Branched-chain alpha-keto acids isolated as oxime derivatives: relationship to the corresponding hydroxy acids and amino acids in maple syrup urine disease.
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Amino Acids↗
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Phenotypic variation of lipid composition in Burkholderia cepacia: a response to increased growth temperature is a greater content of 2-hydroxy acids in phosphatidylethanolamine and ornithine amide lipid.
Burkholderia cepacia produces an unusual range of polar lipids, which includes two forms each of phosphatidylethanolamine (PE) and ornithine amide lipid (OL), differing in the presence or absence of 2-hydroxy fatty acids. By using chemostat cultures in chemically defined media, variations in the lipid content and the proportions of individual lipids have been studied as a function of (a) growth temperature, (b) growth rate and (c) growth-limiting nutrient (carbon, magnesium, phosphorus or oxygen). Total cellular lipid in carbon-limited cultures was lowest at high growth temperatures and low growth rates. Increases in growth temperature over the range 25-40 degrees C led to increases in the proportions of molecular species of PE and OL containing 2-hydroxy acids, without changing the PE:OL ratio. Growth temperature did not alter the balance between neutral and acidic lipids, but the contribution of phosphatidylglycerol to the latter increased with rising growth temperature and growth rate. Pigmentation of cells and the presence of flagella were also temperature-dependent. Change in growth rate also affected the PE:OL ratio and the extent to which monoenoic acids were replaced by their cyclopropane derivatives. Whereas similar lipid profiles were found for carbon-, magnesium- and oxygen-limited cultures, ornithine amides were the only polar lipids detected in phosphorus-limited cells.
Burkholderia cepacia↗
Biodegradable implants from poly-(alpha-hydroxy acid) polymers for isoniazid delivery.
SETTING: In vitro and in vivo study of an isoniazid (INH) drug delivery system. OBJECTIVE: To develop a system for the treatment of tuberculosis using a subcutaneous polymer implant with a large drug load released slowly over a long period. INH delivery by biodegradable poly-(alpha-hydroxy acid) polymers was evaluated using ground polymer and compression molded implants. DESIGN: Rate of drug release and structural stability of the implant in an aqueous environment were measured, as were in vivo evaluations of the duration of measurable levels of INH in serum and urine. RESULTS: Factors that influenced the suitability of an implant in an in vitro system included polymer molecular weight and crystallinity, polymer and drug particle size, drug loading dose, and press temperature and pressure. The implant characteristics that most closely approached optimal conditions include a polymer of 100% L-lactide with low intrinsic viscosity, polymer particle size <75 micron, and INH particle = 126-180 micron, INH loading dose not to exceed 46%, and press conditions of 70 degrees C and 345000 kPa. Studies of subcutaneous implants in rabbits and baboons show that INH is released from the implant for 15 to 26 weeks. CONCLUSIONS: An INH-containing polymer was developed that was structurally stable in an aqueous environment and that released INH over a period of at least 15 weeks. Studies with infected animals will be necessary to determine the dose required for prophylaxis and treatment of active disease.
Animals↗
Quantitative analysis of simvastatin and its beta-hydroxy acid in human plasma using automated liquid-liquid extraction based on 96-well plate format and liquid chromatography-tandem mass spectrometry.
An assay based on automated liquid-liquid extraction (LLE) and liquid chromatography-tandem mass spectrometry (LC/MS/MS) has been developed and validated for the quantitative analysis of simvastatin (SV) and its beta-hydroxy acid (SVA) in human plasma. A Packard MultiProbe II workstation was used to convert human plasma samples collected following administration of simvastatin and quality control (QC) samples from individual tubes into 96-well plate format. The workstation was also used to prepare calibration standards and spike internal standards. A Tomtec Quadra 96-channel liquid handling workstation was used to perform LLE based on 96-well plates including adding solvents, separating organic from aqueous layer and reconstitution. SV and SVA were separated through a Kromasil C18 column (50 mm x 2 mm i.d., 5 microm) and detected by tandem mass spectrometry with a TurboIonspray interface. Stable isotope-labeled SV and SVA, 13CD(3)-SV and 13 CD(3)-SVA, were used as the internal standards for SV and SVA, respectively. The automated procedures reduced the overall analytical time (96 samples) to 1/3 of that of manual LLE. Most importantly, an analyst spent only a fraction of time on the 96-well LLE. A limit of quantitation of 50 pg/ml was achieved for both SV and SVA. The interconversion between SV and SVA during the 96-well LLE was found to be negligible. The assay showed very good reproducibility, with intra- and inter-assay precision (%R.S.D.) of less than 7.5%, and accuracy of 98.7-102.3% of nominal values for both analytes. By using this method, sample throughput should be enhanced at least three-fold compared to that of the manual procedure.
Chromatography, Liquid↗
The occurrence and distribution of alpha-hydroxy-acid dehydrogenase in some members of the order Kinetoplastida.
LDH-X is the isoenzyme of lactate dehydrogenase found in mammalian spermatozoa, occurring in cytosolic and mitochondrial locations. Gossypol strongly inhibits it, and the spermicidal action of this compound is attributed to the disruption of a reducing shuttle. The flagellated protozoan, Trypanosoma cruzi, contains an enzyme activity similar to LDH-X, called alpha-hydroxy-acid dehydrogenase, which is here shown to possess cytosolic and glycosomal components. The glycosome is a microbody-like organelle containing the early glycolytic enzymes. We postulate that the inhibition of replication of T. cruzi by gossypol derives from interference with glycosomal reducing shuttles. T. lewisi resembles T. cruzi in this respect.
Alcohol Oxidoreductases↗
Evolutionary relationship of NAD(+)-dependent D-lactate dehydrogenase: comparison of primary structure of 2-hydroxy acid dehydrogenases.
A comparison of the primary structures of NAD(+)-dependent D-lactate dehydrogenase with L-lactate dehydrogenase and L-malate dehydrogenase failed to show any sequence similarity. However, D-2-hydroxyisocaproate dehydrogenase from Lactobacillus casei, glycerate dehydrogenase from cucumber, D-3-phosphoglycerate dehydrogenase and erythronate 4-phosphate dehydrogenase from Escherichia coli showed 38%, 24%, 24% and 22% amino acid identity, respectively. The profile analysis of the aligned sequences confirmed their relatedness. The hydropathy profiles of the aligned dehydrogenases were almost identical between residues 100-300 indicating largely preserved folding patterns of their polypeptide chains. The data suggest that L- and D-specific 2-hydroxy acid dehydrogenase genes evolved from two different ancestors and thus represent two different sets of enzyme families.
Alcohol Oxidoreductases↗
Surface perspectives in the biomedical applications of poly(alpha-hydroxy acid)s and their associated copolymers.
Impressive advances in biotechnology, bioengineering, and biomaterials with unique properties have led to increased interest in polymers and other novel materials in biological and biomedical research and development over the past two decades. Although biomaterials have already made an enormous impact in biomedical research and clinical practice, there is a need for better understanding of the surface and interfacial chemistry between tissue (or cells) and biomedical materials. This is because the detailed physicochemical events related to the biological response to the surface of materials still often remain obscure, even though surface properties are important determinants of biomedical material function. In this regard, data available in the literature show the complexity of the interactions (surface reorganization, non-specific/specific protein adsorption, and chemical reactions such as acid-base, ion pairing, ion exchange, hydrogen bonding, divalent-ion bridging) and the interrelationship between biological environments, interfacial properties, and surface functional groups responsible for the biological responses. Because of the multidisciplinary nature of surface and interfacial phenomena at the surface of biomedical polymers, this review focuses on several aspects of current work published on poly(alpha-hydroxy acid)s and their associated copolymers:surface structure-biomedical function relationships;physicochemical strategies for surface modification; and, finally,synthetic strategies to increase biocompatibility for specific in-vivo and/or in-vitro biomedical applications.
Biocompatible Materials↗
Characterization of the 2-hydroxy-acid dehydrogenase McyI, encoded within the microcystin biosynthesis gene cluster of Microcystis aeruginosa PCC7806.
The cyanobacterium Microcystis aeruginosa is widely known for its production of the potent hepatotoxin microcystin. This cyclic heptapeptide is synthesized non-ribosomally by the thio-template function of a large modular enzyme complex encoded within the 55-kb microcystin synthetase gene (mcy) cluster. The mcy gene cluster also encodes several stand-alone enzymes, putatively involved in the tailoring and export of microcystin. This study describes the characterization of the 2-hydroxy-acid dehydrogenase McyI, putatively involved in the production of d-methyl aspartate at position 3 within the microcystin cyclic structure. A combination of bioinformatics, molecular, and biochemical techniques was used to elucidate the structure, function, regulation, and evolution of this unique enzyme. The recombinant McyI enzyme was overexpressed in Escherichia coli and enzymatically characterized. The hypothesized native activity of McyI, the interconversion of 3-methyl malate to 3-methyl oxalacetate, was demonstrated using an in vitro spectrophotometric assay. The enzyme was also able to reduce alpha-ketoglutarate to 2-hydroxyglutarate and to catalyze the interconversion of malate and oxalacetate. Although NADP(H) was the preferred cofactor of the McyI-catalyzed reactions, NAD(H) could also be utilized, although rates of catalysis were significantly lower. The combined results of this study suggest that hepatotoxic cyanobacteria such as M. aeruginosa PCC7806 are capable of producing methyl aspartate via a novel glutamate mutase-independent pathway, in which McyI plays a pivotal role.
Alcohol Oxidoreductases↗
Bone-derived growth factor release from poly(alpha-hydroxy acid) implants in vitro.
Matrix proteins were extracted from bovine cortical bone and polymer implant discs (13 mm x 2 mm composed of 50:50 poly DL-lactide-co-glycolide; mol. wt. approximately 9000) prepared by compression moulding granules with lyophilized bone matrix extracts (BMX) 10.1 (w/w). BMX-containing polymers were cultured for 5 wk in either serum-free Dulbecco's modification of Eagle's medium (DMEM) or phosphate buffer, and growth factor activity released into the media assayed by its ability to stimulate the proliferation of murine fibroblast BALB/c/3T3 cells. Approximately 60-75% of the biological activity was released during the first week of culture; however, less than half of the growth factor units originally incorporated into the implants retained biological activity. Scanning electron microscopy revealed the development of significant internal porosity by week 2; the size of the channels, pores and surface openings suggested they were of the right order for bone ingrowth. These preliminary findings suggest that poly(alpha-hydroxy acid) polymers containing bone-derived growth factors could have potential for stimulating osseous regeneration in vivo.
3T3 Cells↗
Incorporation of 1-chlorooctadecane into FA and beta-hydroxy acids of Marinobacter hydrocarbonoclasticus.
The lipids of the gram-negative marine bacterium Marinobacter hydrocarbonoclasticus, cultivated in synthetic seawater supplemented with 1-chlorooctadecane as sole source of carbon, were isolated, purified, and their structures determined. Three pools of lipids were isolated according to the sequential procedure used: unbound lipids extracted by organic solvents, ester-bound lipids released under alkaline conditions, and amide-bound lipids released by acid hydrolysis. FA isolated from the unbound lipids included omega-chlorinated (21%, w/w, of this fraction; C16 predominant) and nonchlorinated compounds (22%, w/w; C18 predominant). These acids were accompanied by a high proportion of omega-chloro-C18 alcohols (43%, w/w) and a lower amount of omega-chloro-beta-hydroxy-C18, -C16, and -C14 acids (5%, w/w). These data, together with the isolation from the culture medium of gamma-butyrolactone, suggested a metabolism of 1-chlorooctadecane through oxidation into omega-chloro acid and then the classic beta-oxidation pathway. The analysis of the ester-bound and amide-bound lipids revealed that significant amounts of omega-chloro-beta-hydroxy C10-C12 acids were incorporated into the lipopolysaccharides of the bacterium. Incorporation of these omega-chloro-beta-hydroxy acids into the lipopolysaccharides represents a novel route for chloroalkane assimilation in hydrocarbonoclastic gram-negative bacteria. The formation of chlorinated hydroxy acids, like the omega-chloro FA in the cellular lipids, could account for an incomplete mineralization of chloroparaffins in the environment.
Fatty Acids↗
Biosynthesis of 2-aceto-2-hydroxy acids: acetolactate synthases and acetohydroxyacid synthases.
Two groups of enzymes are classified as acetolactate synthase (EC 4. 1.3.18). This review deals chiefly with the FAD-dependent, biosynthetic enzymes which readily catalyze the formation of acetohydroxybutyrate from pyruvate and 2-oxobutyrate, as well as of acetolactate from two molecules of pyruvate (the ALS/AHAS group). These enzymes are generally susceptible to inhibition by one or more of the branched-chain amino acids which are ultimate products of the acetohydroxyacids, as well as by several classes of herbicides (sulfonylureas, imidazolinones and others). Some ALS/AHASs also catalyze the (non-physiological) oxidative decarboxylation of pyruvate, leading to peracetic acid; the possible relationship of this process to oxygen toxicity is considered. The bacterial ALS/AHAS which have been well characterized consist of catalytic subunits (around 60 kDa) and smaller regulatory subunits in an alpha2beta2 structure. In the case of Escherichia coli isozyme III, assembly and dissociation of the holoenzyme has been studied. The quaternary structure of the eukaryotic enzymes is less clear and in plants and yeast only catalytic polypeptides (homologous to those of bacteria) have been clearly identified. The presence of regulatory polypeptides in these organisms cannot be ruled out, however, and genes which encode putative ALS/AHAS regulatory subunits have been identified in some cases. A consensus sequence can be constructed from the 21 sequences which have been shown experimentally to represent ALS/AHAS catalytic polypeptides. Many other sequences fit this consensus, but some genes identified as putative 'acetolactate synthase genes' are almost certainly not ALS/AHAS. The solution of the crystal structures of several thiamin diphosphate (ThDP)-dependent enzymes which are homologous to ALS/AHAS, together with the availability of many amino acid sequences for the latter enzymes, has made it possible for two laboratories to propose similar, reasonable models for a dimer of catalytic subunits of an ALS/AHAS. A number of characteristics of these enzymes can now be better understood on the basis of such models: the nature of the herbicide binding site, the structural role of FAD and the binding of ThDP-Mg2+. The models are also guides for experimental testing of ideas concerning structure-function relationships in these enzymes, e.g. the nature of the substrate recognition site. Among the important remaining questions is how the enzyme suppresses alternative reactions of the intrinsically reactive hydroxyethylThDP enamine formed by the decarboxylation of the first substrate molecule and specifically promotes its condensation with 2-oxobutyrate or pyruvate.
Acetolactate Synthase↗
OXIDATION WITH NICKEL PEROXIDE. 3. OXIDATIVE CLEAVAGE OF ALPHA-GLYCOLS, ALPHA-HYDROXY ACIDS, ALPHA-KETO ALCOHOLS, AND ALPHA-KETO ACIDS.
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Alcohols↗
[Phenols & ether-soluble aromatic hydroxy acids in the blood of patients with renal diseases & the mechanism of their renal excretion].
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Acids↗
[Synthesis of aliphatic 2-amino-3-hydroxy acids and separation of their diastereoisomers with the aid of copper chelates].
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Amino Acids↗
Effects of inhibitors on mitochondrial D-alpha-hydroxy acid dehydrogenase.
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Alcohol Oxidoreductases↗
[Respiratory activity of the mitochondria of the liver and the heart as well as of "electron-transfer particles" with 2-hydroxy acids].
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Electrons↗
Alpha hydroxy acids for skin care.
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Cosmetics↗
Identification of an archaeal 2-hydroxy acid dehydrogenase catalyzing reactions involved in coenzyme biosynthesis in methanoarchaea.
Two putative malate dehydrogenase genes, MJ1425 and MJ0490, from Methanococcus jannaschii and one from Methanothermus fervidus were cloned and overexpressed in Escherichia coli, and their gene products were tested for the ability to catalyze pyridine nucleotide-dependent oxidation and reduction reactions of the following alpha-hydroxy-alpha-keto acid pairs: (S)-sulfolactic acid and sulfopyruvic acid; (S)-alpha-hydroxyglutaric acid and alpha-ketoglutaric acid; (S)-lactic acid and pyruvic acid; and 1-hydroxy-1,3,4,6-hexanetetracarboxylic acid and 1-oxo-1,3,4, 6-hexanetetracarboxylic acid. Each of these reactions is involved in the formation of coenzyme M, methanopterin, coenzyme F(420), and methanofuran, respectively. Both the MJ1425-encoded enzyme and the MJ0490-encoded enzyme were found to function to different degrees as malate dehydrogenases, reducing oxalacetate to (S)-malate using either NADH or NADPH as a reductant. Both enzymes were found to use either NADH or NADPH to reduce sulfopyruvate to (S)-sulfolactate, but the V(max)/K(m) value for the reduction of sulfopyruvate by NADH using the MJ1425-encoded enzyme was 20 times greater than any other combination of enzymes and pyridine nucleotides. Both the M. fervidus and the MJ1425-encoded enzyme catalyzed the NAD(+)-dependent oxidation of (S)-sulfolactate to sulfopyruvate. The MJ1425-encoded enzyme also catalyzed the NADH-dependent reduction of alpha-ketoglutaric acid to (S)-hydroxyglutaric acid, a component of methanopterin. Neither of the enzymes reduced pyruvate to (S)-lactate, a component of coenzyme F(420). Only the MJ1425-encoded enzyme was found to reduce 1-oxo-1,3,4,6-hexanetetracarboxylic acid, and this reduction occurred only to a small extent and produced an isomer of 1-hydroxy-1,3,4,6-hexanetetracarboxylic acid that is not involved in the biosynthesis of methanofuran c. We conclude that the MJ1425-encoded enzyme is likely to be involved in the biosynthesis of both coenzyme M and methanopterin.
Alcohol Oxidoreductases↗