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Woon Ki Paik - One of the best experts on this subject based on the ideXlab platform.
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Identification of Ng-Methylarginine Residues in Human Heterogeneous RNP Protein A1: Phe/Gly-Gly-Gly-Arg-Gly-Gly-Gly/Phe Is a Preferred Recognition Motif†
Biochemistry, 1997Co-Authors: Barbara M. Merrill, Ramesh Rajpurohit, Amalendra Kumar, Kathryn L. Stone, Vladimir V. Papov, Jennifer M. Schneiders, Wlodzimierz Szer, Samuel H. Wilson, Woon Ki PaikAbstract:Three sites of Ng,Ng-arginine methylation have been located at residues 205, 217, and 224 in the glycine-rich, COOH-terminal one-third of the HeLa A1 heterogeneous ribonucleoprotein. Together with ...
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identification of Ng Methylarginine residues in human heterogeneous rnp protein a1 phe gly gly gly arg gly gly gly phe is a preferred recognition motif
Biochemistry, 1997Co-Authors: Barbara M. Merrill, Woon Ki Paik, Ramesh Rajpurohit, Amalendra Kumar, Kathryn L. Stone, Vladimir V. Papov, Jennifer M. Schneiders, Wlodzimierz Szer, Samuel H. Wilson, Kenneth R WilliamsAbstract:Three sites of Ng,Ng-arginine methylation have been located at residues 205, 217, and 224 in the glycine-rich, COOH-terminal one-third of the HeLa A1 heterogeneous ribonucleoprotein. Together with ...
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studies on Ng Methylarginine derivatives in myelin basic protein from developiNg and mutant mouse brain
Biochemical Journal, 1992Co-Authors: Nenoo Rawal, Woon Ki PaikAbstract:The amounts of Ng-Methylarginine derivatives in myelin basic protein (MBP) purified from dysmyelinatiNg mutant and different stages of normal myelinatiNg mouse brains have been studied by usiNg h.p.l.c. with a highly sensitive post-column o-phthaldialdehyde derivative-formation method. All three naturally occurriNg derivatives (Ng-monoMethylarginine (MeArg), NgN′G-diMethylarginine [Me2(sym)Arg] and NgNg-diMethylarginine [Me2(asym)Arg]) were found in MBP; however, their relative concentrations varied significantly with the age of the animal. The amounts of MeArg and Me2(sym)Arg in MBP increased as a function of the age of the brain, whereas that of Me2(asym)Arg decreased. MBP from early-myelinatiNg mouse brain was shown to contain a high proportion of Me2(asym)Arg, which was hardly detectable in older brain MBP. This derivative, Me2(asym)Arg, was also absent from MBP embedded in the most compact multilamellar myelin, but was present in MBP in the least compact myelin (P3B). CompariNg the extent of total methylation in vivo (sum of all three arginine derivatives), MBP extracted from less-compact myelin (P3A and P3B) showed a level approx. 40% higher than that from compact myelin. MBPs isolated from dysmyelinatiNg mutant mouse brains, such as jimpy (jp/y) and quakiNg (qk/qk), contained a much higher level of Me2(asym)Arg relative to the other two methyl derivatives and also in comparison with those levels in the mother brain MBP. SDS/PAGE analysis of MBPs extracted from the mutant (both jp/y and qk/qk) as well as youNg normal (6-13 days old) mouse brains indicated the presence of a high-molecular-mass isoform of MBP (about 32 kDa), but this isoform was not found in adult brains. These results therefore indicate that structural integrity of myelin membrane in which MBP is embedded appears to play a pivotal role in determiniNg the extent and the kind of Me2Arg formation in MBP at the post-translational level.
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Enzymic methylation of myelin basic protein in myelin.
Biochemical Journal, 1991Co-Authors: S K Ghosh, Woon Ki Paik, N Rawal, S K Syed, Soochong KimAbstract:Myelin fractions with different degrees of compaction were isolated from bovine brain, and post-translational methylation of membrane-associated proteins was studied. When the purified myelin-basic-protein-specific protein methylase I and S-adenosyl-L-[methyl-14C]methionine were added exogenously, the most compact myelin fraction exhibited higher methyl-acceptiNg activity than the less compact dense fractions. The methylated protein was identified as myelin basic protein (18.4 kDa) exclusively amoNg the several myelin proteins from all membrane fractions, by SDS/PAGE/radioautography of methyl-14C-labelled membrane proteins. The methyl-14C-labelled amino acid residue in the basic protein was identified by h.p.l.c. as Ng-Methylarginine, indicatiNg the high degree of specificity for the arginine residue as well as the myelin basic protein in the intact myelin membranes. The possibility of a charge alteration of myelin basic protein resultiNg from its arginine methylation was investigated by usiNg the purified component 1 of myelin basic protein. The methylated component was shown to be less cationic than the unmethylated component by Bio-Rex 70 cation-exchaNge chromatography, since the former preceded the latter. However, in the presence of the denaturant (guanidinium chloride), the two species were co-eluted, indicatiNg that the charge difference between methylated and unmethylated myelin basic protein can only be shown under the renatured condition.
David Watson - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of the nitric oxide synthase inhibitor l Ng Methylarginine hydrochloride in patients with septic shock
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Ziad Hussein, Robert Grover, Bernadette Jordan, Roger Jeffs, Jill Donaldson, David Zaccardelli, Gene Colice, Kalpalatha K Guntupalli, Misba Beerahee, David WatsonAbstract:Objectives To characterize the pharmacokinetics of L-N G-Methylarginine in patients with septic shock. Methods This was an international, uncontrolled, open-label study of L-N G-Methylarginine (546C88) therapy given to 32 patients with septic shock. It was conducted in hospital-based intensive care units that admit general surgical and medical patients. Patient cohorts received an infusion of L-N G-Methylarginine at fixed dose rates of 1, 2.5, 5, 10, and 20 mg/kg/h for up to 8 hours. The 5 dosiNg regimens were administered sequentially to separate groups of patients. Results Of the 32 patients studied, 23 received complete 8-hour infusions. In the other 9 patients, the infusion was terminated prematurely within the first ½ to 4 hours. Median clearance of L-N G-Methylarginine averaged 485 mL/h/kg for the 1 and 2.5 mg/kg/h dosiNg cohorts combined but decreased to 283, 181, and 98 mL/h/kg for the 5, 10, and 20 mg/kg/h dosiNg cohorts, respectively. Median renal clearance was similar at 9 to 26 mL/h for the 1, 2.5, and 5 mg/kg/h dosiNg cohorts but increased to 156 and 284 mL/h for the 10 and 20 mg/kg/h dosiNg cohorts, respectively. Median steady-state volume of distribution was similar in all 5 dosiNg cohorts, averagiNg 0.66 to 0.82 L/kg. Conclusions The 80% decrease in clearance from 485 to 98 mL/h/kg with the increase in dose suggests that a predominant metabolic pathway(s) of L-N G-Methylarginine, accountiNg for at least 80% of clearance, is becomiNg progressively saturable in association with L-N G-Methylarginine infusion rates ≥5 mg/kg/h. Therefore the use of L-N G-Methylarginine infusion rates ≥5 mg/kg/h are typically expected to result in progressive inhibition of nitric oxide synthase activity. Consequently, patient hemodynamics should be monitored closely to avoid an excessive increase in vasomotor tone, which would be manifest by either an increase in mean arterial pressure or a decrease in cardiac output. The infusion rates of conventional vasopressor(s) (eg, norepinephrine [BAN, noradrenaline]) or L-N G-Methylarginine or both may need to be reduced accordiNgly. Clinical Pharmacology & Therapeutics (1999) 65, 1–9; doi:
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Pharmacokinetics of the nitric oxide synthase inhibitor L-Ng-Methylarginine hydrochloride in patients with septic shock
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Ziad Hussein, Robert Grover, Bernadette Jordan, Roger Jeffs, Jill Donaldson, David Zaccardelli, Gene Colice, Kalpalatha K Guntupalli, Misba Beerahee, David WatsonAbstract:Objectives To characterize the pharmacokinetics of L-Ng-Methylarginine in patients with septic shock. Methods This was an international, uncontrolled, open-label study of L-Ng-Methylarginine (546C88) therapy given to 32 patients with septic shock. It was conducted in hospital-based intensive care units that admit general surgical and medical patients. Patient cohorts received an infusion of L-Ng-Methylarginine at fixed dose rates of 1, 2.5, 5, 10, and 20 mg/kg/h for up to 8 hours. The 5 dosiNg regimens were administered sequentially to separate groups of patients. Results Of the 32 patients studied, 23 received complete 8-hour infusions. In the other 9 patients, the infusion was terminated prematurely within the first 1/2 to 4 hours. Median clearance of L-Ng-Methylarginine averaged 485 mL/h/kg for the 1 and 2.5 mg/kg/h dosiNg cohorts combined but decreased to 283, 181, and 98 mL/h/kg for the 5, 10, and 20 mg/kg/h dosiNg cohorts, respectively. Median renal clearance was similar at 9 to 26 mL/h for the 1, 2.5, and 5 mg/kg/h dosiNg cohorts but increased to 156 and 284 mL/h for the 10 and 20 mg/kg/h dosiNg cohorts, respectively. Median steady-state volume of distribution was similar in all 5 dosiNg cohorts, averagiNg 0.66 to 0.82 L/kg. Conclusions The 80% decrease in clearance from 485 to 98 mL/h/kg with the increase in dose suggests that a predominant metabolic pathway(s) of L-Ng-Methylarginine, accountiNg for at least 80% of clearance, is becomiNg progressively saturable in association with L-Ng-Methylarginine infusion rates > or = 5 mg/kg/h. Therefore the use of L-Ng-Methylarginine infusion rates > or = 5 mg/kg/h are typically expected to result in progressive inhibition of nitric oxide synthase activity. Consequently, patient hemodynamics should be monitored closely to avoid an excessive increase in vasomotor tone, which would be manifest by either an increase in mean arterial pressure or a decrease in cardiac output. The infusion rates of conventional vasopressor(s) (eg, norepinephrine [BAN, noradrenaline]) or L-Ng-Methylarginine or both may need to be reduced accordiNgly.
Owen W. Griffith - One of the best experts on this subject based on the ideXlab platform.
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irreversible inactivation of macrophage and brain nitric oxide synthase by l Ng Methylarginine requires nadph dependent hydroxylation
Journal of Medicinal Chemistry, 1993Co-Authors: Paul L Feldman, Owen W. Griffith, Hui Hong, Dennis J StuehrAbstract:: L-Ng-Methylarginine (NMA) is an established mechanism-based inactivator of murine macrophage nitric oxide synthase (mNOS). In this report, NMA is shown to irreversibly inhibit both mNOS (k(inact) = 0.08 min-1) and the recombinant constitutive brain NOS (bNOS). For both NOS isoforms, metabolism of NMA parallels that of the natural substrate L-arginine (ARG), in that it undergoes a regiospecific, NADPH-dependent hydroxylation to form L-Ng-hydroxy-Ng-Methylarginine (NOHNMA). This intermediate then undergoes further NADPH-dependent oxidation to form L-citrulline (CIT). Authentic NOHNMA, synthesized from L-ornithine, irreversibly inhibited both mNOS (k(inact) = 0.10 min-1) and bNOS in an NADPH-dependent reaction. The conversion of either NMA or NOHNMA to CIT correlated with irreversible enzyme inactivation. Thus, the data suggest that enzyme inhibition occurs as a consequence of oxidative metabolism of the intermediate, NOHNMA. A unified mechanism is proposed that accounts for NO biosynthesis from ARG, for the inactivation of NOS by NMA and for the intermediacy of hydroxylated ARG or NMA derivatives in these processes.
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macrophage and endothelial cell nitric oxide synthesis cell type selective inhibition by Ng aminoarginine Ng nitroarginine and Ng Methylarginine
Biochemical and Biophysical Research Communications, 1990Co-Authors: Steven S Gross, Eric A Jaffe, Dennis J Stuehr, Kazuo Aisaka, Roberto Levi, Owen W. GriffithAbstract:Many cell types are known to synthesize nitric oxide (NO.) from Larginine. There appear to be at least two forms of NO. synthase: an inducible, tetrahydrobiopterin- and flavin-dependent activity exemplified by the macrophage enzyme and a constitutive, Ca++-dependent activity exemplified by the endothelial cell enzyme. L-Ng-Methylarginine inhibits NO. synthesis by both cell types. We now report that L-Ng-aminoarginine and L-Ng-nitroarginine are about 100-fold more potent than Ng-Methylarginine in blockiNg endothelial cell NO. synthesis. In contrast, Ng-aminoarginine and Ng-Methylarginine are about equipotent with macrophages whereas Ng-nitroarginine is much less potent. Since macrophage and endothelial cell NO. synthesis are differentially sensitive to the inhibitors, the panel of inhibitors can be used in complex biological systems to determine if macrophage-like or endothelial-like cells are the predominant source of NO.. Indeed, all three inhibitors elicit a stroNg pressor response in the anesthetized guinea pig, a result consistent with the view that endothelial cells continually produce vasodilatory NO..
Ziad Hussein - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of the nitric oxide synthase inhibitor l Ng Methylarginine hydrochloride in patients with septic shock
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Ziad Hussein, Robert Grover, Bernadette Jordan, Roger Jeffs, Jill Donaldson, David Zaccardelli, Gene Colice, Kalpalatha K Guntupalli, Misba Beerahee, David WatsonAbstract:Objectives To characterize the pharmacokinetics of L-N G-Methylarginine in patients with septic shock. Methods This was an international, uncontrolled, open-label study of L-N G-Methylarginine (546C88) therapy given to 32 patients with septic shock. It was conducted in hospital-based intensive care units that admit general surgical and medical patients. Patient cohorts received an infusion of L-N G-Methylarginine at fixed dose rates of 1, 2.5, 5, 10, and 20 mg/kg/h for up to 8 hours. The 5 dosiNg regimens were administered sequentially to separate groups of patients. Results Of the 32 patients studied, 23 received complete 8-hour infusions. In the other 9 patients, the infusion was terminated prematurely within the first ½ to 4 hours. Median clearance of L-N G-Methylarginine averaged 485 mL/h/kg for the 1 and 2.5 mg/kg/h dosiNg cohorts combined but decreased to 283, 181, and 98 mL/h/kg for the 5, 10, and 20 mg/kg/h dosiNg cohorts, respectively. Median renal clearance was similar at 9 to 26 mL/h for the 1, 2.5, and 5 mg/kg/h dosiNg cohorts but increased to 156 and 284 mL/h for the 10 and 20 mg/kg/h dosiNg cohorts, respectively. Median steady-state volume of distribution was similar in all 5 dosiNg cohorts, averagiNg 0.66 to 0.82 L/kg. Conclusions The 80% decrease in clearance from 485 to 98 mL/h/kg with the increase in dose suggests that a predominant metabolic pathway(s) of L-N G-Methylarginine, accountiNg for at least 80% of clearance, is becomiNg progressively saturable in association with L-N G-Methylarginine infusion rates ≥5 mg/kg/h. Therefore the use of L-N G-Methylarginine infusion rates ≥5 mg/kg/h are typically expected to result in progressive inhibition of nitric oxide synthase activity. Consequently, patient hemodynamics should be monitored closely to avoid an excessive increase in vasomotor tone, which would be manifest by either an increase in mean arterial pressure or a decrease in cardiac output. The infusion rates of conventional vasopressor(s) (eg, norepinephrine [BAN, noradrenaline]) or L-N G-Methylarginine or both may need to be reduced accordiNgly. Clinical Pharmacology & Therapeutics (1999) 65, 1–9; doi:
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Pharmacokinetics of the nitric oxide synthase inhibitor L-Ng-Methylarginine hydrochloride in patients with septic shock
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Ziad Hussein, Robert Grover, Bernadette Jordan, Roger Jeffs, Jill Donaldson, David Zaccardelli, Gene Colice, Kalpalatha K Guntupalli, Misba Beerahee, David WatsonAbstract:Objectives To characterize the pharmacokinetics of L-Ng-Methylarginine in patients with septic shock. Methods This was an international, uncontrolled, open-label study of L-Ng-Methylarginine (546C88) therapy given to 32 patients with septic shock. It was conducted in hospital-based intensive care units that admit general surgical and medical patients. Patient cohorts received an infusion of L-Ng-Methylarginine at fixed dose rates of 1, 2.5, 5, 10, and 20 mg/kg/h for up to 8 hours. The 5 dosiNg regimens were administered sequentially to separate groups of patients. Results Of the 32 patients studied, 23 received complete 8-hour infusions. In the other 9 patients, the infusion was terminated prematurely within the first 1/2 to 4 hours. Median clearance of L-Ng-Methylarginine averaged 485 mL/h/kg for the 1 and 2.5 mg/kg/h dosiNg cohorts combined but decreased to 283, 181, and 98 mL/h/kg for the 5, 10, and 20 mg/kg/h dosiNg cohorts, respectively. Median renal clearance was similar at 9 to 26 mL/h for the 1, 2.5, and 5 mg/kg/h dosiNg cohorts but increased to 156 and 284 mL/h for the 10 and 20 mg/kg/h dosiNg cohorts, respectively. Median steady-state volume of distribution was similar in all 5 dosiNg cohorts, averagiNg 0.66 to 0.82 L/kg. Conclusions The 80% decrease in clearance from 485 to 98 mL/h/kg with the increase in dose suggests that a predominant metabolic pathway(s) of L-Ng-Methylarginine, accountiNg for at least 80% of clearance, is becomiNg progressively saturable in association with L-Ng-Methylarginine infusion rates > or = 5 mg/kg/h. Therefore the use of L-Ng-Methylarginine infusion rates > or = 5 mg/kg/h are typically expected to result in progressive inhibition of nitric oxide synthase activity. Consequently, patient hemodynamics should be monitored closely to avoid an excessive increase in vasomotor tone, which would be manifest by either an increase in mean arterial pressure or a decrease in cardiac output. The infusion rates of conventional vasopressor(s) (eg, norepinephrine [BAN, noradrenaline]) or L-Ng-Methylarginine or both may need to be reduced accordiNgly.
Dennis J Stuehr - One of the best experts on this subject based on the ideXlab platform.
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irreversible inactivation of macrophage and brain nitric oxide synthase by l Ng Methylarginine requires nadph dependent hydroxylation
Journal of Medicinal Chemistry, 1993Co-Authors: Paul L Feldman, Owen W. Griffith, Hui Hong, Dennis J StuehrAbstract:: L-Ng-Methylarginine (NMA) is an established mechanism-based inactivator of murine macrophage nitric oxide synthase (mNOS). In this report, NMA is shown to irreversibly inhibit both mNOS (k(inact) = 0.08 min-1) and the recombinant constitutive brain NOS (bNOS). For both NOS isoforms, metabolism of NMA parallels that of the natural substrate L-arginine (ARG), in that it undergoes a regiospecific, NADPH-dependent hydroxylation to form L-Ng-hydroxy-Ng-Methylarginine (NOHNMA). This intermediate then undergoes further NADPH-dependent oxidation to form L-citrulline (CIT). Authentic NOHNMA, synthesized from L-ornithine, irreversibly inhibited both mNOS (k(inact) = 0.10 min-1) and bNOS in an NADPH-dependent reaction. The conversion of either NMA or NOHNMA to CIT correlated with irreversible enzyme inactivation. Thus, the data suggest that enzyme inhibition occurs as a consequence of oxidative metabolism of the intermediate, NOHNMA. A unified mechanism is proposed that accounts for NO biosynthesis from ARG, for the inactivation of NOS by NMA and for the intermediacy of hydroxylated ARG or NMA derivatives in these processes.
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macrophage and endothelial cell nitric oxide synthesis cell type selective inhibition by Ng aminoarginine Ng nitroarginine and Ng Methylarginine
Biochemical and Biophysical Research Communications, 1990Co-Authors: Steven S Gross, Eric A Jaffe, Dennis J Stuehr, Kazuo Aisaka, Roberto Levi, Owen W. GriffithAbstract:Many cell types are known to synthesize nitric oxide (NO.) from Larginine. There appear to be at least two forms of NO. synthase: an inducible, tetrahydrobiopterin- and flavin-dependent activity exemplified by the macrophage enzyme and a constitutive, Ca++-dependent activity exemplified by the endothelial cell enzyme. L-Ng-Methylarginine inhibits NO. synthesis by both cell types. We now report that L-Ng-aminoarginine and L-Ng-nitroarginine are about 100-fold more potent than Ng-Methylarginine in blockiNg endothelial cell NO. synthesis. In contrast, Ng-aminoarginine and Ng-Methylarginine are about equipotent with macrophages whereas Ng-nitroarginine is much less potent. Since macrophage and endothelial cell NO. synthesis are differentially sensitive to the inhibitors, the panel of inhibitors can be used in complex biological systems to determine if macrophage-like or endothelial-like cells are the predominant source of NO.. Indeed, all three inhibitors elicit a stroNg pressor response in the anesthetized guinea pig, a result consistent with the view that endothelial cells continually produce vasodilatory NO..