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A novel enzymatic process for the synthesis of D-(+)-pantothenic acid through the asymmetric reduction of the 2' -ketopantothenate ester is described. Candida macedoniensis AKU 4588 was found to convert ethyl 2' -ketopantothenate (80 mg/ml) almost specifically to ethyl D-(+)-pantothenate (>98% enantiomeric excess), with a molar yield of 97.2%.
Current lipid-altering agents that lower low density lipoprotein cholesterol (LDL-C) primarily through increased hepatic LDL receptor activity include statins, bile acid sequestrants/resins and cholesterol absorption inhibitors such as ezetimibe, plant stanols/sterols, polyphenols, as well as nutraceuticals such as oat bran, psyllium and soy proteins; those currently in development include newer statins, phytostanol analogues, squalene synthase inhibitors, bile acid transport inhibitors and SREBP cleavage-activating protein (SCAP) activating ligands. Other current agents that affect lipid metabolism include nicotinic acid (niacin), acipimox, high-dose fish oils, antioxidants and policosanol, whilst those in development include microsomal triglyceride transfer protein (MTP) inhibitors, acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, gemcabene, lifibrol, pantothenic acid analogues, nicotinic acid-receptor agonists, anti-inflammatory agents (such as Lp-PLA(2) antagonists and AGI1067) and functional oils. Current agents that affect nuclear receptors include PPAR-alpha and -gamma agonists, while in development are newer PPAR-alpha, -gamma and -delta agonists, as well as dual PPAR-alpha/gamma and 'pan' PPAR-alpha/gamma/delta agonists. Liver X receptor (LXR), farnesoid X receptor (FXR) and sterol-regulatory element binding protein (SREBP) are also nuclear receptor targets of investigational agents. Agents in development also may affect high density lipoprotein cholesterol (HDL-C) blood levels or flux and include cholesteryl ester transfer protein (CETP) inhibitors (such as torcetrapib), CETP vaccines, various HDL 'therapies' and upregulators of ATP-binding cassette transporter (ABC) A1, lecithin cholesterol acyltransferase (LCAT) and scavenger receptor class B Type 1 (SRB1), as well as synthetic apolipoprotein (Apo)E-related peptides. Fixed-dose combination lipid-altering drugs are currently available such as extended-release niacin/lovastatin, whilst atorvastatin/amlodipine, ezetimibe/simvastatin, atorvastatin/CETP inhibitor, statin/PPAR agonist, extended-release niacin/simvastatin and pravastatin/aspirin are under development. Finally, current and future lipid-altering drugs may include anti-obesity agents which could favourably affect lipid levels.
Palmitate metabolism was determined in isolated perfused hearts containing elevated levels of coenzyme A (CoA). CoA levels were elevated by perfusing hearts with Krebs-Henseleit buffer containing 0.1 mM cysteine, 0.2 mM dithiothreitol, 15 microM pantothenic acid, and no energy substrate. After 45 min, CoA levels had increased from 537 +/- 14 to 818 +/- 44 nmol/g dry wt. When these hearts containing high CoA were subsequently perfused as working hearts with buffer containing 11 mM glucose and 1.2 mM palmitate, long chain acyl CoA levels increased (94 +/- 5-305 +/- 6 nmol/g dry wt). Oxidation of exogenous palmitate (as measured by 14CO2 production from [U-14C]palmitate) was significantly depressed in hearts containing elevated CoA levels. This apparent reduction in fatty acid oxidation was not due to increased glucose or glycogen utilization. When the concentration of palmitate was decreased to 0.4 mM, acyl CoA levels increased much less, and the apparent rate of [14C]palmitate oxidation was unaffected by elevated CoA. Hearts containing high CoA also incorporated [14C]palmitate into triacylglycerols to a greater extent than did control hearts. To determine whether the apparent decrease in exogenous palmitate oxidation resulted from an increased utilization of unlabeled endogenous triacylglycerol fatty acid, [14C]palmitate specific activity was measured in myocardial acylcarnitine. The specific activity of this pool of fatty acid was similar in both control hearts and hearts containing elevated CoA. Thus dilution of the total cellular [14C]acyl carnitine by triacylglycerol hydrolysis was not sufficient to account for the decrease in [U-14C]palmitate oxidation. The possibility that a small pool of rapidly turning over acyl carnitine becomes dilated is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)
1. Pantothenate kinase, which is present in cytosol, was studied in preparations from livers of rats fed normal or clofibrate-enriched diets. Effects of CoA, dephospho-CoA and different acyl-CoA derivatives on this enzyme activity were examined in vitro. 2. With partially purified pantothenate kinase or crude particle-free supernatant from the liver of normal or clofibrate-treated rats, Km for pantothenic acid was 0.016 mmol/l at the pH optimum 6.1. 3. Acetyl-CoA, propionyl-CoA, malonyl-CoA and other short-chain acyl-CoA derivatives were strong inhibitors of pantothenate kinase, with Ki in the range 0.001-0.003 mmol/l. The mechanism of inhibition appeared to be of an uncompetitive type. 4. Free CoA has been held to be the main regulator of pantothenate kinase. We found, however, that free CoASH, dephospho-CoA and long-chain acyl-CoA (with Ki 0.003-0.08 mmol/l) were less efficient inhibitors than acetyl-CoA. 5. With pantothenate kinase from clofibrate-treated animals, all inhibitors were less potent. This was most pronounced when the enzyme was assayed in a crude supernatant fraction, possibly because the inhibitors were degraded and/or protein bound. Such a reduction of normal inhibition may contribute to the increased biosynthesis of CoA previously observed during clofibrate treatment. 6. Fasting or diabetes leads to an increase of long-chain acyl-CoA and total CoA in the liver. The increase of CoA has been explained by increased acylation of CoA, and thereby reduced feed-back inhibition by free CoASH at the pantothenate kinase level. We propose another explanation. In these metabolic states, the cytosolic pool of acetyl-CoA is decreased. Since pantothenate kinase is present only in the cytosol, its activity will be released and the biosynthesis of CoA will increase. 7. Acetyl-CoA is probably a more important physiological regulator of pantothenate kinase activity than is free CoASH.
For improved production of coenzyme A (CoA), a mutant of Brevibacterium ammoniagenes IFO127071 resistant to oxypantetheine, the corresponding oxygen analog of pantetheine, was obtained. In the mutant, activity of pantothenate kinase (EC 2.7.1.33), the first-step enzyme for the biosynthesis of CoA from pantothenic acid, l-cysteine, and ATP, was about threefold higher than that in the parent strain. As the main regulation mechanism of CoA biosynthesis in this bacterium is negative feedback inhibition of pantothenate kinase by CoA, the mutant is very useful as a catalyst for practical production of CoA. When added to culture broth of the mutant, pantothenate, l-cysteine, and AMP gave 9.3 mg of CoA per ml. With pantetheine and AMP, 11.5 mg of CoA per ml accumulated. These values were about threefold higher than those with the parent strain, and more than 70% of the added AMP was converted to CoA.
The role of B group vitamins in preventing neuronal death against excitotoxicity was investigated. Neuronal death of cultured mouse cerebellar granule neurons (CGNs) caused by glutamate (50 microM) or NMDA (200 microM) was delayed in CGNs that had been treated with riboflavin (B2), folic acid (B9) or cynocobalamin (B12) for 18 h. Such neuroprotection by B2, B9 and B12 was in a dose- and time-dependent manner. In contrast, application of thiamin (B1), nicotinamide (B3), d-pantothenic acid (B5), pyridoxine (B6) or carnitine (BT) did not ameliorate glutamate or NMDA-mediated excitotoxicity to CGCs. These results are the first indication that certain B group vitamins are not only required for the normal brain function, but can also play a protective role against excitotoxicity to the brain.
The dosages of aflatoxin B1 (AFB1) required to produce significant changes in concentrations of B vitamins in plasma and bile and of amino acids in plasma of rabbits were determined. Folate increased by 98% in plasma, whereas concentration of thiamine, vitamin B6, and biotin decreased by more than 50%. In bile, choline and biotin increased 14- and 18-fold, respectively, whereas folate and niacin decreased by more than 50%. All amino acids in plasma increased between 76 and 155%. The dosages of AFB1 required to induce these changes were usually between 12.5 and 37.5 microgram/kg of body weight per day. Except for changes in biliary concentrations of pantothenic acid, folic acid, and biotin, lower threshold dosages of aflatoxin were required to produce weight loss and anorexia (5.0 and 8.5 microgram of AFB1/kg per day, respectively) than for changes in vitamins and amino acids (approximately 25 to 50 microgram of AFB1/kg per day). The data indicated that AFB1 interfered with the metabolism of B vitamins and amino acids in rabbits.
B-vitamin supplementation of diets for 144 shipping-stressed crossbred calves (116 kg) at levels up to 10 times that recommended for growing pigs did not influence (P greater than .20) weight gain or feed conversion during a 56-d receiving trial. However, vitamin supplementation tended (P less than .10) to reduce morbidity. In a second trial, supplemental B-vitamins had no effect (P greater than .20) on efficiency of microbial growth or site and extent of digestion of organic matter, acid detergent fiber and N. Supplemental dietary riboflavin, niacin, folic acid, B12 and ascorbic acid were largely metabolized [degraded and (or) absorbed] anterior to the small intestine, with escape values of 1, 3, 10 and 0% of added vitamins, respectively, while dietary B6 and biotin largely escaped the rumen. Thiamine and pantothenic acid were intermediate in ruminal escape (52 and 22%, respectively). Small intestinal absorption of thiamine, niacin, riboflavin, B6 and B12 averaged 75, 79, 25, 79 and 48%, respectively. Coefficients for ruminal escape and microbial synthesis for each B-vitamin were calculated using the slope-ratio technique. Measured flows for thiamine, riboflavin and B12 in a third experiment were similar to flows predicted from escape and synthesis equations, though flow of niacin and B6 were under-predicted by 37 and 44%, respectively. Results are interpreted to indicate that intestinal B-vitamin supply can be predicted based on dietary composition and intake.
Effects of deficiency of vitamins on early development of brain have been reviewed. Unusual developmental problems in neurogenesis specific for the brain and impairment of its functional capacities due to vitamin deficiency have been discussed. The species-specific "critical periods" in development of various systems have been mentioned. Indices such as reflex activity, locomotion, special senses, cognition and adaptive behavior were used for assessing brain maturation in experimental models and humans. Significant examples include brain anomalies in humans and other mammals caused by retinoid excess or deficit; increase in calbindin D28K, a vitamin D dependent calcium-binding protein during postnatal period in rat; hydrocephalus and exencephaly in prenatal rats and subarachnoidal or intracerebral hemorrhage in infants caused by vitamin E deficiency. Peripheral neuropathic lesions leading to infantile beriberi is caused by thiamine deficiency. Impaired growth in retinal layers leading to delay in maturation of electroretinogram and depth-perception in postnatal rats occur due to pyridoxine deficiency. Infants of severely vitamin B12 deficient mothers show abnormalities in behavior involving basal ganglia and pyramidal tract. Folic acid deficiency results in delayed maturation of the basic electroencepalographic patterns. In addition, vitamin-interactions leading to developmental errors have been pointed out. Vitamin B6 deficiency impairs vitamin B12 absorption and biotin deficiency may be aggravated by pantothenic acid deficiency. Vitamin C deficiency resulting in impaired metabolism may produce symptoms of deficiency of folic acid. Another characteristic examples is that iron absorption from dietary sources is dependent on ascorbic acid.
Mycobacillin synthetase lacks aspartic acid racemase, alanine racemase and glutamic acid racemase activities. The enzyme also does not respond to ATP-[32P]Pi exchange, nor does it catalyse the antibiotic synthesis in presence of amino acids of configuration opposite to that present in the molecule. Preincubation with optical isomers of opposite configuration inhibited the ATP-[32P]Pi exchange reaction to the extent of 60-90%. None of the three fractions of mycobacillin synthetase contained a pantothenic acid arm. Two molecules of ATP are required to synthesize one peptide bond of mycobacillin. Intermediate peptides of mycobacillin are not covalently linked to the three-fraction mycobacillin synthetase.
Some physical, catalytic, and regulatory properties of ketopantoate hydroxymethyltransferase (5,10-methylenetetrahydrofolate: alpha-ketoisovalerate hydroxymethyltranferase) from Escherichia coli are described. This enzyme catalyzes the reversible synthesis of ketopantoate (Reaction 1), an essential precursor of pantothenic acid. (1) HC(CH3)2COCOO- + 5,10-methylene tetrahydrofolate f in equilibrium r HOCH2C(CH3)2COCOO- + tetrahydrofolate It has a molecular weight by sedimentation equilibrium of 255,000, a sedimentation coefficient (S20,w) of 11 S, a partial specific volume of 0.74 ml/g, an isoelectric point of 4.4, and an absorbance, (see article), of 0.85. Polyacrylamide gel electrophoresis in sodium dodecyl sulfate and amino acid analyses give a subunit molecular weight of 27,000 and 25,700, respectively; both procedures indicate the presence of 10 identical subunits. The NH2-terminal sequence is Met-Tyr---. The enzyme is stable and active over a broad pH range, with an optimum from 7.0 to 7.6. It requires Mg2+ for activity; Mn2+, Co2+, Zn2+ are progressively less active. The enzyme is not inactivated by borohydride reduction in the presence of excess substrates, i.e. it is a Class II aldolase. Reaction 1f is partially inhibited by concentrations of formaldehyde (0.8 mM) and tetrahydrofolate (0.38 mM) below or near the Km values, apparent Km values are 0.18, 1.1 and 5.9 mM for tetrahydrofolate, alpha-ketoisovalerate, and formaldehyde, respectively. For Reaction 1r, apparent Km values are 0.16 and 0.18 mM, respectively, for ketopantoate and tetrahydrofolate, and the saturation curves for both substrates show positive cooperativity. Forward and reverse reactions occur at similar maximum velocities (Vmax approximately equal to 8 mumol of ketopantoate formed or decomposed per min per mg of enzyme at 37 degrees). Only 1-tetrahydrofolate is active in Reaction 1; d-tetrahydrofolate, folate, and methotrexate were neither active nor inhibitory. However, 1-tetrahydrofolate was effectively replaced with conjugates containing 1 to 6 additional glutamate residues; of these, tetrahydropterolpenta-, tetra-, and triglutamate were effective at lower concentrations than tetrahydrofolate itself; they were also the predominant conjugates of tetrahydrofolate present in E. coli. Alpha-Ketobutyrate, alpha-ketovalerate, and alpha-keto-beta-methylvalerate replaced alpha-ketoisovalerate as substrates; pyruvate was inactive as a substrate, but like isovalerate, 3-methyl-2-butanone and D- or L-valine, inhibited Reaction 1. the transferase has regulatory properties expected of an enzyme catalyzing the first committed step in a biosynthetic pathway. Pantoate (greater than or equal to 500 muM) and coenzyme A (above 1 mM) all inhibit; the Vmax is decreased, Km is increased, and the cooperativity for substrate (ketopantoate) is enhanced. Catalytic activity of the transferase is thus regulated by the products of the reaction path of which it is one component; transferase synthesis is not repressed by growth in the presence of pantothenate.
As natural eggs can contribute significantly to overcoming dietary deficits, we have designed and studied the composition of multiple-enriched eggs (Benefic eggs) whose composition is close to the natural egg. They are obtained by feeding laying hens in the usual way, but using additional autoclaved linseed, minerals, vitamins and lutein to provide the extra components. These eggs have greater nutritional value than standard. Thus 100 g of these eggs contains 6 times more of the omega-3 fatty acid ALA (15% of the French recommended daily allowance (RDA)), 3 times more DHA (100% of RDA), 3 times more vitamin D (30% of RDA), 4 times more folic acid (70% of RDA), 6 times more vitamin E (66% of RDA), 6 times more lutein and zeaxanthine (70% of international recommendation), 2.5 times more iodine (100% RDA), and 4 times more selenium (45% RDA). As the content of omega-6 fatty acids remains unchanged, the omega-6/omega-3 ratio is lower, and thus improved. These eggs contain a little less cholesterol and, like standard eggs, are rich in vitamin B12 (160% of RDA) and vitamin A (25% of RDA), plus vitamin B2 (riboflavin), vitamin B5 (pantothenic acid) and phosphorus. Proteins quality is indeed excellent. These eggs are interesting for everybody, and particularly appropriate for older people. The nutritional value of enriched eggs (similar to the multiple-enriched eggs of this study) has been assessed in animals and in human volunteers in terms of their influence on blood lipids. They improve the blood concentration of omega-3 fatty acids, HDL cholesterol, LDL cholesterol and triglycerides.
In general, low dietary intakes can account for much of poor vitamin nutriture reported among various elderly populations. Despite problems in assessing vitamin nutriture in the elderly, the 1980 RDAs for thiamin, riboflavin, and ascorbic acid seem appropriate for those populations. However, RDAs for vitamin A and folate may be too high and the RDAs for vitamin D, vitamin B-6, and vitamin B-12 may be too low, due to specified age-related changes in the metabolism of these vitamins. For vitamin E, vitamin K, niacin, biotin, and pantothenic acid, the data is conflicting and/or insufficient to make a judgment about the appropriateness of the RDAs or to estimate safe and adequate daily intakes for the elderly.
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Rat embryos explanted at 9.0, 9.5, and 10.5 days of gestation were cultured for periods of 61, 49, or 45 h, respectively, in extensively dialysed rat serum supplemented with various combinations of glucose, amino acids, and vitamins. Glucose was found to be a necessary and sufficient energy source for embryos of all three ages, and virtually no development took place in its absence. Only the youngest embryos required free amino acids for good development in dialysed serum, whereas at all three ages, vitamin supplementation was necessary. However, lack of vitamins had a much more marked deleterious effect on the younger embryos than on those explanted at 10.5 d. Experiments with media deficient in individual vitamins showed that for normal development, 9.0-d embryos required a number of vitamins--principally pantothenic acid, riboflavin, inositol, folic acid and niacinamide, whereas 10.5-d embryos needed only riboflavin. For embryos explanted at 9.5 d, the position was intermediate, with riboflavin and inositol the most significant vitamins. Inositol deficiency in embryos explanted at 9.5 d produced a characteristic neural tube defect--failure of closure at the level of the hindbrain. Thus it appears that both the range of micromolecular nutrients and the severity of developmental impairment in their absence decrease with advancing gestational age.
Phosphate-buffered (PBBM) and carbonate-buffered (CBBM) basal media were used in the formulation of defined media for the cultivation of Eubacterium limosum KIST612 with carbon monoxide (CO) as the sole energy source. The bacterium was adapted to the minimal media by sequential passage in media containing casamino acids and those containing ammonium chloride in the place of yeast extract. Biological growth was slower with a lower growth yield in the defined minimal media than in PBBM or CBBM. More butyrate was produced in phosphate-buffered media than in carbonate-buffered media. The bacteria grew without any organic nitrogen in the presence of trace quantities of biotin and pantothenic acid. Anaerobic digester fluid stimulated bacterial growth.
In this report, a complete defined medium and a minimally defined medium are described for Edwardsiella ictaluri. The complete defined medium consists of 46 individual components, including a basal salt solution, glucose, magnesium sulfate, iron sulfate, six trace metals, four nucleotides, 10 vitamins, and 19 amino acids. This medium supports growth in broth and on solid media. Optimal growth at 30(deg)C was obtained at pH 7.0, and at an osmolality of 390 mosmol/kg of H(inf2)O, with a glucose concentration of 4 g/liter. The defined minimal medium reduces the 46 components of the complete medium to eight essential components, including the basal salt solution, glucose, magnesium sulfate, pantothenic acid, and niacinamide. In addition, specific amino acids that depend on the specific requirements of the individual strains of E. ictaluri are added.
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