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Biomedical subjects

W F Moo-Penn

Publications and source records attributed to W F Moo-Penn.

At least 19 recordsLinked to original sources
PubMed1992

Hb Rancho Mirage [beta 143(H21)His----Asp]; a variant in the 2,3-DPG binding site showing normal oxygen affinity at physiological pH.

Hb Rancho Mirage was detected in a 17-year-old male in association with a mild anemia. Hemoglobin electrophoresis revealed the variant had a mobility between Hbs A and J on cellulose acetate (pH 8.6) and a mobility like Hb F on citrate agar (pH 6.4). A substitution of His----Asp was found at position 143 in the beta chain, a residue that contributes to the anionic 2,3-DPG binding site in Hb. This variant exhibited normal oxygen affinity at physiologic pH and reduced affinity at alkaline pH. This suggested a subtle shift in the allosteric equilibrium due most likely to the introduction of a negative charge that stabilized the 2,3-DPG pocket. Both homotrophic (heme-heme) and heterotropic (2,3-DPG and protons) effects were reduced; this might be a consequence of an alteration in the carboxyl terminal region of the beta-subunits. Although a His----Asp substitution would be considered to cause reasonable disruption of the 2,3-DPG and C-terminal conformation of the beta- subunits, the properties of Hb Rancho Mirage suggest that, in fact, there appear to be no major perturbation of the critical C-terminal residues.

2,3-Diphosphoglycerate↗
PubMed1979

Hemoglobin Dunn: alpha 6 (A4) aspartic acid replaced by asparagine.

Hemoglobin Dunn, alpha 6 (A4) Asp leads to Asn was found in a 39-year-old black woman and her daughter. The hematological data on the propositus were normal and there were no apparent clinical or pathological findings associated with this abnormal hemoglobin. The structural characterization of this variant is described.

Adult↗
PubMed1978

Hemoglobin Detroit: beta95 (FG2) lysine leads to asparagine.

Hb Detroit is a mutant which migrates between Hb A and Hb J Baltimore on cellulose acetate (pH 8.5), and with Hb A on citrate agar (pH 6.0). Globin chain analyses in alkaline and acid buffers reveal an abnormal beta chain with a mobility between the betaA and betaJ Baltimore chains. Structural characterization of this abnormal chain shows that lysine at position 95 is replaced by asparagine. No hematological abnormalities could be attributed to the presence of the mutant, and the oxygen affinity properties of the stripped hemoglobin are similar to those of Hb A. The beta95 residue which is substituted in Hb Detroit and also in Hb N Baltimore ((beta95 Lys leads to Glu) does not appear to be in a critical functional area of the molecule.

Adult↗
PubMed1977

Hemoglobin S Travis: a sickling hemoglobin with two amino acid substitutions [beta6(A3)glutamic acid leads to valine and beta142 (h20) alanine leads to valine).

Hb S Travis is a previously undescribed sickling hemoglobin with two amino acid substitutions in the beta chain: beta6 Glu leads to Val and beta142 Ala leads to Val. The beta6 Glu leads to Val mutation imparts to Hb S Travis the characteristic properties of sickling hemoglobin, namely its association with erythrocyte sickling, the insolubility of the hemoglobin in the reduced form, and a minimum gelling concentration value identical to Hb S. Unlike Hb S, Hb S Travis exhibits an increased oxygen affinity and a decreased affinity for 2,3-bisphosphoglycerate and inositol hexakisphosphate. In addition, the variant hemoglobin's tendency to autoxidize and its mechanical precipitability suggest that there are conformational differences between Hb S and Hb S Travis.

Alanine↗
PubMed1977

Hemoglobin Tarrant: alpha126(H9) Asp leads to Asn. A new hemoglobin variant in the alpha1beta1 contact region showing high oxygen affinity and reduced cooperativity.

Hemoglobin (Hb) Tarrant was detected by its electrophoretic mobility on cellulose acetate (pH 8.4) and citrate agar (pH 6.2). On cellulose acetate it moved as a band between hemoglobins F and S, and on citrate agar as a band at hemoglobin S. The test for solubility in 2 M phosphate buffer with Na2S2O4 was negative. The new variant has a substitution of asparagine for aspartic acid in position 126 of the alpha-chain, one of the sites involved in the alpha1beta1 contact. Furthermore, in deoxyhemoglobin aspartic acid 126 of each alpha chain also forms a non-covalent electrostatic salt bridge with arginine 141 of the corresponding alpha chain (Perutz, M. F. and Ten Eyck, L. F. (1972) Cold Spring Harbor Symp. Quant. Biol. 36, 295-310 and Perutz, M. F. (1970) Nature 228, 726-739). As a consequence of this substitution in hemoglobin Tarrant, the deoxy conformation or T state is destabilized because these two bridges cannot be formed. This condition is reflected in high oxygen affinity and low cooperativity.

Amino Acid Sequence↗
PubMed1977

Hemoglobin Lufkin: beta 29 (B11) Gly replaced by Asp. An unstable hemoglobin variant involving an internal amino acid residue.

Hemoglobin Lufkin was found in a Black-American family. Structural analysis of the abnormal hemoglobin indicates a substitution of aspartic acid for glycine at position 29 in the beta chain. Marked instability of the variant hemoglobin is demonstrated by the rapid formation of inclusion bodies upon exposure of the red cells to redox dyes and by the large percentage of precipitated hemoglobin at 65 degrees C. The oxygen affinity, the Bohr effect, and the degree of cooperativity of Hb Lufkin and Hb A are similar over the physiologic pH range. However, at acid pH the oxygen affinity of the variant is increased. Unlike several other reported variants in the B helix, Hb Lufkin is not associated with methemoglobinemia.

Amino Acids↗
PubMed1976

Hemoglobin Fannin-Lubbock [alpha2 beta 2 119 (GH2) Gly replaced by Asp]. A new hemoglobin variant at the alpha1 beta 1 contact.

Hemoglobin Fannin-Lubbock was found in a 9-year-old Mexican-American female. The abnormal hemoglobin was detected as a fast-moving variant by electrophoresis on cellulose acetate at pH 8.4. Structural analysis indicated a substitution in the beta-chain of aspartic acid for glycine at position 119, a position involved in the alpha1beta1 contact of the hemoglobin tetramer. This contact between unlike chains is larger and undergoes a smaller shift during the process of oxygenation and deoxygenation that the alpha1beta2 contact (Perutz, M.F., Muirhead, H., Cox, J.M. and Goaman, L.C.G. (1968) Nature 219, 131-139). Mutations in this contact tend to cause slight or no changes in functional behavior. Apart from a mild anemia, the propositus did not exhibit any obvious clinical symptoms.

Amino Acids↗
PubMed1976

Hemoglobin Providence. A human hemoglobin variant occurring in two forms in vivo.

Hemoglobin Providence Asn and Hemoglobin Providence Asp are two abnormal hemoglobins which apparently arise from a single genetic change that substitutes asparagine for lysine at position 82 (EF6) in the beta chain of human hemoglobin. The second form appears to be thr result of a partial in vivo deamidation of the asparagine situated at position beta 82. Cellulose acetate and citrate agar electrophoresis of hemolysates from patients with this abnormality shows three bands. Globin chain electrophoresis at acid and alkaline pH shows three beta chains. These three chains correspond to the normal beta A chain and two abnormal beta chains. Sequence analysis indicates that the two abnormal chains differ from beta A at only position beta 82. In the two abnormal chains, the residue which is normally lysine is substituted either by asparagine or by aspartic acid. These substitutions are notable because beta 82 lysine is one of the residues involved in 2,3-diphosphoglycerate binding. Additionally, beta 82 lysine is typically invariant in hemoglobin beta chain sequences. Sequence data on the two forms of Hemoglobin Providence are given in this paper. The functional properties of these two forms are described in the next paper.

Adult↗
PubMed1976

Hemoglobin providence. Functional consequences of two alterations of the 2,3-diphosphoglycerate binding site at position beta 82.

Position beta 82 in human hemoglobin (Hb) is normally occupied by lysine, a positively charged residue that is involved in the binding of anionic cofactors. This residue is substituted by a neutral residue in Hb Providence Asn and by a negatively charged residue in Hb Providence Asp. Hb Providence Asp shows more differences from Hb A than does Hb Providence Asn in studies of the kinetics and equilibria of ligand binding. For both forms, homotropic (cooperative) interactions are normal with n values of 2.5 to 2.7, while heterotropic (pH and anion) interactions are reduced greatly. The reduction in anion sensitivity is attributed to the absence of a positive residue at position beta 82. Reduction in pH sensitivity may be due to a ligand-linked change in the pK of a neighboring residue, beta 143 histidine, which normally is not a Bohr group. This change in pK would act in opposition to the normal Bohr effect. Reduction in the net positive charge of the central cavity has a further consequence. Relative to Hb A, both Hb Providence Asn and Hb Providence Asp show decreased oxygen affinities at neutral pH in the absence of cofactors. This suggests that in Hb A the binding of anionic cofactors directly influences the oxygen affinity by neutralizing the charged groups of the diphosphoglycerate binding site and thus stabilizing the low affinity (T) conformation. From pH 6 to 9 in the presence of 1 M NaCl, where all the charged groups may be masked, the oxygen-binding properties of Hb A and the Hb Providence mutants are identical. Moreover, subunit dissociation of the liganded Hb Providence mutants appears to be increased, as is known to occur for Hb A in the presence of high salt. The results obtained with Hb Providence Asn and Hb Providence Asp illustrate how single amino acid substitutions can modify hemoglobins' pH and anion interactions without altering cooperative interactions between subunits. The alteration in cofactor effects observed with these mutants also illustrates differences between the allosteric effects induced by organic and inorganic anions.

Adult↗