Model compounds for R-state and T-state hemoglobins

Geibel, Jon F.; Cannon, John F.; Campbell, D. H.; Traylor, T. G.

doi:10.1021/ja00479a047

Cited by 100 publications

(52 citation statements)

References 11 publications

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“…The increase of k off for NO dissociation from HSA-heme-Fe(II)-NO upon stabilization of the six-coordinated heme-Fe(II)-NO-atom is reminiscent with what reported for warfarin-induced six-coordination of HSA-heme-Fe(II)-NO [41], and for 1-methyl-imidazole-(1-MeIm-) mediated six-coordination of the heme-Fe(II)-NO model compound [43] (Table 1), clearly indicating that (unlike for the heme-Fe-atom ligand CO [49]) penta-coordinated heme-Fe(II)-NO is characterized by a slower NO dissociation rate than the hexacoordinated species.…”

Section: Methodssupporting

confidence: 72%

Ibuprofen modulates allosterically NO dissociation from ferrous nitrosylated human serum heme-albumin by binding to three sites

Ascenzi

Masi

Sanctis

et al. 2009

Biochemical and Biophysical Research Communications

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a b s t r a c tHuman serum albumin (HSA) is a monomeric allosteric protein. Here, the effect of ibuprofen on denitrosylation kinetics (k off ) and spectroscopic properties of HSA-heme-Fe(II)-NO is reported. The k off value increases from (1.4 ± 0.2) Â 10 À4 s À1 , in the absence of the drug, to (9.5 ± 1.2) Â 10 À3 s À1 , in the presence of 1.0 Â 10 À2 M ibuprofen, at pH 7.0 and 10.0°C. From the dependence of k off on the drug concentration, values of the dissociation equilibrium constants for ibuprofen binding to HSA-heme-Fe(II)-NO (K 1 = (3.1 ± 0.4) Â 10 À7 M, K 2 = (1.7 ± 0.2) Â 10 À4 M, and K 3 = (2.2 ± 0.2) Â 10 À3 M) were determined. The K 3 value corresponds to the value of the dissociation equilibrium constant for ibuprofen binding to HSA-heme-Fe(II)-NO determined by monitoring drug-dependent absorbance spectroscopic changes (H = (2.6 ± 0.3) Â 10 À3 M). Present data indicate that ibuprofen binds to the FA3-FA4 cleft (Sudlow's site II), to the FA6 site, and possibly to the FA2 pocket, inducing the hexa-coordination of HSA-heme-Fe(II)-NO and triggering the heme-ligand dissociation kinetics.

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Section: Methodssupporting

confidence: 72%

Ibuprofen modulates allosterically NO dissociation from ferrous nitrosylated human serum heme-albumin by binding to three sites

Ascenzi

Masi

Sanctis

et al. 2009

Biochemical and Biophysical Research Communications

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“…This effect was postulated to decrease the affinity of CO (16). A corollary suggestion is that Fel-OO, being bent already, should not suffer this steric effect, and CO binding in the hemoproteins should be impaired relative to that in simple model complexes (7,16).In contrast to these predictions, the model compounds chelated protoheme and chelated mesoheme were reported to bind both 02 and CO in aqueous suspension at 20°C with affinities and kinetics similar to those of the high-affinity proteins R-state hemoglobin and hemoglobin chains (8,17,18). A number of other simple model systems have CO affinities similar to those of the chelated hemes (6,9,19,20) although the corresponding studies with 02 have not been made.…”

mentioning

confidence: 90%

Binding of O2 and CO to hemes and hemoproteins.

Traylor¹,

Berzinis²

1980

Proc. Natl. Acad. Sci. U.S.A.

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Enthalpies and entropies have been determined for the reversible binding of 02 Structural and dynamic studies of hemoproteins have led to three distinct but not necessarily exclusive proposals for the effects of the protein on the reactivity of heme toward 02 and CO. Two of these postulates, the proximal base tension effect (1, 2) and the proximal imidazole deprotonation effect (3-5), have recently been documented by studies of model compounds (6-11). The third postulate, of a distal side steric effect, has been the subject of some controversy in model compound studies (7,9).In hemoproteins studied by x-ray crystallography, the Fell-CO has the ligand "pushed" off the axis by a nearby histidine or other distal side residue (12)(13)(14), in contrast to the observations in simple complexes (15). This effect was postulated to decrease the affinity of CO (16). A corollary suggestion is that Fel-OO, being bent already, should not suffer this steric effect, and CO binding in the hemoproteins should be impaired relative to that in simple model complexes (7,16).In contrast to these predictions, the model compounds chelated protoheme and chelated mesoheme were reported to bind both 02 and CO in aqueous suspension at 20°C with affinities and kinetics similar to those of the high-affinity proteins R-state hemoglobin and hemoglobin chains (8,17,18). A number of other simple model systems have CO affinities similar to those of the chelated hemes (6,9,19,20) although the corresponding studies with 02 have not been made.Based upon these observations we suggested that in R-state hemoglobin or isolated hemoglobin chains the protein served only to keep the heme five-coordinated and to prevent oxidation, imparting no special effect on the heme affinity for CO or 02-Other hemoproteins having lower CO or 02 affinities were presumed to accomplish this alteration from the standard hemoglobin chain behavior by one of the effects mentioned above (18).The more elaborate iron complexes such as cyclophane heme (21,22), capped heme (23), or picket-fence heme (7,24,25), all of which have bulky groups around one face of the heme, either do not mimic the hemoproteins or do so only in part. Picket-fence heme was reported to bind 02 in toluene or in solid state (7) with an affinity similar to that of chelated heme or R-state hemoglobin but to bind CO "irreversibly" in the solid state (24) and with greatly increased affinity in solution (25). These observations led to the conclusion that model compounds bind CO more strongly than do hemoproteins (24), in contrast to the proposal discussed above.We now report the thermodynamics of the binding of 02 and CO (Eqs. 1 and 2) and the replacement reaction (Eq. 3) which are very nearly the same as those of hemoglobin (R-state) Kinetics were determined with a microprocessor-controlled laser flash photolysis apparatus as described (9,26

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“…Changes in the strength of the Fe-N(His) bond can be brought about by changes in the angles of imidazole with the heme plane and/or by changes in Support for the hypothesis that porphyrin provides steric hindrance in the formation of the iron-ligand bond comes from the kinetic data on model compounds. The ligand combination rates for the pentacoordinate heme derivative (compound II, i' = 1.1 X 107 M-1 sec') are about 1/12th (after correcting for the statistical factor) of the corresponding rates for the fourcoordinate derivative (compound II without the proximal base, i' = 3 X 108 M-1 sec') (7). The position of iron relative to the porphyrin ring and the incoming ligand is such that metalto-ligand bond formation is difficult in the pentacoordinate derivative as compared to the corresponding four-coordinate heme derivative.…”

Section: Discussionmentioning

confidence: 95%

“…1). The details of the synthesis, purification, structure-analysis (NMR, infrared, and C,H analysis), and some of the kinetic data in Table 1 are described elsewhere (7).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

"Tension" on heme by the proximal base and ligand reactivity: conclusions drawn from model compounds for the reaction of hemoglobin.

Sharma¹,

Geibel²,

Ranney³

1978

Proc. Natl. Acad. Sci. U.S.A.

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The kinetic data on model compounds of hemoglobin indicate that in oxy derivatives ligand dissociation rates are sensitive to the "tension" exerted by the proximal base on the metal-to-ligand bond;-the corresponding rates for carboxy derivatives are not sensitive to the tension. It is suggested that the metal-to-ligand bond becomes weaker with increased "pull" (or tension) on Fe from the proximal base due to the steric and/or electronic interaction between the ligand, the porphyrin ring, and the proximal base. In model compounds the linear heme Fe-to-CO bond vis-a-vis the bent heme Fe-to-02 bond probably makes such interactions less significant in carboxy derivatives. It is proposed that the kinetic a,#-chain nonequivalence in Hb4(02)4 is due to the difference in the tension in the two chains on Fe by the proximal base. The absence of a,#-chain differences large enough to show up in CO dissociation rates from Hb4(CO)4 is explained on the basis of lack of sensitivity of the Fe-CO bond to tension from the proximal base. The implications of the results for the observed cooperative effects in ligand combination (for CO) and dissociation (for 02 and NO) rates of hemoglobin have also been discussed.The stereochemical mechanism for cooperativity proposed by Perutz (1) rationalizes a large amount of data on the functional behavior of hemoglobins. From its inception the model was in disagreement with the kinetic results regarding the relative order of reactivity of a and # chains. Since then, the presence of a water molecule in the heme pocket of the a chains has been demonstrated, and on this basis the reactivity of a chains might well be lower than that of fl chains (2); this is consistent with the kinetic data (3). The kinetic differences in a and ft chains are either small or absent in buffers of low ionic strength but become significant in more concentrated phosphate buffers. For human hemoglobin (Hb A), the 02 off rates for the two chains differ by a factor of two; for pig and rabbit hemoglobins they differ by a factor of seven (4, 5). Recent studies on nitrosylhemoglobin show rather large chain differences in NO off rates in the presence of phosphate, particularly inositol hexaphosphate (inositol-P6) (unpublished data). When the ligand is CO, the a,#-chain differences are observed in the ligand combination rates but not in CO off rates. Details of the mechanism by which organic phosphates generate or accentuate the chain differences are not very well understood. Is it the narrowing or steric crowding of the heme pocket on the binding of phosphates and phosphate analogs that results in the accentuated kinetic nonequivalence of a and A chains? Or is it the difference in the "tension" on iron from the proximal base that results in different ligand dissociation and combination rates in the two chains. Or are both factors responsible?The cooperativity in the reactions of hemoglobin, if considered in terms of ligand combination and dissociation rates, is highly dependent on the nature of the ligand. Thus, whi...

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Model compounds for R-state and T-state hemoglobins

Cited by 100 publications

References 11 publications

Ibuprofen modulates allosterically NO dissociation from ferrous nitrosylated human serum heme-albumin by binding to three sites

Ibuprofen modulates allosterically NO dissociation from ferrous nitrosylated human serum heme-albumin by binding to three sites

Binding of O2 and CO to hemes and hemoproteins.

"Tension" on heme by the proximal base and ligand reactivity: conclusions drawn from model compounds for the reaction of hemoglobin.

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