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Query: UMLS:C0162473 (Frey)
 2,599 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 1928, Frey and co-workers discovered kallikrein in human urine and described its prolonged hypotensive effect in the dog. Four years later, the same authors first reported a blood glucose-lowering effect of orally administered kallikrein in diabetic patients. However, the observed blood glucose-lowering effect of kallikrein appeared to fade with repeated administration, and therefore its possible metabolic role was not further investigated and fell into disregard. One decade ago, experimental data yielded indirect evidence that the regulation of local skeletal muscle blood flow and glucose uptake during work was mediated by proteolytically cleaved kinins. Further experiments demonstrated that in insulin-resistant states such as postoperative stress and type II diabetes, reduced muscular insulin sensitivity was increased and partly restored by continuous low-dose infusion of synthetic bradykinin. Recent work showing that tissue kallikrein is present in a number of different tissue sites, including skeletal muscle and our own observation of local kinin overflow after muscle work in healthy subjects, but not in type II diabetics, support the concept of a skeletal muscle kallikrein-kinin system (KKS) that is locally activated upon contraction. Moreover, in isolated perfused rat heart preparations, favorable effects of kinins on myocardial glucose uptake, oxidation, and glycolytic flux have been reported. Most interestingly, cardioprotective effects of kinins have been observed and attributed to improved energy and substrate metabolism in ischemic hearts. Taken together, these data gave rise to the concept that tissue KKS might be involved in the local modulation of skeletal muscle and myocardial tissue blood flow and substrate metabolism, and that activation of the KKS is defective in insulin-resistant states.
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PMID:Metabolic effects of kinins: historical and recent developments. 169 62

Two-dimensional crystals of beef heart mitochondrial cytochrome c oxidase dimers were labeled at Cys-115 of subunit III with a monomaleimide derivative of an undecagold cluster compound. The binding site of the gold cluster compound and hence the site of subunit III were identified by image processing of cryoelectron micrographs of the crystals preserved in a mixture of glucose and uranyl acetate. The shape of the cytochrome oxidase dimer can be approximated as a parallelogram which is 44 by 82 A with an included angle of 80 degrees oriented with its long dimension along the a axis of the crystal. Labeling of subunit III was confirmed by a shift in the mobility of approximately 50% of subunit III molecules upon electrophoresis in polyacrylamide gels in the presence of sodium dodecyl sulfate. Averaged images of undecagold cluster labeled crystals and of unlabeled crystals were calculated; each image represents an average of approximately 17,000 molecules of either labeled or unlabeled cytochrome oxidase. On the basis of a statistical analysis of the differences between the two images, the gold cluster binds along a line 30 degrees from the a axis and 29 A from the center of the dimer. This result is interpreted in the context of other structural studies including the site of cytochrome c binding which Frey and Murray found to be near the a axis and 18 A from the center of the dimer [Frey, T. G., & Murray, J. M. (1994) J. Mol. Biol. 237, 275-297].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Electron microscopy of cytochrome c oxidase crystals: labeling of subunit III with a monomaleimide undecagold cluster compound. 794 82

Strain BV1 was isolated from the exudate of the footpad abscess of a black vulture (Coragyps atratus). The colonies had a "fried-egg" appearance consistent with that of mycoplasmal species. Electron microscopic examination of the cells revealed irregular elongated or elliptical forms and smaller circular budding processes. Profuse growth was observed in Frey medium supplemented with 20% swine serum at 37 degrees C in a humidified atmosphere of 10% CO2 and air. Typical of mycoplasma, strain BV1 required sterol for growth and catabolized glucose but did not hydrolyze arginine or urea. The guanine-plus-cytosine content of the DNA was 28 mol%. The organism demonstrated the ability to hemolyze, absorb onto, and agglutinate the erythrocytes from several animal species. Strain BV1 was serologically unrelated by the growth inhibition test to previously established Mycoplasma, Acholeplasma, Entomoplasma, and Mesoplasma species, as well as to strains belonging to these genera but not identified to species level. Moreover, BV1 had a 16S rRNA gene with a nucleotide sequence distinct from reported sequences of other mycoplasmas. This organism represents a new species for which the name Mycoplasma corogypsi is proposed. Strain BV1 (ATCC 51148T) is the type strain of Mycoplasma corogypsi sp. nov.
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PMID:Mycoplasma corogypsi sp. nov., a new species from the footpad abscess of a black vulture, Coragyps atratus. 834 15

The reversible reaction of UDP-glucose with imidazole (Im) to produce uridine 5'-phoshoimidazolate (UMPIm) and glucose-1-P is catalyzed by UDP-hexose synthase, which is the mutant H166G of hexose-1-P uridylyltransferase (EC 2.7.7.12) [Kim, J., Ruzicka, F.J., & Frey, P.A. (1990) Biochemistry 29, 10590-10593]. The availability of UDP-hexose synthase allows the equilibrium constant for the reaction UDP-glucose + Im = UMPIm + glucose-1-P to be measured, and it is found to be 2.2 x 10(-2) at pH 8.5 and 27 degrees C. At pH 7.0 and 27 degrees C the equilibrium constant is 6.4 x 10(-4). The equilibrium constant for the formation of the covalent uridylyl-enzyme intermediate of hexose-1-P uridylyltransferase (E-His(166) + UDP-glucose = E-His(166)-UMP + glucose-1-P) is found to be 1.8 x 10(-4) at pH 7.0 and 25 degrees C, which is slightly less favorable than the formation of UMPIm from UDP-glucose and Im. These equilibrium constants, when considered in the light of other data in the literature, allow the standard free energy changes for the hydrolysis of UMPIm and the analogous covalent uridylyl-enzyme intermediate to be calculated. The results show that delta G' degrees (delta G degrees (ph)(7.0)) for the hydrolyses of UMPIm and E-His(166)-UMP are -14.7 and -15.4 kcal mol(-1), respectively at pH 7.0. At pH 8.5, the corresponding values of delta G degrees (ph) (8.5) are -12.6 and -9.9 kcal mol(-1), respectively. It is concluded that noncovalent binding interactions between the active site and the UMP group of E-His(166)-UMP provide little or no stabilization in the formation of this species as an intermediate in the reaction of hexose-1-P uridylyltransferase.
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PMID:Standard free energies for uridylyl group transfer by hexose-1-P uridylyltransferase and UDP-hexose synthase and for the hydrolysis of uridine 5'-phosphoimidazolate. 863 92

Galactose-1-phosphate uridylyltransferase catalyzes the reaction of UDP-glucose with galactose 1-phosphate to form UDP-galactose and glucose 1-phosphate during normal cellular metabolism. The reaction proceeds through a double displacement mechanism characterized by the formation of a stable nucleotidylated histidine intermediate. This paper describes the preparation of the uridylyl-enzyme complex on the crystalline enzyme from Escherichia coli and its subsequent structure determination by X-ray crystallography. The refined structure has an R-factor of 19.6% (data between 65 and 1.86 A resolution) and reveals modest conformational changes at the active site compared to the inactive UMP/UDP-enzyme complex reported previously [Wedekind, J.E., Frey, P.A., & Rayment, I. (1995) Biochemistry 34, 11049-11061]. In particular, positions of the respective UMP alpha-phosphoryl groups differ by approximately 4 A. Well-defined electron density for the nucleotidylated imidazole supports the existence of a covalent bond between N epsilon 2 of the nucleophile and the alpha-phosphorus of UMP. A hydrogen bond that is conserved in both complexes between His 166 N delta 1 and the carbonyl O of His 164 serves to properly orient the nucleophile and electrostatically stabilize the positively charged imidazolium that results from nucleotidylation. Hydrogen bonds from side-chain Gln 168 to the nonbridging phosphoryl oxygens of the nucleotidyl intermediate appear crucial for the formation and reaction of the uridylyl-enzyme complex as well. The significance of the latter interaction is underscored by the fact that the predominant cause of the metabolic disease galactosemia is the mutation of the corresponding Gln (Gln 188 in humans) to Arg. A comparison to other phosphohistidyl enzymes is described, as well as a revised model for the mechanism of the uridylyltransferase.
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PMID:The structure of nucleotidylated histidine-166 of galactose-1-phosphate uridylyltransferase provides insight into phosphoryl group transfer. 879 35

mu-Monothiopyrophosphate (MTP, (2-)O3P-S-PO3(-2)) is an excellent substrate for inorganic pyrophosphatase. The maximum velocity for the hydrolysis of MgMTP by inorganic pyrophosphatase is 24% of that for MgPPi at pH 8.0 and 5 degrees C and 190% at pH 9.0 and 15 degrees C. The hydrolyses of MnMTP and CoMTP proceed at 24 and > or = 7%, respectively, of the maximum velocity for the reaction of MgMTP at pH 8 and 5 degrees C. The maximum velocities for hydrolyses of MnPPi and CoPPi are 31 and 13% of that for MgPPi, respectively. There is no evidence that Mn2+ or Co2+ coordinate with bridging sulfur in MTP in such a way as to affect the rate of hydrolysis. The apparent Michaelis constants at pH 8 and 5 degrees C in the presence of 195 microM divalent metal ion are as follows: MgPPi, 12 microM; MnPPi, 19 microM; CoPPi, 12 microM; MgMTP, 45 microM; MnMTP, 5.3 microM; and CoMTP, 16 microM. The apparent Michaelis constants at pH 9 and 15 degrees C in the presence of 10 mM divalent metal ion are MgPPi, 1.9 microM and MgMTP, 19.1 microM. The values of kcat for MgPPi at pH 8 and 5 degrees C and at pH 9 and 15 degrees C are 8 s(-1) and 12.4 s(-1), respectively. The values of kcat for MgMTP under the same conditions are 2 s(-1) and 24 s(-1), respectively. MTP and MgMTP undergo nonenzymatic hydrolysis by a mechanism in which monomeric metaphosphate monoanion (PO3) is a discrete intermediate (Lightcap, E.S., and Frey, P.A. (1992) J. Am. Chem. Soc. 114, 9750-9755). This reaction is accommodated at the active site of inorganic pyrophosphatase, indicating that the mechanism of enzymatic hydrolysis is dissociative. MgMTP is also a substrate for UDP-glucose pyrophosphorylase, reacting at 4.8% of the maximum velocity of MgPPi and with a Michaelis constant 17 times larger than that for MgPPi. The P-S bonds of MgMTP are not cleaved in the pyrophosphorylase reaction, but the product UTP beta gamma S is chemically unstable and undergoes hydrolysis to UDP beta S and Pi, making the cleavage of UDP-glucose to glucose-1-P, UDP beta S and Pi, experimentally irreversible.
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PMID:mu-Monothiopyrophosphate as a substrate for inorganic pyrophosphatase and UDP-glucose pyrophosphorylase. 891 49

Drainage and resection are the principles of surgery in chronic pancreatitis. The techniques of duodenum-preserving resection of the head of the pancreas as described by Beger and Frey combine both to different degrees. In a prospective randomized trial both procedures were compared: 74 patients were randomly allocated to either Beger's (n = 38) or Frey's, (n = 36) group. In addition to routine pancreatic diagnostic work-up a multidimensional psychometric quality-of-life questionnaire and a pain score were used. Assessment of endocrine and exocrine function included oral glucose tolerance test, serum concentrations of insulin, C-peptide, and HbA1c, as well as fecal chymotrypsin and pancreolauryl test. The mean interval between symptoms and surgery was 5.1 years (1-12 years). The median follow-up was 30 months. There was no mortality. Overall morbidity was 27% (32% Beger, 22% Frey). Complications from adjacent organs were definitively resolved in 91% (92% Beger, 91% Frey). A decrease in pain score of 95% and 93% after Beger's and Frey's procedure, respectively, and an increase of 67% in the overall quality-of-life index in both groups were observed. Endocrine and exocrine function did not differ between the two groups. Both techniques of duodenum-preserving resection of the head of the pancreas are equally safe and effective with regard to pain relief, improvement of quality of life, and control of complications affecting adjacent organs. Neither procedure leads to further deterioration of endocrine and exocrine pancreatic function.
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PMID:[Drainage versus resection in surgical therapy of chronic pancreatitis of the head of the pancreas: a randomized study]. 920 31

Galactose-1-phosphate (galactose-1-P) uridylyltransferase from Escherichia coli catalyzes the interconversion of UDP-glucose and galactose-1-P with UDP-galactose and glucose-1-P by a double-displacement mechanism through a uridylyl-enzyme intermediate, in which the uridine-5'-phosphoryl group is covalently bonded to Nepsilon of His 166. The point variant H166G displays a UDP-hexose synthase activity, in that it catalyzes the reaction of uridine 5'-phosphoimidazolide (UMPIm) with glucose-1-P to form UDP-glucose and imidazole. Inasmuch as the wild-type uridylyltransferase catalyzes its cognate reaction with ping-pong kinetics, an intrinsically ordered substrate binding mechanism, the kinetic mechanism of the UDP-hexose synthase activity of H166G became of interest. The synthase activity follows sequential kinetics [Kim, J., Ruzicka, F., and Frey, P. A. (1990) Biochemistry 29, 10590-10593]. In this work, product inhibition patterns for the synthase activity of H166G indicate random equilibrium binding of substrates. Comparison of the synthase activities of the variants H166G and H166A showed that the glycine variant is about 340- and 600-fold more active than the alanine variant in the forward and reverse directions, respectively. The kinetic consequences of varying the amino acid at position 166 were largely kcat effects, with more modest Km effects. Comparison of the synthase activities of these variants with that of the wild-type enzyme in the production of glucose-1-P showed that the loss of the beta-carbon of His 166 in the complex H166G-UMPIm increases the activation energy for uridylyl group transfer by 2.4 kcal mol-1, and the presence of two additional hydrogen atoms in the complex H166A-UMPIm increases the activation energy by 6.2 kcal mol-1. It is concluded that the active site is much less tolerant of additional steric bulk in the locus of the beta-carbon of His 166 than it is of the loss of the beta-carbon. The sensitivities to additional steric bulk around other positions of the His 166-imidazole ring are much less severe, as indicated by the reactivities of methylated analogues of UMPIm in the synthase reaction of H166G. Uridine 5'-phospho-N-methylimidazolide is more reactive as a synthase substrate than UMPIm, and this is attributed to the positive charge of the imidazole ring. The fact that the imidazole ring of the wild-type covalent uridylyl-enzyme retains its proton and is positively charged is supported by the pH-rate profile for hydrolysis of the intermediate.
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PMID:Kinetic mechanism of UDP-hexose synthase, a point variant of hexose-1-phosphate uridylyltransferase from Escherichia coli. 969 86

Galactose-1-phosphate uridylyltransferase catalyzes the reaction of UDP-glucose with galactose 1-phosphate (Gal-1-P) to form UDP-galactose and glucose 1-phosphate (Glc-1-P) through a double displacement mechanism, with the intermediate formation of a covalent uridylyl-enzyme (UMP enzyme). Gln 168 in E. coli uridylyltransferase engages in hydrogen bonding with the phosphoryl oxygens of the UMP moiety, which is bonded to His 166 in the intermediate [Wedekind, J. E., Frey, P. A., and Rayment, I. (1996) Biochemistry 35, 11560-11569]. In humans, the point variant Q188R accounts for 60% of galactosemia cases. The corresponding E. coli variant Q168R has been overexpressed and purified. In preparation for kinetic correlation of Q168R and wild-type uridylyltransferases, we tested the kinetic competence of the wild-type UMP-enzyme. At 4 degreesC, the first-order rate constant for uridylylation by UDP-glucose is 281 +/- 18 s-1, and for deuridylylation it is 226 +/- 10 s-1 with Glc-1-P and 166 +/- 10 s-1 with Gal-1-P. Inasmuch as the overall turnover number at 4 degreesC is 62 s-1, the covalent intermediate is kinetically competent. The variant Q168R is uridylylated by UDP-glucose to the extent of about 65% of the potential active sites. Uridylylation reactions of Q168R with UDP-glucose proceed with maximum first-order rate constants of 2.2 x 10(-)4 s-1 and 4.2 x 10(-)4 s-1 at 4 and 27 degreesC, respectively. In experiments with uridylyl-Q168R and glucose-1-P, the mutant enzyme undergoes deuridylylation with maximum first-order rate constants of 4.8 x 10(-)4 s-1 and 1.68 x 10(-)3 s-1 at 4 and 27 degreesC, respectively. The value of Km for uridylylation of Q168R is slightly higher than for the wild-type enzyme, and for deuridylylation it is similar to the wild-type value. The wild-type enzyme undergoes uridylylation and deuridylyation about 10(6) times faster than Q168R. The wild-type activity in the overall reaction is 1.8 x 10(6) times that of Q168R. The wild-type enzyme contains 1.9 mol of Zn+Fe per mole of subunits, whereas the Q168R-variant contains 1.36 mol of Zn+Fe per mole of subunits. The mutation stabilizes the uridylyl-enzyme by 1.2 kcal mol-1 in comparison to the wild-type enzyme. These results show that the low activity of Q168R is not due to overstabilization of the intermediate or to the absence of structural metal ions. Instead, the main defect is very slow uridylylation and deuridylation.
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PMID:Transient kinetics of formation and reaction of the uridylyl-enzyme form of galactose-1-P uridylyltransferase and its Q168R-variant: insight into the molecular basis of galactosemia. 977 78

The present study was conducted to characterize the development of tactile allodynia in the streptozotocin-induced rat model of diabetes, and to evaluate the antinociceptive effects of systemically administered morphine and the adenosine kinase inhibitor, 5'-deoxy-5-iodotubercidin (5'd-5IT) in this model. Rats were injected with 75 mg/kg streptozotocin (i.p.), and blood glucose levels were determined 3-4 weeks later. Diabetic (blood glucose levels > or = 250 mg/dl) and vehicle-injected rats were examined weekly for the development of tactile allodynia by measuring the threshold for hind paw withdrawal using von Frey hairs. Withdrawal thresholds were reduced to 6.8+/-0.6 g (mean+/-S.E.M.) in approximately one-third of streptozotocin-treated rats 7 weeks after streptozotocin treatment as compared to control thresholds (13.2+/-0.1 g), and this allodynia persisted for at least an additional 7 weeks. In additional experiments, morphine sulfate (5-21 micromol/kg, i.p.) produced dose-dependent antinociceptive effects on tactile allodynia for up to 2 h post-dosing. The adenosine kinase inhibitor, 5'd-5IT (2.5 and 5 micromol/kg, i.p.) also dose-dependently attenuated tactile allodynia. Pretreatment with the opioid receptor antagonist, naloxone (27 micromol/kg, i.p.) or the non-selective adenosine receptor antagonist, theophylline (111 micromol/kg, i.p.) significantly diminished the anti-allodynic effects of morphine and 5'd-5IT, respectively. The present study demonstrates that the potent and selective adenosine kinase inhibitor, 5'd-5IT, is equally effective as morphine in blocking tactile allodynia in this model.
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PMID:An adenosine kinase inhibitor attenuates tactile allodynia in a rat model of diabetic neuropathic pain. 993 16


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