tolerability and costs of available agents.

Photoaging is a cumulative degenerative process induced by solar irradiation with well defined clinical and histological correlates. Because of its huge psychological impact, there is much demand for effective treatment. Many well constructed trials confirm the clinical efficacy of topical tretinoin for improving fine wrinkling and mild to moderate hyperpigmentation; coarse wrinkling and severe hyperpigmentation respond less well. Histological improvement is well documented, but the precise relationship to clinical response is not clearly established. Tolerability can be a problem. Optimal concentrations are not firmly established and vary between patients. Claims that topical isotretinoin is better tolerated than tretinoin need to be confirmed with well constructed trials. Despite many claims, there have been no adequate trials documenting the efficacy of fish cartilage polysaccharide extracts or alpha-hydroxy acids. Careful patient selection with consideration of alternative treatments such as chemical peeling, dermabrasion and surgery is important to successful management of photoaging.

Economics, Pharmaceutical↗
PubMed2004

Acid-catalyzed reactions of aromatic aldehydes with ethyl diazoacetate: an investigation on the synthesis of 3-hydroxy-2-arylacrylic acid ethyl esters.

Several commercial Lewis acids, including those of the Bronsted type, specifically HBF(4).OEt(2), are able to catalyze the reaction between aromatic aldehydes and ethyl diazoacetate to produce 3-hydroxy-2-arylacrylic acid ethyl esters and 3-oxo-3-arylpropanoic acid ethyl esters. Reactions catalyzed by the iron Lewis acid [(eta(5)-C(5)H(5))Fe(+)(CO)(2)(THF)]BF(4)(-) (i.e., 1) have the best yields and greatest ratio of 3-hydroxy-2-arylacrylic acid ethyl ester. The product distribution of 1 is not affected in the presence of Proton Sponge, but is dependent on temperature and the nature of the substrate aldehyde, whereas the activity of HBF(4).OEt(2) is affected by the presence of Proton Sponge and is reactive at temperatures as low as -78 degrees C. Consequently, both 1 and HBF(4).OEt(2) are valuable catalysts in producing important 3-hydroxy-2-arylacrylic acid ethyl esters as precursors to biologically active compounds.

Journal Article↗
PubMed2000

Metabolism of N'-nitrosonornicotine enantiomers by cultured rat esophagus and in vivo in rats.

People who use tobacco products are exposed to considerable amounts of N'-nitrosonornicotine (NNN), a well-established esophageal carcinogen in rats. NNN is believed to play a significant role as a cause of esophageal and oral cavity cancer in smokers and snuff dippers. The carcinogenicity of NNN is dependent on its metabolic activation. However, virtually all studies carried out to date on NNN metabolism have used racemic material. In this study, we examined the metabolism of [5-(3)H]-(S)-NNN and [5-(3)H]-(R)-NNN in cultured rat esophagus and in vivo in rats. Cultured rat esophagus metabolized (S)-NNN (1 microM) predominantly to products of 2'-hydroxylation, 4-oxo-4-(3-pyridyl)butanoic acid (keto acid) and 4-hydroxy-1-(3-pyridyl)-1-butanone (keto alcohol). In contrast, the major metabolite of (R)-NNN under these conditions was 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid), a product of NNN 5'-hydroxylation. The 2'-hydroxylation:5'-hydroxylation metabolite ratio ranged from 6.22 to 8.06 at various time intervals in the incubations with (S)-NNN, while the corresponding ratios were 1.12-1.33 in the experiments with (R)-NNN. These differences were statistically significant (P<0.001). Since 2'-hydroxylation is believed to be the major metabolic activation pathway of NNN in the rat esophagus, the results demonstrate that (S)-NNN is metabolically activated more extensively than (R)-NNN in this tissue, and therefore may be more carcinogenic. Rats were treated with 0.3 mg/kg of [5-(3)H]-(R)-NNN, [5-(3)H]-(S)-NNN, or racemic [5-(3)H]NNN by gavage, and the urinary metabolites were analyzed. The major metabolites were hydroxy acid and keto acid. As in the in vitro studies, products of 2'-hydroxylation predominated in the urine of the rats treated with (S)-NNN while products of 5'-hydroxylation were more prevalent in the rats treated with (R)-NNN. 2'-Hydroxylation:5'-hydroxylation metabolite ratios ranged from 1.66 to 2.04 in the urine at various times after treatment with (S)-NNN, while the ratios were 0.398-0.450 for the rats treated with (R)-NNN (P<0.001). The results of this study provide new insights into NNN metabolism in rats and suggest that the carcinogenicity of (S)-NNN, the predominant enantiomer in tobacco products, may be greater than that of (R)-NNN or racemic NNN.

Animals↗
PubMed2005

Stereoselective beta-hydroxy-alpha-amino acid synthesis via an ether-directed, palladium-catalysed aza-Claisen rearrangement.

A highly diastereoselective synthesis of (2S,3S)-beta-hydroxy-alpha-amino acids has been developed from enantiopure alpha-hydroxy acids using a MOM-ether-directed, palladium(II)-catalysed, aza-Claisen rearrangement of allylic acetimidates to effect the key step. This highly stereoselective process gave allylic amides in diastereomeric ratios of up to 14 : 1. Problems associated with the isolation of 1,3-products (anti-Claisen) from sterically demanding substrates via an insitu palladium(0)-catalysed rearrangement process were overcome by the addition of a re-oxidant, p-benzoquinone, leading to cleaner reactions and improved yields of the 3,3-products (Claisen). The target beta-hydroxy-alpha-amino acids are an important class of natural products that are also components of more complex organic compounds with significant biological properties.

Amino Acids↗
PubMed1989

Quantification of urinary 3-hydroxyisovaleric acid using deuterated 3-hydroxyisovaleric acid as internal standard.

Deficiency of biotin at the tissue level can be assessed indirectly by measuring the urinary excretion of 3-hydroxyisovaleric acid. This paper describes the application of an improved method of quantifying urinary 3-hydroxyisovaleric acid using unlabeled and uniformly deuterated 3-hydroxyisovaleric acid. These compounds were synthesized by a modification of the lithioacetic acid method for generation of beta-hydroxy acids. Elemental analysis, nuclear magnetic resonance, gas chromatographic and gas chromatographic/mass spectrometric data demonstrated that the compounds are greater than 95% pure. Mass spectrometry confirmed the identity of the unlabeled compound, demonstrated that the deuterated compound is uniformly labeled, and offered insight into the pattern of mass fragmentation. The method for determination of the concentration of 3-hydroxyisovaleric acid in rat urine uses gas chromatographic/mass spectrometric quantification of the di-trimethylsilyl derivative with the deuterated compound as the internal standard. Results provide evidence that this method is more accurate than a previously published method that did not utilize the unlabeled and deuterated standards.

Animals↗
PubMed1985

Gas chromatography-mass spectrometry method for determination of phospholipid peroxides; II. Transesterification to form pentafluorobenzyl esters and detection with picogram sensitivity.

The purpose of this study is to develop a higher sensitivity method to detect phospholipid peroxides in tissues to more effectively investigate the role of lipid peroxidation in pathology. We recently presented a gas chromatography-mass spectrometry (GC-MS) method for identification and measurement of phospholipid peroxides at the 10 ng level (van Kuijk, et al. J. Free Rad. Biol. Med., 1:215-225, 1985) based on transesterification to form fatty acid methyl ester derivatives. While this method is quite useful under some circumstances, more sensitivity was desirable to analyse trace amounts of lipid peroxidation products in small samples of various tissues. We present a method to prepare pentafluorobenzyl esters of fatty acids and hydroxy fatty acids directly from phospholipids by transesterification at room temperature or from triglycerides at 60 degrees C. Oxidized lipids are extracted into dichloromethane and peroxide functions are reduced with sodium borohydride. Transesterification of phospholipids is carried out in dichloromethane with 20% (v/v) pentafluorobenzyl alcohol, 1% (w/v) potassium tert-butoxide and 0.2 N (m-trifluoromethyl phenyl) trimethyl ammonium hydroxide at room temperature for 30 min. Pentafluorobenzyl esters are purified on open silica columns, O-trimethyl silyl derivatives of the alcohol functions are formed, and GC-MS is carried out with negative ion chemical ionization detection. The single or double oxidation products of oleate, linoleate, arachidonate, and docosahexaenoate were detected with 10 pg sensitivity in oxidized rat retina phospholipids or synthetic phospholipids, by negative ion chemical ionization with specific ion monitoring of carboxylate anions.

Borohydrides↗
PubMed2000

Rhodococcus L-phenylalanine dehydrogenase: kinetics, mechanism, and structural basis for catalytic specificity.

Phenylalanine dehydrogenase catalyzes the reversible, pyridine nucleotide-dependent oxidative deamination of L-phenylalanine to form phenylpyruvate and ammonia. We have characterized the steady-state kinetic behavior of the enzyme from Rhodococcus sp. M4 and determined the X-ray crystal structures of the recombinant enzyme in the complexes, E.NADH.L-phenylalanine and E.NAD(+). L-3-phenyllactate, to 1.25 and 1.4 A resolution, respectively. Initial velocity, product inhibition, and dead-end inhibition studies indicate the kinetic mechanism is ordered, with NAD(+) binding prior to phenylalanine and the products' being released in the order of ammonia, phenylpyruvate, and NADH. The enzyme shows no activity with NADPH or other 2'-phosphorylated pyridine nucleotides but has broad activity with NADH analogues. Our initial structural analyses of the E.NAD(+).phenylpyruvate and E.NAD(+). 3-phenylpropionate complexes established that Lys78 and Asp118 function as the catalytic residues in the active site [Vanhooke et al. (1999) Biochemistry 38, 2326-2339]. We have studied the ionization behavior of these residues in steady-state turnover and use these findings in conjunction with the structural data described both here and in our first report to modify our previously proposed mechanism for the enzymatic reaction. The structural characterizations also illuminate the mechanism of the redox specificity that precludes alpha-amino acid dehydrogenases from functioning as alpha-hydroxy acid dehydrogenases.

Amino Acid Oxidoreductases↗
PubMed1999

Phenylalanine dehydrogenase from Rhodococcus sp. M4: high-resolution X-ray analyses of inhibitory ternary complexes reveal key features in the oxidative deamination mechanism.

The molecular structures of recombinant L-phenylalanine dehydrogenase from Rhodococcus sp. M4 in two different inhibitory ternary complexes have been determined by X-ray crystallographic analyses to high resolution. Both structures show that L-phenylalanine dehydrogenase is a homodimeric enzyme with each monomer composed of distinct globular N- and C-terminal domains separated by a deep cleft containing the active site. The N-terminal domain binds the amino acid substrate and contributes to the interactions at the subunit:subunit interface. The C-terminal domain contains a typical Rossmann fold and orients the dinucleotide. The dimer has overall dimensions of approximately 82 A x 75 A x 75 A, with roughly 50 A separating the two active sites. The structures described here, namely the enzyme.NAD+.phenylpyruvate, and enzyme. NAD+.beta-phenylpropionate species, represent the first models for any amino acid dehydrogenase in a ternary complex. By analysis of the active-site interactions in these models, along with the currently available kinetic data, a detailed chemical mechanism has been proposed. This mechanism differs from those proposed to date in that it accounts for the inability of the amino acid dehydrogenases, in general, to function as hydroxy acid dehydrogenases.

Amino Acid Oxidoreductases↗
PubMed2004

Toward assessing the position-dependent contributions of backbone hydrogen bonding to beta-sheet folding thermodynamics employing amide-to-ester perturbations.

An amide-to-ester backbone substitution in a protein is accomplished by replacing an alpha-amino acid residue with the corresponding alpha-hydroxy acid, preserving stereochemistry, and conformation of the backbone and the structure of the side chain. This substitution replaces the amide NH (a hydrogen bond donor) with an ester O (which is not a hydrogen bond donor) and the amide carbonyl (a strong hydrogen bond acceptor) with an ester carbonyl (a weaker hydrogen bond acceptor), thus perturbing folding energetics. Amide-to-ester perturbations were used to evaluate the thermodynamic contribution of each hydrogen bond in the PIN WW domain, a three-stranded beta-sheet protein. Our results reveal that removing a hydrogen bond donor destabilizes the native state more than weakening a hydrogen bond acceptor and that the degree of destabilization is strongly dependent on the location of the amide bond replaced. Hydrogen bonds near turns or at the ends of beta-strands are less influential than hydrogen bonds that are protected within a hydrophobic core. Beta-sheet destabilization caused by an amide-to-ester substitution cannot be directly related to hydrogen bond strength because of differences in the solvation and electrostatic interactions of amides and esters. We propose corrections for these differences to obtain approximate hydrogen bond strengths from destabilization energies. These corrections, however, do not alter the trends noted above, indicating that the destabilization energy of an amide-to-ester mutation is a good first-order approximation of the free energy of formation of a backbone amide hydrogen bond.

Amides↗
PubMed2003

Biological effects of glycolic acid on dermal matrix metabolism mediated by dermal fibroblasts and epidermal keratinocytes.

Glycolic acid (GA), one of the alpha-hydroxy acids, is widely used as an agent for chemical peeling. Although there are several reports about the clinical effects of GA in the literature, its biological mechanism remains mostly unclear, and there are only a few reports about its effects on skin rejuvenation mediated by keratinocytes. The aim of this study was to investigate the effect of GA on the dermal matrix metabolism of keratinocytes and fibroblasts using in vitro and ex vivo systems. Our study shows that GA not only directly accelerates collagen synthesis by fibroblasts, but it also modulates matrix degradation and collagen synthesis through keratinocyte-released cytokines. We confirm that IL-1alpha is one of the primary mediators for matrix degradation released from keratinocytes after GA treatment. These results suggest that GA contributes to the recovery of photodamaged skin through various actions, depending on the skin cell type.

Dermis↗
PubMed1976

Studies on peroxisomes. VI. Relationship between the peroxisomal core and urate oxidase.

The peroxisomal core from the liver of rats was purified 450-fold as a marker of urate oxidase [EC 1.7.3.3.] activity. This preparation has a high specific activity of urate oxidase but not of other peroxisomal enzymes: D-amino acid oxidase [EC 1.4.3.3.], L-alpha-hydroxy acid oxidase [EC 1.1.3.15], or catalase [EC 1.11.1.6]. No activity of marker enzymes for other subcellular particles; cytochrome c oxidase [EC1.9.3.1] (mitochondria), acid phosphatase [EC 3.1.3.2] (lysosomes), or glucose-6-phosphatase [EC 3.1.3.9] (microsomes), was detected in this preparation. The core obtained showed a single protein band in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the position of the band was found to correspond to a molecular weight 35,000. When the peroxisomal core was subjected to treatment at various pH's with 0.1 M carbonate buffer, urate oxidase was almost completely solubulized at pH 11.0, although approximately 35% of the core protein still remained in the pellet After solubilization of the core at pH 11.0, the specific activity of urate oxidase in the supernatant increased about 1.6 times; the density of the insoluble protein remaining in the pellet was identical with the that of the original core on sucrose density gradient centrifugation.

Animals↗
PubMed2004

Saccharibacter floricola gen. nov., sp. nov., a novel osmophilic acetic acid bacterium isolated from pollen.

Three Gram-negative, aerobic, rod-shaped bacterial strains were isolated, from the pollen of Japanese flowers, as producers of xylitol; these strains were subjected to a polyphasic taxonomic study. Phylogenetic analyses of the 16S rRNA gene sequences demonstrated that these three isolates formed a new cluster within a group of acetic acid bacteria in the alpha-Proteobacteria. The characteristics of the three isolates were as follows: (i) their predominant quinone was Q-10; (ii) their cellular fatty acid profile contained major amounts of 2-hydroxy acids and an unsaturated straight-chain acid (C(18 : 1)omega7c); and (iii) their DNA G+C contents were in the range 51.9-52.3 mol%, which is around the lower limit of the reported range for the genera of acetic acid bacteria. The negligible or very weak productivity of acetic acid from ethanol and the osmophilic growth properties distinguished these strains from other acetic acid bacteria. The unique phylogenetic and phenotypic characteristics suggest that the three isolates should be classified within a novel genus and species with the proposed name Saccharibacter floricola gen. nov., sp. nov. The type strain is strain S-877(T) (=AJ 13480(T)=JCM 12116(T)=DSM 15669(T)).

Acetic Acid↗
PubMed2000

Novel scheme for biosynthesis of aryl metabolites from L-phenylalanine in the fungus Bjerkandera adusta.

Aryl metabolite biosynthesis was studied in the white rot fungus Bjerkandera adusta cultivated in a liquid medium supplemented with L-phenylalanine. Aromatic compounds were analyzed by gas chromatography-mass spectrometry following addition of labelled precursors ((14)C- and (13)C-labelled L-phenylalanine), which did not interfere with fungal metabolism. The major aromatic compounds identified were benzyl alcohol, benzaldehyde (bitter almond aroma), and benzoic acid. Hydroxy- and methoxybenzylic compounds (alcohols, aldehydes, and acids) were also found in fungal cultures. Intracellular enzymatic activities (phenylalanine ammonia lyase, aryl-alcohol oxidase, aryl-alcohol dehydrogenase, aryl-aldehyde dehydrogenase, lignin peroxidase) and extracellular enzymatic activities (aryl-alcohol oxidase, lignin peroxidase), as well as aromatic compounds, were detected in B. adusta cultures. Metabolite formation required de novo protein biosynthesis. Our results show that L-phenylalanine was deaminated to trans-cinnamic acid by a phenylalanine ammonia lyase and trans-cinnamic acid was in turn converted to aromatic acids (phenylpyruvic, phenylacetic, mandelic, and benzoylformic acids); benzaldehyde was a metabolic intermediate. These acids were transformed into benzaldehyde, benzyl alcohol, and benzoic acid. Our findings support the hypothesis that all of these compounds are intermediates in the biosynthetic pathway from L-phenylalanine to aryl metabolites. Additionally, trans-cinnamic acid can also be transformed via beta-oxidation to benzoic acid. This was confirmed by the presence of acetophenone as a beta-oxidation degradation intermediate. To our knowledge, this is the first time that a beta-oxidation sequence leading to benzoic acid synthesis has been found in a white rot fungus. A novel metabolic scheme for biosynthesis of aryl metabolites from L-phenylalanine is proposed.

Basidiomycota↗
PubMed2004

Overexpression of Lactobacillus casei D-hydroxyisocaproic acid dehydrogenase in cheddar cheese.

Metabolism of aromatic amino acids by lactic acid bacteria is an important source of off-flavor compounds in Cheddar cheese. Previous work has shown that alpha-keto acids produced from Trp, Tyr, and Phe by aminotransferase enzymes are chemically labile and may degrade spontaneously into a variety of off-flavor compounds. However, dairy lactobacilli can convert unstable alpha-keto acids to more-stable alpha-hydroxy acids via the action of alpha-keto acid dehydrogenases such as d-hydroxyisocaproic acid dehydrogenase. To further characterize the role of this enzyme in cheese flavor, the Lactobacillus casei d-hydroxyisocaproic acid dehydrogenase gene was cloned into the high-copy-number vector pTRKH2 and transformed into L. casei ATCC 334. Enzyme assays confirmed that alpha-keto acid dehydrogenase activity was significantly higher in pTRKH2:dhic transformants than in wild-type cells. Reduced-fat Cheddar cheeses were made with Lactococcus lactis starter only, starter plus L. casei ATCC 334, and starter plus L. casei ATCC 334 transformed with pTRKH2:dhic. After 3 months of aging, the cheese chemistry and flavor attributes were evaluated instrumentally by gas chromatography-mass spectrometry and by descriptive sensory analysis. The culture system used significantly affected the concentrations of various ketones, aldehydes, alcohols, and esters and one sulfur compound in cheese. Results further indicated that enhanced expression of d-hydroxyisocaproic acid dehydrogenase suppressed spontaneous degradation of alpha-keto acids, but sensory work indicated that this effect retarded cheese flavor development.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2005

Review: derivatization in mass spectrometry-6. Formation of mixed derivatives of polyfunctional compounds.

The review describes chemical transformations of multifunctional compounds (amino acids and peptides, amino alcohols, amino thiols, hydroxy acids, oxo acids, oxo alcohols, compounds containing simultaneously three or more different groups etc.) by using step-wise or one-step modification or protection of functional groups. Some chemical aspects of mixed derivatization performed for improving the physical-chemical properties and mass spectral characteristics are discussed. Application of mixed derivatization to qualitative and quantitative analysis of various multifunctional compounds mainly in biological fluids and other matrices by gas chromatography/mass spectrometry in electron ionization, chemical ionization, negative-ion chemical ionization and selected ion monitoring modes is considered.

Biochemistry↗
PubMed1979

Identification of the prosthetic group of urocanase. The mode of its reaction with sodium borohydride and of its photochemical reactivation.

Urocanase from Pseudomonas putida and from beef liver were isolated by modifying described procedures. Both enzymes were inactivated and labeled on treatment with tritiated sodium borohydride and gave, upon subsequent hydrolysis, a radioactive acid. The previously reported identity of this acid as 2-hydroxybutanoic acid was disproved by several criteria. Other hydroxy acids were also proved to be different from the radioactive acid derived from urocanase. A large portion of the radioactive material from P. putida was found to be nicotinic acid by 1H NMR spectroscopy, gas-liquid chromatography of its methyl ester, and co-crystallization with authentic reference compounds both as the acid and as the hydrazide. A significant portion of the radioactive material derived from beef liver urocanase also co-crystallized with nicotinic acid. Sodium borohydride-treated inactive urocanase was partially reactivated by light. The action spectrum of the photoreactivation showed a maximum at 330 nm. Treatment of urocanase with sodium borodeuteride followed by hydrolysis afforded a sample of nicotinic acid which carried deuterium mainly in position 6. Both the reversible reducibility of urocanase and its action spectrum of photoreactivation suggest that urocanase contains an enzyme-bound nicotinamide nucleotide molecule which is essential for enzymic activity.

Animals↗
PubMed1978

Determination of prostaglandins and other products of arachidonate oxygenation in perfusates and during platelet aggregation.

Some analytical aspects of prostaglandin research are discussed. We present our latest results of the determination of the various products of arachidonate oxygenation in biological fluids and during platelet aggregation. These products were determined by (GLC) in combination with electron-capture detection or mass spectrometry (multiple-ion detection). The major component released from isolated perfused heart and lung was prostacyclin, determined as its hydrolysis product 6-oxo-PGF1alpha. Spleen released much thromboxane and monohydroxy acids. Normal rat platelets formed also much hydroxy acids during aggregation but at essential fatty acid deficiency, only very small amounts of product were detected.

Animals↗