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Dive into the research topics where Bhupendra P. Doctor is active.

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Featured researches published by Bhupendra P. Doctor.


Biochemistry | 1997

Differences in active site gorge dimensions of cholinesterases revealed by binding of inhibitors to human butyrylcholinesterase

Ashima Saxena; Ann M.G. Redman; Xuliang Jiang; Oksana Lockridge; Bhupendra P. Doctor

Amino acid sequence alignments of cholinesterases revealed that 6 of 14 aromatic amino acid residues lining the active center gorge of acetylcholinesterase are replaced by aliphatic amino acid residues in butyrylcholinesterase. The Y337 (F330) in mammalian acetylcholinesterase, which is replaced by A328 in human butyrylcholinesterase, is implicated in the binding of ligands such as huperzine A, edrophonium, and acridines and one end of bisquaternary compounds such as BW284C51 and decamethonium. Y337 may sterically hinder the binding of phenothiazines such as ethopropazine, which contains a bulky exocyclic substitution. Inhibition studies of (-)-huperzine A with human butyrylcholinesterase mutants, where A328 (KI = 194.6 microM) was modified to either F (KI = 0.6 microM, as in Torpedo acetylcholinesterase) or Y (KI = 0.032 microM, as in mammalian acetylcholinesterase), confirmed previous observations made with acetylcholinesterase mutants that this residue is important for binding huperzine A. Inhibition studies of ethopropazine with butyrylcholinesterase mutants, where A328 (KI = 0.18 microM) was modified to either F (KI = 0.82 microM) or Y (KI = 0.28 microM), suggested that A328 was not solely responsible for the selectivity of ethopropazine. Volume calculations for the active site gorge showed that the poor inhibitory activity of ethopropazine toward acetylcholinesterase was due to the smaller dimension of the active site gorge which was unable to accommodate the bulky inhibitor molecule. The volume of the butyrylcholinesterase active site gorge is approximately 200 A3 larger than that of the acetylcholinesterase gorge, which allows the accommodation of ethopropazine in two different orientations as demonstrated by rigid-body refinement and molecular dynamics calculations.


Archive | 1995

Enzymes of the cholinesterase family

Daniel M. Quinn; A. S. Balasubramanian; Bhupendra P. Doctor; Palmer Taylor

GENE STRUCTURE AND EXPRESSION OF CHOLINESTERASES: Presentations: Antisense Oligonucleotides Suppressing Expression of Cholinesterase Genes Modulate Hematopoiesis in vivo and ex vivo (H. Soreq et al.). Posters: Alternative Exon 6 Directs Synaptic Localization of Recombinant Human Acetylcholinesterase in Neuromuscular Junctions of Xenopus laevis Embryos (M. Sternfeld et al.). POLYMORPHISM AND STRUCTURE OF CHOLINESTERASES: Presentations: Structures of Complexes of Acetylcholinesterase with Covalently and Noncovalently Bound Inhibitors (J.L. Sussman et al.). Posters: Hydrophobicity on Esterase Activity of Human Serum Cholinesterase (L. Jaganathan et al.). MECHANISM OF CATALYSIS OF CHOLINESTERASES: Presentations: Amino Acid Residues that Control Mono and Bisquaternary Oximeinduced Reactivation of OEthyl Methylphosphorylated Cholinesterases (Y. Ashani et al.). Posters. CELLULAR BIOLOGY OF CHOLINESTERASES: Presentations. Posters. STRUCTURE-FUNCTION RELATIONSHIPS OF ANTICHOLINESTERASE AGENTS: Presentations. Posters. NONCHOLINERGIC FUNCTIONS OF CHOLINESTERASES: Presentations. Posters. PHARMACOLOGICAL UTILIZATION OF ANTICHOLINESTERASES: Presentations. Posters. 99 additional articles. Appendixes. Index.


Biochemical Pharmacology | 1998

Inhibition of acetylcholinesterase and butyrylcholinesterase by chlorpyrifos-oxon.

Gabriel Amitai; Deborah R. Moorad; Rachel Adani; Bhupendra P. Doctor

Phosphorothionate insecticides such as parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate) and chlorpyrifos (CPS; O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothioate; Dursban) are metabolically converted by oxidative desulfuration into paraoxon and chlorpyrifos-oxon (CPO). The insecticidal action of chlorpyrifos stems from inhibition of acetylcholinesterase (AChE) by CPO, resulting in severe cholinergic toxicity. Sensory peripheral neuropathy was observed in people exposed environmentally to chlorpyrifos sprayed in confined areas. We have examined the kinetics of inhibition of AChE and butyrylcholinesterase (BChE) by paraoxon and CPO. The bimolecular rate constants (ki) for inhibition by paraoxon of recombinant human (rH) AChE, recombinant mouse (rM) AChE, and fetal bovine serum (FBS) AChE were 7.0, 4.0, and 3.2 x 10(5) M(-1) min(-1). The ki values for the inhibition by CPO of rH AChE, fetal bovine serum AChE, human RBC AChE, Torpedo AChE, and recombinant mouse (rM) AChE were 9.3, 2.2, 3.8, 8.0, and 5.1 x 10(6) M(-1) min(-1), respectively. Inhibition of human serum BChE, rH BChE, and rM BChE by CPO yielded ki values of 1.65, 1.67, and 0.78 x 10(9) M(-1) min(-1), respectively. The ki values obtained for BChE from various species were 160- to 750-fold larger than those of AChE from parallel sources. Inhibition of the single-site mutant A328Y of rH BChE by CPO displayed a 21-fold lower rate than that of wild-type rH BChE (ki, 7.9 x 10(7) vs 1.67 x 10(9) M(-1) min(-1)). The double mutant of acyl pocket residues of rH AChE, F295L/F297V, was inhibited by CPO with a 150-fold larger ki than wild type (1.5 x 10(9) vs 1.0 x 10(7) M(-1) min(-1)). The increased rate obtained with the double mutant displaying characteristics of the BChE active center provides a rationale for higher efficacy of CPO scavenging by BChE, compared with AChE.


Neuroscience & Biobehavioral Reviews | 1991

Enzymes as pretreatment drugs for organophosphate toxicity

Bhupendra P. Doctor; Lily Raveh; Alan D. Wolfe; Donald M. Maxwell; Yacov Ashani

We have successfully demonstrated that exogenously administered acetyl- or butyrylcholinesterase (AChE, BChE respectively) will sequester organophosphates (OPs) before they reach their physiological targets. In addition, a third enzyme, endogenous carboxylesterase is known to be capable of scavenging OPs. In these studies, we have administered AChE and BChE to three different species of animals (mice, marmosets and monkeys) which were challenged with three different OPs (VX, MEPQ and soman). Results obtained from these systematic studies demonstrate that: (a) a quantitative linear correlation exists between blood AChE levels and the protection afforded by exogenously administered ChEs in animals challenged with OP, (b) approximately one mole of either AChE or BChE sequesters one mole of OP, (c) such prophylactic measures are sufficient to protect animals against OPs without the administration of any supportive drugs. Thus the OP dose, the blood-level of esterase, the ratio of the circulating enzyme to OP challenge, and the rate of reaction between them determine the overall efficacy of an enzyme as a pretreatment drug. The biochemical mechanism underlying the sequestration of various OPs by the use of exogenously administered scavenging esterases is the same in all species of animals studied. Therefore, the extrapolation of the results obtained by the use of ChE prophylaxis in animals to humans should be more reliable and effective than extrapolating the results from currently used multidrug antidotal modalities.


Biochemical and Biophysical Research Communications | 1992

Mechanism of inhibition of cholinesterases by huperzine A.

Yacov Ashani; James O. Peggins; Bhupendra P. Doctor

Huperzine A, an alkaloid isolated from Huperzia serrata was found to reversibly inhibit acetylcholinesterases (EC 3.1.1.7) and butyrylcholinesterases (EC 3.1.1.8) with on- and off-rates that depend on both the type and the source of enzyme. Long-term incubation of high concentrations of purified cholinesterases (1-8 microM) with huperzine A did not show any chemical modification of huperzine A. A low dissociation constant KI was obtained for mammalian acetylcholinesterase-huperzine (20-40 nM) compared to mammalian butyrylcholinesterase-huperzine (20-40 microM). This indicates that the thermodynamic stability of huperzine-cholinesterase complex may depend on the number and type of aromatic amino acid residues in the catalytic pocket region of the cholinesterase molecule.


Neuroreport | 1997

Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate

Haresh S. Ved; Michael L. Koenig; Jitendra R. Dave; Bhupendra P. Doctor

HUPERZINE A, a potential therapeutic agent for Alzheimers disease, inhibits acetylcholinesterase in primary cultures derived from forebrain, hippocampus, cortex and cerebellum of embryonic rat brain. Glutamate induces cell death in cultures from all these brain regions. Maximum cell toxicity was observed in cerebellar cultures. Pretreatment of cell cultures with Huperzine A reduced cell toxicity, as evidenced by cytotoxicity assay and general morphology. Huperzine A pretreatment also reduced glutamate-induced calcium mobilization, but did not affect elevations in intraneuronal free Ca2+ ([Ca]i) caused by KCl or (–)Bay K 8644. The data suggest that Huperzine A could be a potent neuroprotective agent not only where cholinergic neurons are impaired, but also under conditions in which glutamatergic functions are compromised.


Toxicological Sciences | 1987

Acetylcholinesterase prophylaxis against organophosphate toxicity

A. D. Wolfe; R. S. Rush; Bhupendra P. Doctor; I. Koplovitz; D. Jones

Fetal bovine serum acetylcholinesterase (FBS-AChE) protected mice from multiple LD50 doses of organophosphorus (OP) nerve agents. Mice were injected intraperitoneally (ip) with up to 3.3 mg (11,000 U) of FBS-AChE which exhibited a relatively long serum half-life and appeared well tolerated. The enzyme protected mice from the OP ethyl-S-2-diisopropylamino-ethylmethylphosphonothiolate (VX) with a stoichiometry equal to approximately 2 moles of enzyme active site per mole of VX. FBS-AChE, at a lower enzyme OP ratio, protected mice from 2 LD50s of the nerve agent methylphosphonofluoridic acid 1,2,2,-trimethylpropyl ester (soman) when used in conjunction with atropine and 2[(hydroxyimino)methyl]-1-methylpyridinium chloride. It is concluded that sequestration of highly toxic OPs by administration of AChE occurs in mice and suggests a new approach to treatment of OP intoxication.


Life Sciences | 1986

A simplified procedure for the purification of large quantities of fetal bovine serum acetylcholinesterase

Denise De La Hoz; Bhupendra P. Doctor; J.Scott Ralston; Robert S. Rush; A.David Wolfe

A simple procedure has been developed for the large scale purification of fetal bovine serum acetylcholinesterase (AChE) (EC 3.1.1.7). The procedure involves two steps: batch adsorption of the AChE from 250 L of serum onto a procainamide affinity Sepharose 4B gel; and analytical procainamide affinity chromatography of the step-1 product. Over 100 mg of AChE was purified in 10 days to apparent homogeneity with this procedure.


Biochemical Pharmacology | 2011

Prophylaxis with human serum butyrylcholinesterase protects guinea pigs exposed to multiple lethal doses of soman or VX

Ashima Saxena; Wei Sun; James M. Fedorko; Irwin Koplovitz; Bhupendra P. Doctor

Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a bioscavenger for the prophylaxis of organophosphorus (OP) nerve agent toxicity in humans. It is estimated that a dose of 200mg will be required to protect a human against 2×LD(50) of soman. To provide data for initiating an investigational new drug application for the use of this enzyme as a bioscavenger in humans, we purified enzyme from Cohn fraction IV-4 paste and initiated safety and efficacy evaluations in mice, guinea pigs, and non-human primates. In mice, we demonstrated that a single dose of enzyme that is 30 times the therapeutic dose circulated in blood for at least four days and did not cause any clinical pathology in these animals. In this study, we report the results of safety and efficacy evaluations conducted in guinea pigs. Various doses of Hu BChE delivered by i.m. injections peaked at ∼24h and had a mean residence time of 78-103h. Hu BChE did not exhibit any toxicity in guinea pigs as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. Efficacy evaluations showed that Hu BChE protected guinea pigs from an exposure of 5.5×LD(50) of soman or 8×LD(50) of VX. These results provide convincing data for the development of Hu BChE as a bioscavenger that can protect humans against all OP nerve agents.


Toxicology and Applied Pharmacology | 1992

Use of cholinesterases as pretreatment drugs for the protection of rhesus monkeys against soman toxicity

Alan D. Wolfe; Dennis W. Blick; Michael R. Murphy; Stephanie A. Miller; Mary K. Gentry; Stanley L. Hartgraves; Bhupendra P. Doctor

Purified fetal bovine serum acetylcholinesterase (FBS AChE) and horse serum butyrylcholinesterase (BChE) were successfully used as single pretreatment drugs for the prevention of pinacolyl methylphosphonofluoridate (soman) toxicity in nonhuman primates. Eight rhesus monkeys, trained to perform Primate Equilibrium Platform (PEP) tasks, were pretreated with FBS AChE or BChE and challenged with a cumulative level of five median lethal doses (LD50) of soman. All ChE-pretreated monkeys survived the soman challenge and showed no symptoms of soman toxicity. A quantitative linear relation was observed between the soman dose and the neutralization of blood ChE. None of the four AChE-pretreated animals showed PEP task decrements, even though administration of soman irreversibly inhibited nearly all of the exogenously administered AChE. In two of four BChE-pretreated animals, a small transient PEP performance decrement occurred when the cumulative soman dose exceeded 4 LD50. Performance decrements observed under BChE protection were modest by the usual standards of organophosphorus compound toxicity. No residual or delayed performance decrements or other untoward effects were observed during 6 weeks of post-exposure testing with either ChE.

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Ashima Saxena

Walter Reed Army Institute of Research

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Richard K. Gordon

Walter Reed Army Institute of Research

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Madhusoodana P. Nambiar

Walter Reed Army Institute of Research

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Wei Sun

Walter Reed Army Institute of Research

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Mary K. Gentry

Walter Reed Army Institute of Research

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Yacov Ashani

Weizmann Institute of Science

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Chunyuan Luo

Walter Reed Army Institute of Research

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David E. Lenz

United States Army Medical Research Institute of Chemical Defense

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Donald M. Maxwell

United States Army Medical Research Institute of Chemical Defense

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