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D Palm

Publications and source records attributed to D Palm.

At least 73 records · Page 4Linked to original sources
PubMed1988

Differentiation of beta 1- and beta 2-adrenoceptor-mediated effects in humans.

To differentiate beta 1- and beta 2-adrenoceptor-mediated effects in humans, we studied the effects of a 2-wk treatment of 12 male volunteers with the selective beta 1-adrenoceptor antagonist bisoprolol (1 x 10 mg/day) and the beta 2-selective antagonist ICI 118,551 (3 x 25 mg/day) on lymphocyte beta 2-adrenoceptor density and responsiveness [10 microM l-isoproterenol (IPN) evoked adenosine 3',5'-cyclic monophosphate (cAMP) increase] as well as on exercise- and IPN-induced changes in lymphocyte beta 2-adrenoceptor density, blood pressure, heart rate, and plasma norepinephrine levels. ICI 118,551 administration increased lymphocyte beta 2-adrenoceptor density and responsiveness by approximately 50%, whereas bisoprolol had no effect. Dynamic exercise on a bicycle and infusion of graded doses of IPN led to an approximately 100% increase in lymphocyte beta 2-adrenoceptor density; this was abolished by ICI 118,551 but not affected by bisoprolol. ICI 118,551 markedly attenuated IPN-induced decrease in diastolic blood pressure but did not affect increase in systolic blood pressure, whereas bisoprolol had opposite effects. The IPN-induced increase in heart rate, however, was antagonized by both bisoprolol and (to a greater extent) ICI 118,551. Finally, ICI 118,551 completely abolished the IPN-induced increase in plasma norepinephrine levels, whereas bisoprolol had no effect. These results indicate that bisoprolol and ICI 118,551 are suitable tools to differentiate in humans beta 1- and beta 2-adrenoceptor-mediated effects.

Adult↗
PubMed1988

Beta adrenoceptor subtype binding activity in plasma and beta blockade by propranolol and beta-1 selective bisoprolol in humans. Evaluation with Schild-plots.

In the present study we investigated whether the beta adrenoceptor subtype binding activity in plasma samples can predict selective and nonselective beta blockade in humans. From the right shifts of isoprenaline dose-response curves 0 to 84 hr after administration of propranolol and the beta-1 selective bisoprolol, in vivo beta blockade was assessed. In an in vitro radioreceptor assay with membrane preparations of beta-1 or beta-2 adrenoceptors, plasma samples were assayed for subtype selective blocking activity. After propranolol administration, in vitro beta-1 and beta-2 adrenoceptor occupancy declined from initially 97% to less than 10% within 48 hr. An isoprenaline dose ratio (DR)-1 of 1 coincided with a 50% occupancy of the beta-1 or the beta-2 subtype in vitro. In Schild-plots using plasma concentrations (radioreceptor assay) and the isoprenaline DR-1 for heart rate, diastolic blood pressure and inotropy (QS2C), slopes of unity were observed. After bisoprolol administration, in vitro beta-1 occupancy shifted from initially 95% to less than 10% within 72 hr. For the beta-2 subtype, an occupancy of greater than 10% was detectable only within the first 12 hr. An isoprenaline DR-1 of 1 coincided with a 50% occupancy of beta-1 adrenoceptors. The bisoprolol Schild-plots yielded a slope of unity for inotropy, but less than unity for the heart rate and diastolic blood pressure. From an extended analysis of subtype selective antagonism in Schild-plots, the fractions of the beta-2 adrenoceptor subtype participating in the isoprenaline response were calculated: heart rate 0.45 +/- 0.12 and diastolic blood pressure 0.23 +/- 0.13. It is concluded that in vitro receptor occupancy can predict beta blockade in humans for propranolol. Beta adrenoceptor subtype-mediated effects in humans can be evaluated with a selective antagonist and a refined analysis of Schild-plot data.

Adult↗
PubMed1987

Agonist binding at alpha 2-adrenoceptors of human platelets using 3H-UK-14,304: regulation by Gpp(NH)p and cations.

The agonist/alpha 2-adrenoceptor interactions at human platelet membranes have been examined in radioligand binding studies with the full agonist ligand 3H-UK-14,304 [5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline] and the antagonist ligand 3H-yohimbine. From association kinetics of different concentrations of 3H-UK-14,304 (0.75-8.1 nmol/l) a KD-value of 2.37 nmol/l in agreement with the high-affinity KD-value (KDH = 1.60 +/- 0.15 nmol/l) obtained from equilibrium binding studies was derived. In the presence of Gpp(NH)p about 6% of specific radioligand binding was observed in the association reaction. Addition of Gpp(NH)p at equilibrium resulted in a rapid loss (t 1/2 less than 1 min) of approximately 80% of bound radioligand. Dissociation after addition of an excess of phentolamine (10 mumol/l) showed a biphasic time course independent of the radioligand concentration with the proportions of 1/5 of rapidly (t 1/2 less than 2 min) and 4/5 of slowly dissociating ligand (k-1 = 0.033 +/- 0.004 min-1). Application of a sequential binding model resulted in KD-values from this approach also in agreement with KDH from equilibrium binding studies. The rank order of potency for different agonists and antagonists to compete for binding with 3H-UK-14,304 indicated an alpha 2-adrenoceptor interaction: (-)adrenaline greater than or equal to clonidine greater than (-)noradrenaline greater than (-)isoprenaline and yohimbine = rauwolscine greater than phentolamine greater than prazosin greater than or equal to corynanthine greater than timolol respectively. The analysis of competition isotherms of UK-14,304 versus 3H-yohimbine (Hill-coefficient = 0.59 +/- 0.03) showed that the agonist binds to two affinity states of the alpha 2-adrenoceptor, with high (KDH = 1.77 +/- 0.50 nmol/l) and low affinity (KDL = 71.2 +/- 11.6 nmol/l) respectively. From these experiments a fraction of 56.9% +/- 2.1% of the total number of alpha 2-adrenoceptors (Bmax = 198.4 +/- 8.0 fmol/mg of protein) in the high-affinity state was calculated. Similar results were obtained from 3H-UK-14,304 saturation isotherms according to a two-state binding model (KDH = 1.60 +/- 0.15 nmol/l; KDL = 66.2 +/- 10.7 nmol/l; BmaxH = 57.6% +/- 2.3%). Adrenoceptor agonists competed for specific binding of 3H-UK-14,304 and 3H-yohimbine in a manner that suggests that the 3H-UK-14,304 (approximately 3.5 nmol/l) labeled sites represent predominantly the agonist induced or stabilized high-affinity state of the alpha 2-adrenoceptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Agonists↗
PubMed1987

Reduction of exercise tachycardia in man after propranolol, atenolol and bisoprolol in comparison to beta-adrenoceptor occupancy.

In a double blind, placebo controlled study, propranolol (240 mg), atenolol (200 mg) or bisoprolol (100 mg) were administered as a single oral dose to groups of 6 healthy male volunteers. Exercise tachycardia was monitored for 84 hours after administration of the drugs to monitor beta blockade in vivo. Plasma samples drawn in parallel with these effects were used to detect beta 1- or beta 2-adrenoceptor occupancy in two subtype selective in vitro receptor binding assays. Reduction of exercise tachycardia parallels beta 1-adrenoceptor occupancy. Furthermore, at comparable beta 1-adrenoceptor occupancy, less beta 2-adrenoceptor occupancy was observed after bisoprolol than after atenolol. The latter finding is in agreement with the two-fold higher beta 1/beta 2-selectivity ratio of bisoprolol (75-fold) versus atenolol (35-fold). It is concluded, that beta blockade observed via the reduction of exercise tachycardia can be delineated from the in vitro occupancy of beta 1-adrenoceptors by an antagonist present in plasma samples.

Adrenergic beta-Antagonists↗
PubMed1987

E. coli maltodextrin phosphorylase: primary structure and deletion mapping of the C-terminal site.

The complete 796 residue amino acid sequence of maltodextrin phosphorylase was deduced from the E. coli malP nucleotide sequence. The calculated molecular weight of 90,500, including pyridoxal phosphate, is significantly larger than experimentally determined values. Enzymatically active and inactive mutants following deletion or exchange of up to 8 codons (7 amino acids) at the 3' end (C-terminus) confirm the size of the mature native enzyme and disclose the essential functional or structural role of the highly conserved C-terminal region of phosphorylases.

Amino Acid Sequence↗
PubMed1986

Mechanism of the phosphorylase reaction. Utilization of D-gluco-hept-1-enitol in the absence of primer.

alpha-Glucan phosphorylases from rabbit skeletal muscle, potato tubers and Escherichia coli catalyze the utilization of 2,6-anhydro-1-deoxy-D-gluco-hept-1-enitol (heptenitol) in the presence of arsenate or phosphate. 1H-NMR analysis in the presence of 2H2O and arsenate indicated formation of 1-[1-2H]deoxy-alpha-D-glucoheptulose with rates comparable to the arsenolysis of poly- or oligosaccharides. The reaction depends on the presence of a dianionic 5'-phosphate group of pyridoxal in the active conformation of the phosphorylases. Heptenitol is the first known substrate of alpha-glucan phosphorylases which does not require a primer. This is explained by the finding that heptenitol is exclusively used as substrate for the degradative pathway of the phosphorylase reaction where it competes with polysaccharide substrates. In the presence of phosphate the reaction product is 1-deoxy-alpha-D-gluco-heptulose 2-phosphate (heptulose-2-P), which subsequently inhibits the reaction. This characterizes heptulose-2-P as an enzyme-derived inhibitor. The Ki = 1.9 X 10(-6) M with potato phosphorylase suggests the formation of a transition-state-like enzyme-ligand complex. These findings, together with the fact that the phosphates of heptulose-2-P and pyridoxal 5'-phosphate are linked by hydrogen bridges [Klein, H. W., Im, M. J., Palm, D. & Helmreich, E. J. M. (1984) Biochemistry 23, 5853-5861], make it likely that both phosphates are involved in phosphorylase catalysis. A catalytic mechanism of phosphorylase action is proposed in which a 'mobile' phosphate anion plays a versatile role. It serves as proton carrier for the substrate activation, it stabilizes the intermediate and acts as a nucleophile which can accept a glycosyl residue reversibly.

Animals↗
PubMed1986

Transdermal delivery of bupranolol: pharmacodynamics and beta-adrenoceptor occupancy.

Bupranolol is a non-selective beta-adrenoceptor antagonist with a Ki-value of 6-15 nmol/l (equivalent to 1.5-4 ng/ml in plasma) at beta 1- (rat salivary gland) and beta 2-adrenoceptors (rat reticulocytes) in receptor binding studies with 3H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the Ki-value. Elimination from plasma was rapid (t 1/2 = 2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the Ki-value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.

Administration, Cutaneous↗
PubMed1986

Affinity and selectivity of beta-adrenoceptor antagonists in vitro.

The potency order of the catecholamines (-)-isoprenaline (Iso), (-)-noradrenaline (NA), and (-)-adrenaline (Adr) in competition for radiolabelled sites is used for their pharmacological classification. It is shown that the radioligand 3H-CGP 12177 exclusively labels beta 1-adrenoceptors in rat salivary gland membranes (Iso greater than NA greater than Adr), and beta 2-adrenoceptors in rat reticulocytes (Iso greater than Adr greater than or equal to NA). These models are then used to derive the subtype-selectivity of the classical beta-adrenoceptor antagonists (+/-)-propranolol (prop; twofold beta 2-selective) and (+/-)-atenolol (aten; 35-fold beta 1-selective), as well as of the newer antagonists (+/-)-betaxolol and (+/-)-bisoprolol (betax and biso; 35-fold and 75-fold beta 1-selective, respectively). The ligand with the highest selectivity is ICI 118,551 (ICI), with a 300-fold beta 2-subtype selectivity. For comparison with antagonistic effects in humans at given plasma concentrations, the equilibrium dissociation constants of the ligands are measured in the presence of native human plasma and yield values for the relative selectively labelled subtype in the mean (Ki-values in nmol/l): prop: 20, aten: 250, biso: 24, betax: 23, and ICI: 2.5.

Adrenergic beta-Antagonists↗
PubMed1986

Concentration kinetics of propranolol, bisoprolol, and atenolol in humans assessed with chemical detection and a subtype-selective beta-adrenoceptor assay.

After oral administration of single doses of 240 mg of (+/-)propranolol (prop), 200 mg of (+/-)-atenolol (aten), and 100 mg of (+/-)-bisoprolol (biso) to six healthy male volunteers, the plasma concentration time profile was investigated. To measure total plasma concentrations of the parent racemic mixture of drug administered, a HPLC-assay of drug concentrations was used. To detect active metabolites and stereoselective pharmacokinetics of the racemates, plasma concentrations were also monitored by means of a subtype-selective receptor assay, using a beta 1-adrenoceptor preparation from rat salivary glands. It is shown that relevant amounts of active metabolites do not become apparent for either of the three drugs investigated. Furthermore, for neither of them can significant stereoselective elimination characteristics be seen. Monophasic elimination characteristics with t1/2 of 4.8 +/- 0.42 (prop), 6.87 +/- 0.46 (aten), and 9.19 +/- 0.38 h (biso) become apparent. The maximum concentrations observed after administration of the doses mentioned previously were 220 +/- 71 (prop), 904 +/- 104 (aten), and 445 +/- 32 (biso) (ng/ml plasma). One can conclude from comparison with the results from receptor-binding studies that the 100 mg dose of biso is five- to seven-fold more potent than the 200 mg dose of aten, with respect to antagonism versus beta 1-adrenoceptor-mediated effects.

Adrenergic beta-Antagonists↗
PubMed1986

Naloxone effects on plasma vasopressin and oxytocin concentrations elevated by histamine, nicotine, isoproterenol and an acute increase in [NaCl] in cerebrospinal fluid.

Endogenous opioid peptides inhibit secretion of oxytocin during dehydration, hemorrhage and parturition and attenuate release of vasopressin by tail electroshock. Diverse agents were used to stimulate the hypothalamo-neurohypophysial system to investigate the hypothesis that if oxytocin (or vasopressin) release were inhibited by opioid peptides regardless of the stimulus, the site of opiate action may be in the final common pathway (i.e. the magnocellular neuron) or on pituicytes in the neural lobe. Using male Sprague-Dawley rats, we therefore investigated the effect of an opiate receptor antagonist, naloxone (5 mg/kg s.c.), on the plasma concentrations of oxytocin and vasopressin elevated by various pharmacologic stimuli, including histamine (10 mg/kg i.p.), nicotine (0.15 or 1.5 mg/kg i.p.), isoproterenol (30 or 120 micrograms/kg i.m.) and increased [NaCl] in cerebrospinal fluid (CSF; 10 microliter artificial CSF containing 1 M NaCl i.v.t.). Control animals received saline (0.85%) or artificial CSF (containing 0.16 M NaCl). Animals were decapitated 60 s (increases[NaCl] in CSF) or 10 min after the stimulus or vehicle. Vasopressin and oxytocin were extracted from plasma and quantified by RIA. The concentrations of oxytocin and vasopressin in plasma were elevated (p less than 0.05) by histamine, isoproterenol (30 and 120 micrograms/kg), increases[NaCl] in CSF, and nicotine at the higher (1.5 mg/kg) but not lower (0.15 mg/kg) dose. Naloxone increased further (p less than 0.05) the concentration of oxytocin in plasma after histamine, nicotine (0.15 and 1.5 mg/kg), isoproterenol (30 and 120 micrograms/kg) and increases[NaCl] in CSF. Naloxone also increased (p less than 0.05) oxytocin concentration in controls receiving CSF or saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Penbutolol: beta-adrenoceptor interaction and the time course of plasma concentrations explain its prolonged duration of action in man.

Beta-adrenoceptor binding of (-) penbutolol and its active metabolite 4-hydroxy-penbutolol to rat reticulocyte membranes was shown in the presence of native human plasma. Due to the high plasma protein binding (approximately 99%) the apparent Ki-values of penbutolol were shifted 100-fold to the right after inclusion of plasma in the assay; the Ki was approximately 40-70 ng/ml. That value is comparable to the IC50-values calculated from clinical studies. The interaction of 4-hydroxy-penbutolol with beta-adrenoceptors was not affected to the same extent by inclusion of plasma protein binding approximately 80%, apparent Ki-value approximately 7 ng/ml. Thus, the active metabolite of penbutolol displays higher potency at beta-adrenoceptors in vitro due to its lesser degree of plasma protein binding. A prediction procedure for antagonist activity after penbutolol administration using beta-adrenoceptor interaction and plasma concentration kinetics suggests that, in addition to a rapid elimination process from human plasma, a slow elimination phase of penbutolol (or an active metabolite) is necessary to explain the long duration of action observed in clinical studies after a single oral dose. Inhibition in vitro of beta-adrenoceptor binding by plasma samples obtained after oral administration of 40 mg penbutolol to 3 healthy volunteers indicated a biphasic concentration-time profile of the antagonist in plasma and was in accordance with the time course of the reported reduction in exercise tachycardia. Finally, plasma concentrations of penbutolol equivalents derived from the receptor assay were in the range of penbutolol concentrations detected by physico-chemical methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Proteins↗
PubMed1985

Receptor binding of propranolol is the missing link between plasma concentration kinetics and the effect-time course in man.

In a double-blind, placebo-controlled study in 6 healthy volunteers, the correlation between beta-adrenoceptor binding, the time course of the effect and plasma concentration kinetics was investigated from 0 to 48 h after a single oral dose of propranolol 240 mg. First, the in vitro beta-adrenoceptor interaction of propranolol was investigated. Propranolol inhibited beta-adrenoceptor binding to rat parotid (beta 1) and reticulocyte (beta 2) membranes in the presence of pooled human plasma with a Ki of about 8 ng/ml plasma. After oral administration of 240 mg propranolol, concentration kinetics in plasma could be described by a Bateman function with a fictive concentration at time 0 of 275 ng/ml plasma, and a mean elimination half-life of 3.5 h. Using the concentration kinetics of propranolol in plasma together with its in vitro beta-adrenoceptor binding characteristics in the presence of placebo plasma from each individual, the time course of antagonism against beta-adrenoceptor mediated effects was predicted. The latter was in agreement with the time course of propranolol-induced inhibition of tachycardia due to orthostasis. After bicycle ergometry, however, the time course of inhibition of tachycardia was shorter than was predicted. Plasma sampled at various times after propranolol administration inhibited beta-adrenoceptor binding of the radioligand 3H-CGP 12177 to rat reticulocyte membranes in a fashion reflecting the time course of inhibition of exercise tachycardia observed in the volunteers. A direct, linear relation was shown between the in vitro inhibition of beta-adrenoceptor binding by the plasma samples withdrawn after propranolol administration and the inhibition of exercise tachycardia observed in parallel. The results show that the concentrations of antagonist present in plasma are representative of the concentrations in the effect compartment. Deep compartments of drug distribution appear irrelevant to the effects of the drugs. The relation between the plasma concentration of propranolol and the reduction in heart rate at various levels of physical effort shows no significant inhibition at rest and increasing IC50-values from orthostasis to 2 min and to 4 min of ergometry. IC50-values after orthostasis are in the range of the Ki-values from in vitro receptor binding studies, whereas the IC50-values after exercise are shifted 2- to 3-fold to the right relative to the Ki-values. This finding is in agreement with increased beta-adrenoceptor stimulation with increasing effort (release of endogenous noradrenaline), which shifts the antagonist concentration-effect curve to the right.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1985

Dynamic responses to intravenous urapidil and dihydralazine in normal subjects.

Hemodynamic responses after urapidil were compared with those after dihydralazine in placebo-controlled, double-blind studies after cumulative intravenous doses. We recorded heart rate, blood pressure, systolic time intervals corrected for heart rate (electromechanical systole and preejection period), electrical impedance cardiography [(dZ/dt)/RZ index and mean electrical thorax impedance], and M-mode echocardiogram (end-systolic and -diastolic diameters, end-systolic wall stress, fractional shortening, and cardiac output). Both drugs induced dose-dependent reductions in total peripheral resistance, which resulted in reduction in left ventricular end-systolic wall stress and increases in heart rate (limited at +10 bpm with urapidil), fractional shortening, cardiac output, and the (dZ/dt)/RZ index. With each drug, diastolic blood pressure fell by 5 mm Hg, the corrected preejection period shortened (dihydralazine greater than urapidil), the corrected electromechanical systole did not change, and mean electrical thorax impedance rose with urapidil. The spectrum of effects indicates that both drugs reduce left ventricular afterload, thereby increasing left ventricular pump performance. Urapidil also exerts some preload reduction.

Adult↗
PubMed1985

Receptor binding characteristics and pharmacokinetic properties as a tool for the prediction of clinical effects of beta-blockers.

The clinical effects of a single dose of beta-adrenoceptor antagonists (beta-blockers) lasts longer than the respective half-lives in plasma will suggest. This apparent discrepancy is easily explained by a superimposition of the function of plasma concentration kinetics and the function for competitive antagonism at beta-adrenoceptors according to the law of mass action. By taking data from literature as well as those from receptor binding studies and clinical investigations from our laboratories this model was confirmed. Furthermore it can be stated: The plasma concentrations of beta-blockers are representative for the drug concentration at the beta-adrenoceptor in human. "Tight" receptor binding is not the reason for the prolonged effects, but rather the relation between drug concentration and the resp. EC50-value at the respective time of measurement. The extent of antagonism of beta-blockers in vivo can be predicted from ligand binding studies in vitro. Using the time-concentration profile in plasma in addition, the time course of clinical effects can be delineated. This holds true for the non-selective beta-blocker propranolol as well as atenolol, which shows selectively higher affinity at the beta 1-subpopulation. Deviations from the model suggested for the correlation between plasma concentration kinetics, time course of clinical effects and interaction between drug and receptor for beta-blockers may be indicative of additional compartments, active metabolites, partial agonist activity, counterregulatory processes, adaptive mechanisms and must be verified if taken for modelling. In general, any drug acting on the basis of the law of mass action should obey to the described relation between the time course of plasma concentrations and clinical effect (e.g. cardiac glycosides).

Adrenergic beta-Antagonists↗
PubMed1985

In vitro receptor occupancy allows to establish equieffective doses of beta-blockers with different pharmacodynamic profiles in man. Investigations with propranolol and bufuralol.

The aim of the present study was to establish equieffective doses of propranolol (PROP) and bufuralol (BUF) in man. Both drugs compete for radioligand binding of 3H-CGP 12177 at beta-adrenoceptors of rat reticulocytes with Ki-values of 6.7 (PROP) and 19.6 (BUF) ng/plasma in the mean. In contrast to PROP, which is a pure antagonist, BUF shows partial agonism with an intrinsic activity around 5% (relative to isoprenaline) in vitro. After i.v. injection of cumulative doses of both drugs to 10 healthy volunteers, drug present in plasma occupies beta-adrenoceptors in vitro in a dose-dependent manner up to 80%. In man the full beta-adrenoceptor agonist isoprenaline (8 micrograms/min for 3 min) induces an increase in heart rate by 73%, an increase in stroke volume by 47%, a decrease in total peripheral resistance by 63% and a shortening of the preejection period by 70%. PROP exerts effects in man in the opposite direction of isoprenaline (at resting state), whereas BUF does not influence heart rate and stroke volume to a significant extent. Only the preejection period and total peripheral resistance are influenced in analogy to the isoprenaline effects. A direct comparison of the effects of PROP and BUF at 50% in vitro receptor occupancy by the respective plasma samples shows the clear-cut qualitative differences between the pharmacodynamics of both drugs in man as expected from the comparison of the full agonist isoprenaline and the antagonist propranolol. It is concluded that only on the basis of the respective receptor occupancy one may delineate pharmacodynamic differences of different drugs of the same class in man.

Adult↗
PubMed1984

Does pyridoxal 5'-phosphate function in glycogen phosphorylase as an electrophilic or a general acid catalyst?

alpha-D-Glucose 1-diphosphate interacts with pyridoxal-reconstituted rabbit muscle phosphorylase b activated by AMP (AMP-S). Under these conditions, the glucose moiety of alpha-D-[14C]glucose 1-diphosphate is transferred to limit dextrin forming alpha(1----4) glycosidic bonds and simultaneously releasing pyrophosphate as shown by 31P NMR spectroscopy. Thus, specific structural requirements invoked to explain the reactions of pyridoxal(5')diphospho(1)-alpha-D-glucose need not to be assumed in the case of the reactions of alpha-D-glucose 1-diphosphate. Dianions isomorphous to phosphate activate pyridoxal phosphorylase regardless of their pK values while the same anions, when bound covalently to pyridoxal, are inactive. Thus, anions bound noncovalently to pyridoxal phosphorylase act differently than anions linked covalently to pyridoxal, such as the 5'-phosphate group of pyridoxal 5'-phosphate, which is postulated to be part of a proton donor-acceptor pathway. The reaction of 2,6-anhydro-1-deoxy-D-gluco-hept-1-enitol (heptenitol) with phosphorylase yields, in the presence of orthophosphate as a glycosyl acceptor, 1-deoxy-D-gluco-heptulose 2-phosphate (heptulose-2-P). This sugar phosphate is unreactive but a potent competitive inhibitor for rabbit muscle phosphorylase b and potato phosphorylase with respect to alpha-D-glucose 1-phosphate: Ki = 14 X 10(-6) M and 1.9 X 10(-6) M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗