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At least 865 records · Page 48Linked to original sources
PubMed1980

Effects of delta-aminolaevulinic acid on contractile activity of rabbit duodenum.

delta-Aminolaevulinic acid (ALA) inhibited spontaneous contractions and contractions induced by acetylcholine, barium chloride or ouabain in rabbit duodenum preparations suspended in Ringe-Locke solution. Concentrations of ALA between 25--100 micrograms/ml reduced amplitude of spontaneous contractions and at levels above 200 micrograms ALA/ml spontaneous contractions caused. Muscle tone was decreased in proportion to logarithm of AL concentration between 25 and 1000 micrograms/ml. Gut ALA levels were increased by the treatment and returned to control values after washing, and pharmacological effects were full reversed. Neither tetrodotoxin nor atropine affected the gut's response to ALA. The response still occurred in calcium-free, high-calcium, potassium-free and high-potassium bathing fluid. Effects of ouabain resembled those of ALA only when gut had been pretreated with atropine; pretreatment with tetrodotoxin induced slight contracture. The observed pharmacological effects of ALA must be by actions additional to sodium pump inhibition.

Acetylcholine↗
PubMed1985

Effects of delta-aminolaevulinic acid on contractile activity in the isolated small intestine of the rabbit. Role of adrenergic receptors.

The porphyrin precursor, delta-aminolaevulinic acid (ALA) at concentrations of 0.23-7.6 mM caused dose-dependent inhibition of spontaneous contractions in isolated preparations of rabbit small intestine, suspended in Ringer-Locke solution. Contractions which returned after inhibition from 3.8 and 7.6mM ALA showed increased amplitude and from 7.6 mM ALA a reduction in rate. Pretreatment with prazosin (10(-7) M) significantly reduced the duration of inhibition exerted by 3.8 and 7.6 mM ALA and also the amplitude of contractions returning after this inhibition. Pretreatment with yohimbine (10(-6) M) and propranolol (7 X 10(-6) M) had no significant effects. Blocking of the release of noradrenaline in preparations by incubation with 6-hydroxydopamine (10(-3) M) or guanethidine (1.5 X 10(-5) M) did not prevent the inhibitory effects of ALA. The alpha 1 agonist, cirazoline (10(-5) M), inhibited contractile activity. This effect was blocked by prazosin (10(-7) M). The alpha 2 agonist, guanoxabenz (10(-5) M) had no detectable effect, in the presence of prazosin, to block any residual alpha 1 actions. It is concluded that alpha 1 receptors mediate inhibitory effects in this preparation and that ALA appears to have direct effects upon these receptors.

Aminolevulinic Acid↗
PubMed2002

Structure of porphobilinogen synthase from Pseudomonas aeruginosa in complex with 5-fluorolevulinic acid suggests a double Schiff base mechanism.

All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen (PBG) as a common precursor. Porphobilinogen synthase (PBGS) synthesizes PBG through the asymmetric condensation of two molecules of aminolevulinic acid (ALA). Crystal structures of PBGS from various sources confirm the presence of two distinct binding sites for each ALA molecule, termed A and P. We have solved the structure of the active-site variant D139N of the Mg2+-dependent PBGS from Pseudomonas aeruginosa in complex with the inhibitor 5-fluorolevulinic acid at high resolution. Uniquely, full occupancy of both substrate binding sites each by a single substrate-like molecule was observed. Both inhibitor molecules are covalently bound to two conserved, active-site lysine residues, Lys205 and Lys260, through Schiff bases. The active site now also contains a monovalent cation that may critically enhance enzymatic activity. Based on these structural data, we postulate a catalytic mechanism for P. aeruginosa PBGS initiated by a C-C bond formation between A and P-side ALA, followed by the formation of the intersubstrate Schiff base yielding the product PBG.

Aminolevulinic Acid↗
PubMed1969

Intramitochondrial localization of delta-aminolaevulate synthetase and ferrochelatase in rat liver.

Intramitochondrial loci for delta-aminolaevulate synthetase and ferrochelatase, the initial and final enzymes in haem synthesis, have been found in rat liver. Two different methods of fractionation were applied to mitochondria: (a) sonication and density-gradient centrifugation; (b) treatment with digitonin and differential centrifugation. Similar results were obtained with each technique. delta-Aminolaevulate synthetase is distributed similarly to two known matrix enzymes, malate dehydrogenase and glutamate dehydrogenase. Ferrochelatase is firmly bound to the the inner mitochondrial membrane. These results are considered in terms of the regulation of haem synthesis and in relation to mitochondrial biogenesis.

Amino Acids↗
PubMed1981

Conversion of 5-aminolaevulinate into haem by liver homogenates. Comparison of rat and chick embryo.

1. We have studied the kinetics of the conversion of 5-aminolaevulinate into haem and haem precursors in homogenates of livers of rats and chick embryos. Homogenates of fresh liver from both species efficiently convert 5-aminolaevulinate into haem. After frozen storage for 1 year, homogenates of rat, but not chick, liver have decreased rates of formation of haem with accumulation of more protoporphyrin. The rate of haem formation after storage is restored by addition of Fe2+ and menadione. 2. At all initial concentrations of 5-aminolaevulinate tested (2 microM-1 mM), homogenates of rat liver accumulate less protoporphyrin than haem. In contrast, homogenates of chick embryo liver accumulate more protoporphyrin than haem at concentration of 5-aminolaevulinate greater than 10 microM. Conversion of protoporphyrin into haem by homogenates of fresh or frozen chick embryo liver is not increased by addition of Fe2+. 3. Homogenates of liver from both species accumulate porphobilinogen; the kinetic parameters for this process reflect those of 5-aminolaevulinate dehydratase. 4. The results show that the rate-limiting enzyme for the hepatic conversion of 5-aminolaevulinate into protoporphyrin is porphobilinogen deaminase. In addition, chick liver, compared with rat liver, has only about one-fifth the activity of ferrochelatase, the final enzyme of the haem biosynthetic pathway, which inserts Fe2+ into protoporphyrin to form haem. 5. Comparison of these results with previous studies indicates that the homogenate system described here provides physiologically and clinically relevant information for study of hepatic haem synthesis and its control.

Aminolevulinic Acid↗
PubMed1985

Conversion of 5-aminolaevulinate into haem by homogenates of human liver. Comparison with rat and chick-embryo liver homogenates.

To assess whether the synthesis of haem can be studied in small amounts of human liver, we measured kinetics of the conversion of 5-aminolaevulinate into haem and haem precursors in homogenates of human livers. We used methods previously developed in our laboratory for studies of rat and chick-embryo livers [Healey, Bonkowsky, Sinclair & Sinclair (1981) Biochem. J. 198, 595-604]. The maximal rate at which homogenates of human livers converted 5-aminolaevulinate into protoporphyrin was only 26% of that for rat, and 58% of that for chick embryo. In the absence of added Fe2+, homogenates of fresh human liver resembled those of chick embryos in that protoporphyrin and haem accumulated in similar amounts, whereas fresh rat liver homogenate accumulated about twice as much haem as protoporphyrin. However, when Fe2+ (0.25 mM) was added to human liver homogenates, mainly haem accumulated, indicating that the supply of reduced iron limited the activity of haem synthase, the final enzyme in the haem-biosynthesis pathway. Addition of the potent iron chelator desferrioxamine after 30 min of incubation with 5-amino[14C]laevulinate stopped further haem synthesis without affecting synthesis of protoporphyrin. Thus the prelabelled haem was stable after addition of desferrioxamine. Since the conversion of 5-amino[14C]laevulinate into haem and protoporphyrin was carried out at pH 7.4, whereas the pH optimum for rat or bovine hepatic 5-aminolaevulinate dehydratase is about 6.3, we determined kinetic parameters of the human hepatic dehydrase at both pH values. The Vmax was the same at both pH values, whereas the Km was slightly higher at the lower pH. Our results indicate that the synthesis of porphyrins and haem from 5-aminolaevulinate can be studied with the small amounts of human liver obtainable by percutaneous needle biopsy. We discuss the implications of our results in relation to use of rat or chick-embryo livers as experimental models for the biochemical features of human acute porphyria.

Aminolevulinic Acid↗
PubMed1973

Coupling between bacteriochlorophyll and membrane protein synthesis in Rhodopseudomonas spheroides.

Bacteriochlorophyll-containing membranes from Rhodopseudomonas spheroides contain proteins with estimated molecular weights of 26,000, 22,000, 19,000, and 10,000-6,000 (proteins 9, 10, 11, and 15) when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Proteins 9, 10, and 11 may be associated with the reaction center form of bacteriochlorophyll and protein 15, with the light-harvesting form. These proteins were not detected in membranes from nonpigmented wild-type cells grown with high aeration. Proteins 10, 11, and 15 were not found in mutants with blocks in bacteriochlorophyll synthesis, including strain 8-17, which is blocked at the phytolation step. Protein 9 was found in significantly reduced amounts. Apparently, synthesis of the completed bacteriochlorophyll molecule is required for the occurrence of these proteins in the membrane. Gel autoradiography was used to follow the synthesis of membrane proteins in mutant H-5, which requires delta-aminolevulinic acid for bacteriochlorophyll synthesis. Incorporation of labeled amino acids into proteins 9 and 15 was curtailed preferentially in cells deprived of delta-aminolevulinic acid.

Amino Acids↗
PubMed1978

Erythrocyte delta-aminolaevulinic acid dehydratase activity and changes in delta-aminolaevulinic acid concentration in various forms of anaemia.

Whole blood delta-aminolaevulinic acid (ALA) concentrations and erythrocyte ALA dehydratase activity have been measured in patients with iron deficiency anaemia, megaloblastic anaemia and secondary anaemia, and in normal subjects. ALA concentration was found to be significantly increased in all types of anaemia compared with normal. Erythrocyte ALA dehydratase activity was significantly increased in iron deficiency and megaloblastic anaemia but not in secondary anaemia.

Aminolevulinic Acid↗
PubMed1979

Synthesis of model compounds relevant to the active-site-directed inactivation of L-asparaginase by 5-diazo-4-oxo-L-norvaline.

Earlier work has shown that 5-diazo-4-oxo-L-norvaline (DONV) irreversibly inactivates the L-asparaginase from E. coli by formation of a covalent bond in the region of the active site. Model compounds have been prepared to study this acid-labile covalent bond tentatively assigned to a serine or possibly a threonine residue in a decapeptide isolated from 14C-DONV-inactivated enzyme. Appropriately blocked DONV was found to alkylate methanol, and the hydroxyl function of blocked serine or threonine in the presence of boron trifluoride. The labile beta-ketoethers thus formed were reduced to the more stable beta-hydroxyethers. Facile lactonization of these 5-substituted-4-hydroxy-L-norvalines was observed. The diastereoisomers of both the lactonized and open forms of 5-methoxy-4-hydroxy-L-norvaline and related 4-hydroxy-L-2-amino acids of similar length were distinguishable on the amino acid analyzer. The beta-hydroxyethers derived from serine and threonine were hydrolyzed with acid and yielded the expected cleavage products. When the beta-ketoether was reduced by sodium borohydride prior to deblocking, in addition to the beta-hydroxyether, N-blocked amino alcohols were also formed, yielding a complex mixture of products.

Alkylation↗