The effects of inositol hexaphosphate on the allosteric properties of two beta-99-substituted abnormal hemoglobins, hemoglobin Yakima and hemoglobin Kempsey.

(1) Background: Two first-in-class racemic dopamine D1 receptor (D1R) positive allosteric modulator (PAM) chemotypes (1 and 2) were identified from a high-throughput screen. In particular, due to its selectivity for the D1R and reported lack of intrinsic activity, compound 2 shows promise as a starting point toward the development of small molecule allosteric modulators to ameliorate the cognitive deficits associated with some neuropsychiatric disease states; (2) Methods: Herein, we describe the enantioenrichment of optical isomers of 2 using chiral auxiliaries derived from (R)- and (S)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (d- and l-pantolactone, respectively); (3) Results: We confirm both the racemate and enantiomers of 2 are active and selective for the D1R, but that the respective stereoisomers show a significant difference in their affinity and magnitude of positive allosteric cooperativity with dopamine; (4) Conclusions: These data warrant further investigation of asymmetric syntheses of optically pure analogues of 2 for the development of D1R PAMs with superior allosteric properties.

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Allosteric Properties of a Pyruvate Kinase Isoenzyme from Rat Liver Cells in Culture

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)43707-1 ◽

1973 ◽

Vol 248 (13) ◽

pp. 4610-4616

Author(s):

P. Roy Walker ◽

Van R. Potter

Keyword(s):

Pyruvate Kinase ◽

Rat Liver ◽

Liver Cells ◽

Cells In Culture ◽

Rat Liver Cells ◽

Allosteric Properties

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The Effect of Inositol Hexaphosphate on the Kinetics of CO and O2 Binding by Human Hemoglobin

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)45869-9 ◽

1971 ◽

Vol 246 (23) ◽

pp. 7168-7174

Author(s):

Robert D. Gray ◽

Quentin H. Gibson

Keyword(s):

Human Hemoglobin ◽

Inositol Hexaphosphate ◽

Kinetics Of ◽

O2 Binding

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Crystallization and X-ray diffraction data analysis of human deoxyhaemoglobin A0 fully stripped of any anions

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s0907444999009750 ◽

1999 ◽

Vol 55 (11) ◽

pp. 1914-1916 ◽

Cited By ~ 11

Author(s):

F. A. V. Seixas ◽

W. F. de Azevedo ◽

M. F. Colombo

Keyword(s):

Diffraction Data ◽

Oxygen Affinity ◽

X Ray Diffraction ◽

Structural Explanation ◽

Human Haemoglobin ◽

X Ray ◽

High Resolution Structure ◽

Allosteric Properties

In this work, initial crystallographic studies of human haemoglobin (Hb) crystallized in isoionic and oxygen-free PEG solution are presented. Under these conditions, functional measurements of the O2-linked binding of water molecules and release of protons have evidenced that Hb assumes an unforeseen new allosteric conformation. The determination of the high-resolution structure of the crystal of human deoxy-Hb fully stripped of anions may provide a structural explanation for the role of anions in the allosteric properties of Hb and, particularly, for the influence of chloride on the Bohr effect, the mechanism by which Hb oxygen affinity is regulated by pH. X-ray diffraction data were collected to 1.87 Å resolution using a synchrotron-radiation source. Crystals belong to the space group P21212 and preliminary analysis revealed the presence of one tetramer in the asymmetric unit. The structure is currently being refined using maximum-likelihood protocols.

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