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PubMed1985

Effect of FS (alpha 2 gamma beta s) hybrid hemoglobin on Hb S nucleation and aggregation.

Asymmetrical cross-linked FS (alpha 2 gamma beta s) hybrid hemoglobin (Hb FS-fumarate) was prepared by reacting mixtures of hemoglobins F and S with double-headed aspirin, bis(3,5-dibromosalicyl) fumarate. When the molar ratio of hemoglobin to the cross-linking agent was 1 to 2 in a 1:1 FS mixture, the relative ratio of the products, cross-linked hemoglobins F (Hb F-fumarate), FS (HB FS-fumarate), and S (Hb S-fumarate), was 1.0:2.6:2.0, in contrast to a 1:2:1 ratio of cross-linked hemoglobins A, AS, and S in a 1:1 AS mixture. These results suggest that the fumaryl group reacts differently with Hb F, Hb FS and Hb S, and that the difference could be attributed to the difference in the structure in the vicinity of the EF6 Lys of non alpha-chains. The oxygen-binding properties of Hb F-fumarate, Hb FS-fumarate, and Hb S-fumarate were similar, except that the n-value of Hb F-fumarate was slightly lower than n-values of Hb S-fumarate and Hb FS-fumarate. Kinetic studies on aggregation showed that the addition of Hb FS-fumarate to unmodified Hb S did not affect the delay time prior to aggregation, but did increase the total turbidity. Electrophoretic and densitometric scanning analysis of the aggregate phase of this mixture showed the fraction of Hb FS-fumarate to be 19%. Hb F-fumarate's effect on the delay time is concentration-dependent; the greater the concentration of Hb F-fumarate, the longer the delay time. The turbidity after aggregation of the mixture of Hb S and Hb F-fumarate was much less than that of Hb S and Hb FS-fumarate. However, the fraction of Hb F-fumarate in the aggregate phase was 19%, which is similar to that of Hb FS-fumarate. These data suggest that Hb F and FS hybrid hemoglobin cannot participate in nuclei formation, but can participate in aggregation after sufficient amounts of nuclei are formed from Hb S, and that increased levels of Hb F do not have an inhibitory effect on the formation of nuclei but on the growth of aggregates.

Aspirin↗
PubMed1984

Polymerization of AS hybrid hemoglobin. Potent inhibitory effect of hemoglobin A on the polymerization of AS hybrid hemoglobin.

Asymmetrically cross-linked AS hybrid hemoglobin (Hb AS-fumarate) was prepared by reacting a mixture of oxy-Hb A and oxy-Hb S with a cross-linking agent, bis(3,5-dibromosalicyl)fumarate. Kinetics of the polymerization of Hb AS-fumarate in 1.8 M phosphate buffer showed that Hb AS-fumarate polymerized similarly to Hb S-fumarate despite the presence of a beta A chain. The kinetics of the polymerization of a mixture of Hb AS-fumarate and Hb S-fumarate was similar to that of Hb S-fumarate or Hb AS-fumarate alone. However, when Hb AS-fumarate was mixed with Hb A, the delay time prior to polymerization of the mixture was markedly prolonged. Although the solubility of Hb AS-fumarate was similar to that of Hb S-fumarate, it nearly doubled upon the addition of Hb A. Analysis of Hb A in the polymer phase showed that a significant amount (35-40%) of Hb A copolymerized with Hb AS-fumarate. No such effect was observed when Hb A was mixed with Hb S-fumarate, where the delay time prior to polymerization and the solubility of the mixture were regulated by the concentration of Hb S-fumarate in the mixture. The strong inhibitory effect of Hb A on the polymerization of Hb AS hybrid hemoglobin may help explain the benign clinical course in sickle cell trait.

Chromatography, High Pressure Liquid↗
PubMed2005

Characterization of the functional role of allosteric site residue Asp102 in the regulatory mechanism of human mitochondrial NAD(P)+-dependent malate dehydrogenase (malic enzyme).

Human mitochondrial NAD(P)+-dependent malate dehydrogenase (decarboxylating) (malic enzyme) can be specifically and allosterically activated by fumarate. X-ray crystal structures have revealed conformational changes in the enzyme in the absence and in the presence of fumarate. Previous studies have indicated that fumarate is bound to the allosteric pocket via Arg67 and Arg91. Mutation of these residues almost abolishes the activating effect of fumarate. However, these amino acid residues are conserved in some enzymes that are not activated by fumarate, suggesting that there may be additional factors controlling the activation mechanism. In the present study, we tried to delineate the detailed molecular mechanism of activation of the enzyme by fumarate. Site-directed mutagenesis was used to replace Asp102, which is one of the charged amino acids in the fumarate binding pocket and is not conserved in other decarboxylating malate dehydrogenases. In order to explore the charge effect of this residue, Asp102 was replaced by alanine, glutamate or lysine. Our experimental data clearly indicate the importance of Asp102 for activation by fumarate. Mutation of Asp102 to Ala or Lys significantly attenuated the activating effect of fumarate on the enzyme. Kinetic parameters indicate that the effect of fumarate was mainly to decrease the K(m) values for malate, Mg2+ and NAD+, but it did not notably elevate kcat. The apparent substrate K(m) values were reduced by increasing concentrations of fumarate. Furthermore, the greatest effect of fumarate activation was apparent at low malate, Mg2+ or NAD+ concentrations. The K(act) values were reduced with increasing concentrations of malate, Mg2+ and NAD+. The Asp102 mutants, however, are much less sensitive to regulation by fumarate. Mutation of Asp102 leads to the desensitization of the co-operative effect between fumarate and substrates of the enzyme.

Allosteric Site↗