Avram Goldstein
Harvard University
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Archives of Biochemistry and Biophysics | 1951
Avram Goldstein
Summary o 1. A great many alkaloids inhibit human plasma cholinesterase and compete with acetylcholine for the enzyme surface. Urethans related to prostigmine and physostigmine also inhibit competitively but combine with and dissociate from the enzyme extraordinarily slowly, so that competitive displacement by substrate is also very slow. 2. The relationship of this kinetic behavior to the velocity constants of combination and dissociation is discussed. 3. The differences in kinetic behavior are interpreted as showing that alkaloids in general combine with only one locus of an enzyme-active center containing two loci, but that the urethans, like substrates, interact with both loci.
Archives of Biochemistry and Biophysics | 1952
Avram Goldstein; Robert E. Hamlisch
Summary The cholinesterase inhibitors, physostigmine and prostigmine, are destroyed enzymatically by human serum, by a human plasma fraction (IV-6-3) highly purified with respect to cholinesterase, and by the same purified fraction partially denatured by heat. The rate of inhibitor destruction parallels the uninhibited activity toward acetylcholine in all three preparations. This is taken to indicate the probability that these inhibitors are destroyed by the same enzyme that hydrolyzes acetylcholine—i.e., the human plasma cholinesterase. The ratios of inhibitor turnover number to that of acetylcholine have been determined. They are 5.5×10 −7 for physostigmine and 1.2×10 −7 for prostigmine. These findings support the conclusion, arrived at on other grounds (5), that cholinesterase inhibitors of the urethan group are really competitive substrates with exceedingly low turnover numbers.
Clinical Pharmacology & Therapeutics | 1984
Jack H. Mendelson; James Ellingboe; Barbara A Judson; Avram Goldstein
Nine male heroin addicts maintained on L‐α‐acetylmethadol (LAAM) for about 5 mo had normal plasma levels of testosterone and luteinizing hormone 72 hr after a dose of LAAM and also during 2 wk after abrupt LAAM withdrawal.
Archives of Biochemistry and Biophysics | 1951
Avram Goldstein; Mary E. Doherty
Abstract 1. 1. The thermal denaturation of human plasma cholinesterase has been studied, using purified preparations obtained through the Plasma Fractionation Program. 2. 2. Under the conditions of these experiments, the apparent energy of activation in the denaturation process (on the assumption of a first-order reaction) is approximately 60,000 cal./mole, and the corresponding temperature coefficient about 1.3/degree, at the pH of optimal stability. Denaturation is measured in months at 0 °, days at 37 °, and minutes at 50 °. 3. 3. A broad pH optimum for stability is found, centering about pH 6. Denaturation is greatly accelerated above pH 7 and below pH 5. The region of optimal stability does not include the more acidic isoelectric point of the enzyme or the more alkaline pH of optimal enzyme activity. 4. 4. Thermal denaturation is more rapid at low ionic strength than at physiological salt concentration. 5. 5. Enzyme dilution results in a loss of stability which can be prevented by albumin. 6. 6. Human plasma albumin (2–4%) stabilizes cholinesterase, but only in the pH range of optimal stability. The high order of stability of the enzyme in blood serum can be nearly duplicated in a solution of purified cholinesterase made to resemble serum in enzyme activity, ionic strength, and albumin concentration. 7. 7. The reversible inhibitors, prostigmine and methylene blue, stabilize cholinesterase against thermal denaturation. 8. 8. The thermal denaturation of the enzyme does not proceed as a first-order reaction. The denaturation rate diminishes excessively with time and this behavior is not altered by albumin. The most satisfactory explanation appears to be that active enzyme is stabilized by denatured enzyme or by denatured impurities in the fractions employed.
Archives of Biochemistry and Biophysics | 1951
Avram Goldstein; Mary E. Doherty
Abstract Evidence has been presented to show that the inactivation of human plasma cholinesterase by mercuric chloride is the result of two independent mechanisms: 1. 1. At high concentration, mercuric chloride appears to combine rapidly and reversibly at the enzyme active center, causing inhibition that is competitive with respect to substrate. As judged by its insensitivity to two selective sulfhydryl inhibitors, the enzyme active center apparently does not contain readily reactive sulfhydryl, and mercury must be assumed to react with some other group. 2. 2. Mercuric chloride evidently also combines elsewhere on the enzyme surface (possibly through —SH) thereby initiating a slow and irreversible denaturation. This process is most obvious at low mercury concentration.
Cellular and Molecular Life Sciences | 1952
Avram Goldstein
Bei gewissen reversiblen Reaktionen wird, unter bestimmten, stark eingeschränkten, aber doch häufig vorkommenden Bedingungen, die Geschwindigkeit der Gleichgewichtseinstellung für dieHin-Reaktion nur durch die Geschwindigkeitskonstante derRück-Reaktion bestimmt. Diese besondere Anwendung des Massenwirkungsgesetzes wird an der Hemmungsentwicklung in gewissen Enzym-Inhibitor-Systemen illustriert. In einem reversiblen Enzym-Inhibitor-System, in dem der grössere Teil der Inhibitormoleküle frei bleibt, erfolgt die Einstellung eines gegebenen Hemmungsgrades um so langsamer, je fester das Inhibitormolekül im entstehenden Komplex gebunden ist. Kann der Hemmungsgrad gegen die Zeit aufgetragen werden (vom Augenblick der Mischung von Enzym und Inhibitor an gerechnet), so lässt sich aus der erhaltenen Kurve die Geschwindigkeitskonstante der Dissoziation berechnen, selbst wenn die Konzentrationen der Reaktionsteilnehmer unbekannt sind.
Journal of Pharmacology and Experimental Therapeutics | 1960
Avram Goldstein; Lewis Aronow
Journal of Pharmacology and Experimental Therapeutics | 1960
Avram Goldstein; Barbara W. Searle; Robert T. Schimke
Journal of Pharmacology and Experimental Therapeutics | 1949
Avram Goldstein; Otto Krayer; Mary A. Root; George H. Acheson; Mary E. Doherty
Journal of Bacteriology | 1962
Barbara W. Searle; Avram Goldstein