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PubMed1981

Freeze-drying of hemoglobin solutions without adjuvant and in presence of glucose, tris, and beta-alanine: a study by electron spin resonance of the oxidized compounds produced.

Hemoglobin cannot be freeze-dried without the presence of protective compounds. Carbohydrates are a well-known example of such compounds, but we have shown that some amine buffer and amino acids are also very effective. The mechanism of action of all these molecules is unknown. We report here experimental data showing that the protective effect is not the result of a direct bond between iron and the protective compound added.

Absorption↗
PubMed1984

Structural features required for the reactivity and intracellular transport of bis(3,5-dibromosalicyl)fumarate and related anti-sickling compounds that modify hemoglobin S at the 2,3-diphosphoglycerate binding site.

Bis(3,5-dibromosalicyl)fumarate (I) reacts preferentially with oxyhemoglobin to cross-link the two beta 82 lysine residues within the 2,3-diphosphoglycerate (DPG) binding site and as a result markedly increases the solubility of deoxyhemoglobin S. The cross-link acts by perturbing the acceptor site for Val 6 within the sickle cell fiber (Chatterjee, R., Walder, R. Y., Arnone, A., and Walder, J. A. (1982) Biochemistry 21, 5901-5909). In the present studies we have compared a large number of analogs of I to determine the structural features of the reagent required for specificity and for transport into the red cell. Both electrostatic and hydrophobic interactions contribute to the binding of these compounds at the DPG site. The optimal position for the negatively charged groups on the cross-linking agent for productive binding is adjacent to the ester as in the original salicylic acid derivatives. There is a direct correlation between the reactivity toward hemoglobin and the hydrophobicity of the substituent attached at the para position. Phenyl and substituted phenyl derivatives as in the analgesic, antiinflammatory drug diflunisal are particularly effective. These groups probably interact with hydrophobic residues of the amino-terminal tripeptide and the EF corner of the beta chains adjacent to the DPG binding site. Although bis(3,5-dibromosalicyl)fumarate is very reactive toward hemoglobin in solution, it is much less effective in modifying hemoglobin within the red cell. The reaction with intracellular hemoglobin was shown to be limited by competing hydrolysis of the reagent catalyzed at the outer surface of the erythrocyte membrane. Inactivation of the red cell membrane acetylcholinesterase with phenylmethylsulfonyl fluoride did not inhibit this reaction. Introduction of a single methyl group onto the carbon-carbon double bond of the fumaryl moiety decreases the lability of the ester 10-fold, due to steric effects, and allows the reagent to be taken up by the red cell and modify intracellular hemoglobin. The kinetics of transport of the methylfumarate derivative, bis(3,5-dibromosalicyl)mesaconate, are first-order, consistent with passive diffusion. The attachment of larger alkyl groups onto the cross-link bridge further enhances the transport of the reagent into the red cell. The solubility of deoxyhemoglobin S cross-linked with the butylfumarate derivative was found to be increased by almost 10% compared to the original fumarate diester.(ABSTRACT TRUNCATED AT 400 WORDS)

2,3-Diphosphoglycerate↗
PubMed2002

Hydrogen bonding to Trp beta37 is the first step in a compound pathway for hemoglobin allostery.

Human hemoglobin is widely thought to change from the R to the T quaternary structure in a single rate process requiring tens of microseconds. Here we present kinetic evidence that the R --> T allosteric pathway in hemoglobin requires more than one step. We use magnetic circular dichroism (MCD) spectroscopy of the aromatic amino acid bands to show that formation of a tryptophan-aspartate hydrogen bond in the hinge region of the dimer-dimer interface is part of an obligatory R --> T step proceeding more than a factor of 10 faster than the kinetic step previously identified in heme-band absorption studies.

Circular Dichroism↗
PubMed1991

Oxidative condensation of 2-amino-4-methylphenol to dihydrophenoxazinone compound by human hemoglobin.

2-Amino-4-methylphenol was converted to a brownish yellow material by the lysates of human erythrocytes or purified human hemoglobin. The reaction proceeded oxidatively, coupled with the oxidation of hemoglobin. The major component of the brownish yellow material produced by oxidative condensation of 2-amino-4-methylphenol was identified as 3-amino-1,4 alpha-dihydro-4 alpha, 8-dimethyl-2H-phenoxazin-2-one on the basis of its spectral data including NMR spectra, IR spectra, EI mass spectra, and absorption spectra. The changes in 3-amino-1,4 alpha-dihydro-4 alpha,8-dimethyl-2H-phenoxazin-2-one during incubation of purified human hemoglobin and 2-amino-4-methylphenol were analyzed spectrophotometrically and by using HPLC. The reaction mechanism involved may be similar to that of actinomycin synthase, which oxidizes 2-amino-5-methylphenol to the dihydrophenoxazinone.

Cresols↗
PubMed1997

Heme compounds in dinosaur trabecular bone.

Six independent lines of evidence point to the existence of heme-containing compounds and/or hemoglobin breakdown products in extracts of trabecular tissues of the large theropod dinosaur Tyrannosaurus rex. These include signatures from nuclear magnetic resonance and electron spin resonance that indicate the presence of a paramagnetic compound consistent with heme. In addition, UV/visible spectroscopy and high performance liquid chromatography data are consistent with the Soret absorbance characteristic of this molecule. Resonance Raman profiles are also consistent with a modified heme structure. Finally, when dinosaurian tissues were extracted for protein fragments and were used to immunize rats, the resulting antisera reacted positively with purified avian and mammalian hemoglobins. The most parsimonious explanation of this evidence is the presence of blood-derived hemoglobin compounds preserved in the dinosaurian tissues.

Animals↗
PubMed1998

Hb Tak confirmed by DNA analysis: not expressed as thalassemia in a Hb Tak/Hb E compound heterozygote.

Hemoglobin variants in which a frameshift results in chain elongation are unusual and also have a low population frequency. Hb Tak was previously characterized by amino acid analysis, and it was assumed to be due to an insertion of the dinucleotide CA into codon 146 [CAC-->CA(CA)C] which abolishes the normal stop codon at position 147. This insertion causes a frameshift which results in elongation of the beta chain by 11 amino acids. This variant has previously been described in a few Thai families. We report the DNA sequence of Hb Tak in an individual of Cambodian descent who is a Hb E/Hb Tak compound heterozygote. In contrast with extended variants of the alpha-globin chain that are expressed as alpha-thalassemias, the hematologic effect of Hb Tak/Hb E is a mild polycythemia. The combination of Hb Tak/Hb E is not expressed as a thalassemia.

Adult↗
PubMed2005

Compound heterozygosity for unstable hemoglobin Genova and beta(o)-thalassemia associated with early onset of thalassemia major syndrome.

We described the case of an infant with compound heterozygozity for a b0-thalassemic mutation and Hemoglobin (Hb) Genova, an unstable Hb variant. He has required regular transfusions as early as the second month of life and since then, behaves like a thalassemia major patient. This association leads to the most severe clinical course involving an unstable variant, reported so far.

Blood Transfusion↗
PubMed1999

Fetal hemoglobin expression in the compound heterozygous state for -117 (G-->A) Agamma HPFH and IVSII-745 (C-->G) beta+ thalassemia: a case study.

We studied a family in which two inherited defects of the non-alpha-globin cluster segregate: Greek hereditary persistence of fetal hemoglobin (HPFH) and beta-thalassemia. The compound heterozygote is a healthy man with 43% HbF, Ggamma/Agamma ratio (27:73) differing from that of 10 simple heterozygotes for the Greek HPFH (92:8), normal levels of total Hb (13.3 g/dl), and reduced HbA2 levels comparing with the levels of beta-thal heterozygotes for the same mutation. Molecular analysis of the beta-globin genotype revealed the presence of the IVSII-745 (C-->G) beta+ RNA splice mutation in trans with the -117 G-->A Greek HPFH. The beta+ mutation was linked to haplotype VII and the Greek HPFH was associated with haplotype Ia. The father of the compound heterozygote carries the Greek HPFH in trans with the -158 C-->T on the Ggamma promoter, which is linked with haplotype IV. He presented 13.5% HbF with a Ggamma/Agamma ratio 75:25. His daughter was a compound heterozygote for the IVSII-745 mutation in trans with the -158 C-->T, while her HbF levels were 3.7% with a Ggamma/Agamma ratio 31:69.

Adult↗
PubMed1985

Selectivity in the modification of the alpha-amino groups of hemoglobin on reductive alkylation with aliphatic carbonyl compounds. Influence of derivatization on the polymerization of hemoglobin S.

The reactivity of the alpha-amino groups of the alpha- and beta-chains of hemoglobn toward reductive alkylation using limiting concentrations of the aliphatic carbonyl compounds, acetaldehyde (ethylation), glyoxylic acid (carboxymethylation), glycolaldehyde (hydroxyethylation), glyceraldehyde (dihydroxypropylation), and dihydroxyacetone (dihydroxyisopropylation) has been investigated. Hemoglobin A reductively ethylated at the alpha-amino groups eluted on CM-52 ahead of unmodified hemoglobin A, and hemoglobin A reductively ethylated at the epsilon-amino groups. This observation is similar to that seen on hydroxyethylation and dihydroxypropylation of the alpha-amino group of hemoglobin A. The presence of the alpha-hydroxyl or the carboxyl group in the carbonyl component used in the reductive alkylation influences considerably the selectivity pattern during the derivatization. The alpha-amino groups of the alpha- and beta-chains are modified to nearly the same degree during reductive hydroxyethylation as well as during reductive dihydroxypropylation. Reductive ethylation (aldehyde lacking the alpha-hydroxyl group) exhibited a slight preferential reaction at Val-1(beta). The presence of a negatively charged carboxyl group in the carbonyl component, i.e. glyoxylic acid, made this preferential reaction at Val-1(beta) even more pronounced. When the reductive alkylation is carried out with dihydroxyacetone (a ketone instead of an aldehyde), the dihydroxyisopropylation occurred at a slower rate and exclusively at Val-1(beta). The ethylation, hydroxyethylation, carboxymethylation, and dihydroxypropylation of the alpha-amino groups of hemoglobin S increased its solubility from the value of 16 g/dl for the unmodified protein to about 25 g/dl for the modified protein. Thus, the alkyl chains on the alpha-amino groups on the polymerization have a strong inhibitory influence. In order to determine the influence of the alkyl chains at the alpha-amino groups of alpha- and beta-chains on polymerization, hybrid hemoglobin S tetramers with hydroxyethylation either at Val-1(alpha) or at Val-1(beta) have been prepared. The solubility of each hybrid is about 26 g/dl. Thus, the hydroxyethyl group either on the alpha- or the beta-chain appears to interfere with the polymerization of deoxygenated HbS to the same degree. The inhibitory influence of the hydroxyethyl chain at Val-1(alpha) on the polymerization, compared with the lack of such an influence when this alpha-amino group is modified by cyanate, suggests that a carbamoyl group on Val-1(alpha) can be accommodated in the intermolecular contact region involving this segment of the molecule without seriously perturbing the mo

Alkylation↗
PubMed1992

Clinical course and molecular characterization of a compound heterozygote for sickle hemoglobin and hemoglobin Kenya.

We describe a 25-year-old black woman who presented with a long history of anemia requiring transfusions during childhood and adolescence. Molecular analysis revealed her to be a compound heterozygote for the sickle mutation and the approximately 22.7 kb deletion associated with hemoglobin Kenya. This patient's clinical course was more severe than previously reported for the Hb S/Hb Kenya genotype, a probable consequence of concomitant iron deficiency.

Adult↗
PubMed1989

Ubiquitous formation of catalase compound II in hemoglobin-free perfused rat liver and detection of novel spectral species.

Spectral examinations of hemoglobin-free perfused rat livers with a high-sensitivity reflectance spectrophotometer have revealed an accumulation of catalase Compound II to an amount comparable to that of Compound I under the aerobic steady state. This finding is in contrast to a recent proposal that NADPH associated with catalase both prevents and reverses the accumulation of Compound II (Kirkman, H. N., Galiano, S., and Gaetani, G.F. (1987) J. Biol. Chem. 262, 660-666). Furthermore, spectral species with a broad peak extending from 550 to 600 nm were observed in a time range between the methanol-induced decays of Compound I and Compound II. When rats were treated with 3-amino-1,2,4-triazole, catalase Compound I was not detected but spectral species with peaks at 570, 556 and 530 nm were observed. These novel spectral profiles suggest contributions from "peroxy" and "ferryl" forms of cytochrome oxidase.

Amitrole↗