Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:034761 (insulin)
 211,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In perifused isolated pancreatic islets alpha-ketoisocaproic acid (KIC) or alpha-ketocaproic acid (KC) induced a high insulin secretion rate and a steep increase of the fluorescence of reduced pyridine pyridine nucleotides [NAD(P)H] which fell again to almost prestimulatory levels 6 min after medium change. Insulin release in response to alpha-ketooctanoic (KO) acid started slowly and was accompanied by a decrease of the NAD(P)H-fluorescence trace. Beta-phenylpyruvate which is known to initiate insulin release also caused a fluorescence decrease. Alpha-keto-isovaleric (KIV) acid or pyruvate had no significant effects upon insulin secretion or NAD(P)H-fluorescence. In contrast to l-leucine, l-norleucine or l-valine did not enhance insulin release or fluorescence of NAD(P)H. KIV, alpha-keto-beta-methylvaleric acid (KMV), KIC and KC raised the production their corresponding amino acids by islet cells. From these results it is concluded that alpha-ketomonocarboxylic acids as such trigger insulin release by acting upon receptor sites which differ from those occupied by amino acids.
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PMID:Effects of alpha-ketomonocarboxylic acids upon insulin secretion and metabolism of isolated pancreatic islets. 0 87

The specificity of thermomycolase toward glucagon and the oxidized A and B chains of insulin was investigated. Extensive digestion of glucagon occurred when conducted at pH 7.0 and 45 degrees C for 40 min, whereas hydrolysis of only three peptide bonds occurred at pH 7.0 and 28 degrees C for 5 min. A similar situation was observed for the oxidized B chain of insulin, which exhibited only a single major cleavage after 5 min at 25 degrees C. No well-defined specificity for particular amino acid residues was evident, but ready hydrolysis of peptide bonds occurred within sequences containing non-polar residues. This endoproteinase must therefore possess an extended hydrophobic binding site for polypeptides. Thermomycolase hydrolysed acetylalanylalanylalanine methyl ester and elastin-Congo Red at 22 and 8.5 times the rate of porcine elastase respectively. A limited degradation of native collagen and significant hydrolysis of benzyloxycarbonyl-Gly-Pro-Leu-Gly-Pro were suggestive of some collagenase-like activity. No keratinase activity was apparent.
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PMID:The substrate specificity of thermomycolase, an extracellular serine proteinase from the thermophilic fungus Malbranchea pulchella var. sulfurea. 0 73

Preliminary studies have been made of the 250 MHz nuclear magnetic resonance spectra of both insulin and DPI. Differences have been found between DPI and insulin spectra, which indicate that the splitting off of the B-chain C-terminal pentapeptide from insulin has brought about local changes in the conformation of the protein molecule in solution. It seems that these conformational changes have little effect on the biological activity of the hormone. Many studies have revealed that for insulin molecules in solution, an equilibrium exists between aggregation and dissociation, their state of aggregation bearing a close relationship to the concentration as well as pH of the insulin solution. Changes in the concentration and pH value of DPI solutions do not significantly affect the NMR spectra. But as the concentration and pH of the solution are increased, the methyl regions for valine, leucine, and isoleucine and aromatic regions of the insulin spectra are broadened. All these show that zinc-free DPI molecules probably exist as monomers in solution.
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PMID:Structural studies on des-pentapeptide (B26-30)-insulin. V. High resolution NMR studies. 1 Jun 24

Induction of delta-aminolevulinic acid synthetase by allylisopropylacetamide in organ-cultured chick embryo liver was not appreciably influenced by any of cycli AMP, dibutyryl cyclic AMP, theophylline, glucose, insulin, glucagon, epinephrine, isoproterenol, and hydrocortisone, whereas the activity of tyrosine aminotransferase significantly increased in response to cyclic AMP and some of those hormones. Accumulation of delta-aminolevulinic acid synthetase in the cultured liver cytosol fraction was not appreciably increased by the addition of dibutyryl cyclic AMP or insulin to the incubation medium. Apparently the behaviors of the induction of delta-aminolevulinic acid synthetase in chick embryo liver in ovo and in vitro differ from those in the livers of adult chicken and rat. High concentrations of chloramphenicol suppressed significantly the allylisopropylacetamide-induced increase of delta-aminolevulinic acid synthetase as well as incorporation of 14C-leucine into proteins. The activity of tyrosine aminotransferase, however, was rather increased when relatively low concentrations of chloramphenicol were added to the medium.
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PMID:Comparative studies of the effects of cyclic AMP, various hormones and chloramphenicol on the induction of delta-aminolevulinic acid synthetase and tyrosine aminotransferase in the organ-cultured chick embryo liver. 1 73

The endopeptidase, post-proline cleaving enzyme, has been purified 10,500-fold in an overall yield of 18% from lamb kidney. The enzyme possesses a specific activity of 45 mumol/mg/min as tested with the substrate Z-Gly-Pro-Leu-Gly (Km = 6.0 X 10(-5)), has a molecular weight of 115,000, is comprised of two subunits with a molecular weight of 57,000, and exhibits maximal activity at pH 7.5 to 8.0. With the exception of the -Pro-Pro linkage, the -Pro-X-peptide bond (X equals L- and D-amino acid residues) located internally in the peptide sequence can be hydrolyzed (cleavage occurs faster when X = lipophilic side chain as compared to X = acidic side chain). The appropriate -Pro-X- bonds in zinc-free porcine insulin, oxytocin, arginine vasopressin, angiotensin II, bradykinin-potentiating factor were cleaved. Human gastrin, adrenocorticotropic hormone, denatured guinea pig skin collagen, and ascaris cuticle collagen were not degraded. Dipeptides with the structure Z-Pro-LD-X competitively inhibit post-proline cleaving enzyme.
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PMID:Post-proline cleaving enzyme. Purification of this endopeptidase by affinity chromatography. 1 73

A system of preparation of rat hepatocytes with extended viability has been developed to study the role of hormones and other plasma components upon secretory protein synthesis. Hepatocytes maintained in minimal essential medium reduced the levels of all amino acids in the medium except the slowly catabolized amino acids leucine, isoleucine, and valine, which steadily increase as the result of catabolism of liver protein. Although the liver cells catabolize 10-15% of their own protein during a 20-h incubation, the cells continue to secrete protein in a linear fashion throughout the period. The effects of insulin, cortisol, and epinephrine on general protein synthesis, and specifically on fibrinogen and albumin synthesis, have been tested on cells from both normal rats and adrenalectomized rats. Cells from normal animals show preinduction of tyrosine amino transferase (TAT), having at the time of isolation a high level of enzyme which shows only an increase of approximately 60% upon incubation with cortisol. In contrast, cells from adrenalectomized animals initially have a low level of enzyme which increases fourfold over a period of 9 h. The effects of both epinephrine and cortisol on protein synthesis are also much larger in cells from adrenalectomized animals. After a delay of several hours, cortisol increases fibrinogen synthesis sharply, so that at the end of the 20-h incubation, cells treated with hormone have secreted nearly 2.5 times as much fibrinogen as control cells. The effect is specific; cortisol stimulates neither albumin secretion nor intracellular protein synthesis. The combination of cortisol and epinephrine strongly depresses albumin synthesis in both types of cells. Insulin enhances albumin and general protein synthesis but has little effect on fibrinogen synthesis.
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PMID:Plasma protein synthesis by isolated rat hepatocytes. 1 83

Systematic analysis of the hydrolysis of benzyloxycarbonyl (Cbz)-dipeptides by cathepsin A [EC 3.4.12.1] purified from rat liver lysosomes showed that multiple forms of cathepsin A preferentially cleave peptide bonds with leucine, methionine, and phenylalanine. Cbz-Met-Met, -Met-Phe, -Phe-Met, and -Phe-Ala were hydrolyzed 6 to 8 times faster than the standard substrates, Cbz-Glu-Phe and Cbz-Glu-Tyr. The pH optima of the hydrolyses were 4.6 to 5.8. Hydrolysis of peptide bonds with glycine, isoleucine, and proline was very slow, but the rate depended on the nature of the adjacent amino acids. Proteins such as albumin, cytochrome c, gamma-globulin, hemoglobin, histone, myoglobin, and myosin were scarecely degraded. Peptide hormones, such as glucagon and adrenocorticotropic hormone (ACTH) were hydrolyzed markedly with optimum pH's of 4.5 and 4.6, respectively. Angiotensin I, II, bradykinin, Lys- and Met-Lysbradykinin (kallidin and Met-kallidin), and substance P were also hydrolyzed at appreciable rates. pH optima for these peptide hormones were 5.2 to 5.6. On the other hand, insulin and its A chain, luteinizing hormone-releasing hormone (LH-RH), oxytocin and vasopressin were cleaved slowly. In the hydrolyses of glucagon and other peptides, multiple forms of rat liver lysosomal cathepsin A again showed a carboxypeptidase nature, cleaving peptide bonds sequentially from the carboxyl terminal. Almost all of the amino acids were cleaved on prolonged incubation. Vaso-activites of angiotensin II and bradykinin were rapidly lost on hydrolysis by cathepsin A. Lysosomal cathepsin C [dipeptidylaminopeptidase I, EC 3.4.14.1] also activated angiotensin II, but did not inactive bradykinin. Cathepsin A, therefore, can be regarded as one of the lysosomal angiotensinases and kinases. No distinct differences were observed between the multiple forms of cathepsin A in these hydrolyses and inactivations of peptides.
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PMID:Studies on cathepsins of rat liver lysosomes. III. Hydrolysis of peptides, and inactivation of angiotensin and bradykinin by cathepsin A. 1 61

The synthesis of neurotransmitters in mammalian brain responds rapidly to changes in precursor availability. Serotonin synthesis depends largely on the brain concentrations of L-tryptophan, its precursor amino aicd. This relationship appears to be physiologic: when brain tryptophan levels vary because of insulin secretion or meal ingestion, corresponding alterations occur in the rate of serotonin formation. The ability of any food to modify brain tryptophan (and serotonin) depends on how its ingestion changes the serum concentration of not only tryptophan, but also several other large neutral amino acids that compete with tryptophan for uptake into the brain. Such precursor-induced changes in brain serotonin appear to be functionally important: animals having a reduced level of brain serotonin (caused by the chronic ingestion of a naturally tryptophan-poor diet, such as corn) demonstrate a heightened sensitivity to painful stimuli; this pain sensitivity can be acutely restored to normal values by a single injection of L-tryptophan, which rapidly elevates brain serotonin. The synthesis of catecholamines (e.g., dopamine, norepinephrine) in the brain also varies with the availability of the precursor amino acid L-tyrosine. Single injections of this amino acid increase brain tyrosine levels and accelerate brain catechol synthesis, while injections of a competing neutral amino acid (e.g., leucine, tryptophan) reduce brain tyrosine and its rate of conversion to dopa. The rate of catecholamine synthesis, however, appears to be influenced less by precursor levels than is serotonin formation: tyrosine hydroxylase, whcih catalyzes the rate-limiting step in catecholamine synthesis, responds strongly to end-product inhibition and to other controls that reflect variations in neuronal activity. The synthesis of acetylcholine in brain responds to substrate (choline) availability much like serotonin synthesis. Short-term alterations in brain choline levels are mirrored by similar changes in brain acetylcholine concentration. Variations in the daily dietary intake of choline also modify brain choline and acetylcholine. The relationship between choline availability and acetylchyoline synthesis has already foudn a cletween choline availability and acetylchyoline synthesis has already found a clinical application: choline has been used successfully in the treatment of tardive dyskinesia, a disorder of the central nervous system thought to reflect a deficiency in cholinergic transmission. These relationships between precursor availability from the periphery and brain neurotransmitter synthesis may ultimately provide the brain with information about peripheral metabolic state.
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PMID:Effects on the diet on brain neurotransmitters. 1 61

The specificity and mode of action of an acid proteinase (EC 3.4.23.6) from Aspergillus saitoi were investigated with oxidized B-chain of insulin, angiotensin II and bradykinin. Further purification of acid proteinase was performed with N,O-dibenzyloxycarbonyl-tyrosine hexamethylene-diamino-Sepharose 4B affinity chromatography and isoelectric focusing. The purified enzyme was free of any other proteolytic activity demonstrated in Asp. saitoi. Acid proteinase from Asp. saitoi hydrolyzed primarily two peptide bonds in the oxidized B-chain of insulin, the Leu(15)-Tyr(16) bond and the Phe(24)-Phe(25) bond. Additional cleavages of the bonds His(10)-Leu(11), Ala(14)-Leu(15) and Tyr(16)-Leu(17) were also noted. Primary splitting sites at Leu(15)-Tyr(16) and Phe(24-)-Phe(25) with acid proteinase from Asp. saitoi were identical with those reported in the work of cathepsin D (EC 3.4.23.5) from human erythrocyte. Hydrolysis of angiotensin II was observed at the Tyr(4)-Ile(5) bond. In conclusion, peptide bonds which have a hydrophobic amino acid such as phenylalanine, tyrosine, leucine and isoleucine in the P'1 position (as defined by Berger and Schechter, [29]) are preferentially cleaved by the trypsinogenactivating acid proteinase from Asp. saitoi.
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PMID:Purification of an acid proteinase from Aspergillus saitoi and determination of peptide bond specificity. 2 99

In the presence of glucose (2 mg/ml), leucine (10 mM) noticeably increased islets' NADPH contents as well as the NADPH:NADP ratio; the changes occurred as soon as 1 min after its addition. NADH concentrations were also increased by leucine. The NADPH:NADP ratio as well as insulin release stimulated by glucose plus leucine were markedly decreased by methylene blue. The thiol oxidants diamide and tert-butyl hydroperoxide also inhibited insulin secretion in response to glucose plus leucine. Employing the perfused pancreas technique, the insulin-releasing action of p-chloromercuribenzoate was further enhanced by leucine. The combined effects were inhibited by tert-butyl hydroperoxide, however. Our data suggest that the insulin-releasing action of leucine depends on the islets' NADPH and reduced glutathione (GSH); in addition, leucine may contribute to insulin secretion by increasing the islet NADPH:NADP ratio and the NADH:NAD ratio. From the data, we assume that the observed increase of NADPH may lead via GSH to an increase in the number of such thiol groups in the beta-cell membrane, which are believed to be related to stimulation of insulin release and, thus, to increase the sensitivity of the beta-cell to stimulation by glucose and/or leucine.
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PMID:Effect of leucine on the pyridine nucleotide contents of islets and on the insulin released--interactions in vitro with methylene blue, thiol oxidants, and p-chloromercuribenzoate. 3 18


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