Kinetic activation volumes of the binding of oxygen and carbon monoxide to hemoglobin and myoglobin studied on a high-pressure laser flash photolysis apparatus.
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Animals↗
Biomedical subjects
B B Hasinoff
Publications and source records attributed to B B Hasinoff.
Kinetics of the reaction of p-chloromercuribenzoate with the sulfhydryl groups of glutathione, 2-mercaptoethanol, and phosphorylase b.
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Acetamides↗
Kinetics of the oxidation of ferrocyanide by horseradish peroxidase compounds I and II.
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Binding Sites↗
On the rates of enzymatic, protein and model compound reactions: the importance of diffusion control.
A meaningful method of comparison is suggested for saturation kinetics, typical of enzyme-catalyzed reactions, and nonsaturation kinetics, often typical of model compound reactions. True diffusion-controlled reactions do not give saturation behavior; but enzymes may need saturation behavior to attain selectivity and stereospecificity for complicated substrates or for reactions beyond the complexity of electron transfer. However, the diffusion controlled limit provides a better reference point for rate comparisons than does the rate of uncatalyzed reaction. The failure of the Stokes-Einstein equation for small substrates is documented, as are ways of circumventing the problem. Advantages and pitfalls in the use of viscosogens to test for diffusion control are delineated. Finally, the possible advantages of surface diffusion for an enzyme, but lack of experimental evidence, is discussed.
Diffusion↗
The displacement of iron(III) from its complexes with the anticancer drugs piroxantrone and losoxantrone by the hydrolyzed form of the cardioprotective agent dexrazoxane.
Piroxantrone and losoxantrone are new DNA topoisomerase II-targeting anthrapyrazole antitumor agents that display cardiotoxicity both clinically and in animal models. A study was undertaken to see whether dexrazoxane or its hydrolysis product ADR-925 could remove iron(III) from its complexes with piroxantrone or losoxantrone. Their cardiotoxicity may result from the formation of iron(III) complexes of losoxantrone and piroxantrone. Subsequent reductive activation of their iron(III) complexes likely results in oxygen-free radical-mediated cardiotoxicity. Dexrazoxane is in clinical use as a doxorubicin cardioprotective agent. Dexrazoxane presumably acts through its hydrolyzed metal ion binding form ADR-925 by removing iron(III) from its complex with doxorubicin, or by scavenging free iron(III), thus preventing oxygen-free radical-based oxidative damage to the heart tissue. ADR-925 was able to remove iron(III) from its complexes with piroxantrone and losoxantrone, though not as efficiently or as quickly as it could from its complexes with doxorubicin and other anthracyclines. This study provides a basis for utilizing dexrazoxane for the clinical prevention of anthrapyrazole cardiotoxicity.
Anthraquinones↗
The enzymatic hydrolysis-activation of the adriamycin cardioprotective agent (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane.
The cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane, ADR-529] has shown a great deal of promise against what may be an iron-based adriamycin-induced cardiotoxicity. ICRF-187 likely exerts its actions through its rings-opened hydrolysis product, which has a structure similar to EDTA and like-wise strongly binds metal ions. The 105,000g soluble supernatant fraction of homogenates of porcine liver and kidney, but not of heart, enzymatically caused a ring-opening hydrolysis of ICRF-187 at the rate of 1.2, 1.4, and less than 0.15 nmol.(mg protein)-1.min-1, respectively. This enzymatic hydrolysis of ICRF-187 was completely abolished by 4-chlorobenzenesulfonamide, which suggested that dihydropyrimidine amidohydrolase (DHPase) might be, in large part, responsible for the ICRF-187 hydrolase activity. Bovine liver DHPase was isolated and was shown to enzymatically hydrolyze ICRF-187 with a Vmax of 14,900 nmol.(mg DHPase)-1.min-1, a value that exceeded that of its natural substrates. The KM for ICRF-187 of 6.7 mM was, however, much larger than that of its natural substrates. The enzyme kinetics were consistent with DHPase acting on ICRF-187 to form one-ring-opened hydrolysis product only. Thus, DHPase is not able to act on the one-ring-opened hydrolysis product to produce two-ring-opened product. The Ki for 4-chlorobenzenesulfonamide inhibition of DHPase was measured to be 26 microM.
Amidohydrolases↗
The hydrolysis activation of the doxorubicin cardioprotective agent ICRF-187 [+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane).
ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] has shown promise [Speyer et al., N. Engl. J. Med. 319, 745 (1988)] as a cardioprotective agent against what may be an iron-based doxorubicin (Adriamycin)-induced cardiotoxicity. ICRF-187 likely exerts its action through its rings-opened hydrolysis product, a compound that has an EDTA-type structure and, likewise, strongly binds metal ions. The hydrolysis of ICRF-187 was followed spectrophotometrically in the ultraviolet and was shown to be pseudo-first-order over a wide pH range. The hydrolysis mechanism was shown to have a hydroxide-catalyzed path and a pH-independent path similar to the hydrolysis of other imides. The anionic form of ICRF-187 (with a pKa of 9.6 at 37 degrees C) was resistant to hydroxide attack. The kinetically, spectroscopically and potentiometrically determined pKa values were all in excellent agreement and thus provided a test of the mechanism. Each imide group underwent hydrolysis and ionization independently of the other. The rate of ICRF-187 hydrolysis was also followed by observation of the removal of Cu2+ from a Cu2(+)-doxorubicin complex by the ICRF-187 hydrolysis product.
Chemical Phenomena↗
Enzymatic ring-opening reactions of the chiral cardioprotective agent (+) (S)-ICRF-187 and its (-) (R)-enantiomer ICRF-186 by dihydropyrimidine amidohydrolase.
The kinetics of the ring-opening reaction of the cardioprotective agent (+) (S)-ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane, dexrazoxane] and its (-) (R)-analog ICRF-186 by the enzyme dihydropyrimidine amidohydrolase (DHPase) has been studied by HLLC. Chromatographic separation of the two single-ring opened hydrolysis products allowed an estimation of the Michaelis parameters for the opening of each individual ring on the two optical isomers. Under nonsaturating conditions, DHPase acts on ICRF-187 4 times faster than it does on ICRF-186. However, the single-ring opened hydrolysis products of both ICRF-187 and ICRF-186 are not substrates of DHPase. Because the active form of ICRF-187 is thought to be its rings-opened metal ion chelating form, these results suggest that DHPase-catalyzed hydrolysis occurring in the liver and the kidney may lead to differences in the pharmacological action and effectiveness of these two optical isomers.
Amidohydrolases↗