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At least 19 recordsLinked to original sources
PubMed2002

X-ray crystallographic analyses of symmetrical allosteric effectors of hemoglobin: compounds designed to link primary and secondary binding sites.

The rational design and X-ray crystallographic analyses of two symmetrical allosteric effectors of hemoglobin (Hb) are reported. Compound design was directed by the previously solved co-crystal structure of one of the most potent allosteric effectors of Hb, 2-[4-[(3,5-dichlorophenylcarbamoyl)-methyl]-phenoxy]-2-methylpropionic acid (RSR4), which revealed two distinct binding sites for this compound in the Hb central water cavity. The primary binding site has been observed for all compounds of this structural class, which stabilize deoxy Hb by engaging in inter-dimer contacts with three of the four protein subunits. Interactions at the secondary binding site of RSR4 occur primarily between the beta(1) and beta(2) subunits and serve to further constrain the deoxy state. Based on these observations, it was hypothesized that compounds with the ability to simultaneously span and link both of these sites would possess increased potency, but at a lower molar concentration than RSR4. Two symmetrical compounds were designed and synthesized based on this hypothesis. The symmetrical effector approach was taken to minimize the number of compound orientations needed to successfully bind at either of the distinct allosteric sites. X-ray crystallographic analyses of these two effectors in complex with Hb revealed that they successfully spanned the RSR4 primary and secondary binding sites. However, the designed compounds interacted with the secondary binding site in such a way that intra-dimer, as opposed to inter-dimer, interactions were generated. In agreement with these observations, in vitro evaluation of the symmetrical effectors in Hb solution indicated that neither compound possessed the potency of RSR4. A detailed analysis of symmetrical effector-Hb contacts and comparisons with the binding contacts of RSR4 are discussed.

Allosteric Regulation↗
PubMed1992

Differentiation of homozygous hemoglobin E from compound heterozygous hemoglobin E-beta O-thalassemia by hemoglobin E mutation analysis.

OBJECTIVES: To facilitate the differential diagnosis of hemoglobin FE in newborn infants (homozygous hemoglobin E vs hemoglobin E-beta O-thalassemia). METHODS: The beta-globin gene in DNA from infants found to have hemoglobin FE in the California newborn screening program was amplified by the polymerase chain reaction, and the product was digested with Mnl I, which fails to cut the product when the hemoglobin E mutation is present. When both amplified alleles fail to be cut, homozygous EE is diagnosed. If only one allele is cut, a beta-globin allele without the E mutation is present (non-E), which is most likely a gene with a beta O-thalassemia mutation. RESULTS: Samples from 18 infants revealed an EE genotype, and from two samples a non-E/E genotype was determined. Clinical examination of these two patients confirmed a diagnosis of hemoglobin E-beta O-thalassemia. An independent clinical diagnosis agreed with DNA analysis for all 17 of the 20 infants for whom follow-up and family studies were available. The DNA results were obtained within a week, but the clinical diagnoses often could not be resolved unequivocally for months. CONCLUSIONS: The direct analysis of patient DNA samples for the hemoglobin E mutation allowed rapid and accurate diagnosis in this sample of infants with hemoglobin FE on the newborn screen. This rapid discriminatory test should reduce cost and simplify the diagnostic approach for these patients, which currently consists of expensive and lengthy follow-up until clinical data and family studies result in a diagnosis.

Asian↗
PubMed1983

Isolation of intermediate compounds between hemoglobin and carbon monoxide.

A human hemoglobin solution partially saturated with carbon monoxide was rapidly quenched at -25 degrees C into a hydro-organic buffer containing ferricyanide. Under the experimental conditions of pH, ionic strength, and buffer composition used in this work, it was found that the deoxy hemes were rapidly transformed into their met form, whereas practically no carbon monoxide-bound hemes were oxidized before the separation of the mixture from the oxidizing agent. As a preliminary step to the analysis of the resulting solution, carbonylhemoglobin solutions partially oxidized with ferricyanide were studied by isoelectric focusing at -25 degrees C under identical conditions. The relative position in the gel of all nine possible valence hybrids was established as follows (going from the anodic to the cathodic side of the gel) alpha CO2 beta CO2, (alpha CO beta +)(alpha CO beta CO) (alpha CO beta CO), (alpha CO2 beta +2), (alpha + beta CO), (alpha + beta +)-(alpha CO beta CO), (alpha + beta +)(alpha CO beta +), (alpha +2 beta CO2), (alpha + beta +)(alpha + beta CO), alpha +2 beta +2. When carbonylhemoglobin and methemoglobin were mixed in equal proportion at -25 degrees C and then analyzed by isoelectric focusing at the same temperature, it was found that the contribution of valence hybrids other than alpha CO2 beta CO2 and alpha +2 beta +2 to the total amount of hemoglobin in the gel was no more than 6%. When carbonylhemoglobin and deoxyhemoglobin were mixed in the same proportion and incubated at 20 degrees C so to allow the redistribution of the carbon monoxide molecules between all possible binding sites to occur, a substantially higher amount of valence hybrids, derived from the oxidation of intermediate compounds of hemoglobin with carbon monoxide, was found. The isoelectric focusing separation indicated the presence in the original solution of intermediate species other than carbonylhemoglobin and deoxyhemoglobin at a concentration of about 10% of the total.

Carbon Monoxide↗
PubMed1987

Reaction of nitric oxide with heme proteins and model compounds of hemoglobin.

Rates for the reaction of nitric oxide with several ferric heme proteins and model compounds have been measured. The NO combination rates are markedly affected by the presence or absence of distal histidine. Elephant myoglobin in which the E7 distal histidine has been replaced by glutamine reacts with NO 500-1000 times faster than do the native hemoglobins or myoglobins. By contrast, there is no difference in the CO combination rate constants of sperm whale and elephant myoglobins. Studies on ferric model compounds for the R and T states of hemoglobin indicate that their NO combination rate constants are similar to those observed for the combination of CO with the corresponding ferro derivatives. The last observation suggests that the presence of an axial water molecule at the ligand binding site of ferric hemoglobin A prevents it from exhibiting significant cooperativity in its reactions with NO.

Animals↗
PubMed2026

Compound Heterozygous Hemoglobin Minneapolis-Laos and Codon 41/42 (-TTCT) in a Thai Female Adult: A Case Report and Literature Review.

Thalassemia is a prevalent genetic disorder in Southeast Asia. The Hemoglobin Minneapolis-Laos variant is very rarely reported with only two previously published reports that profile a total of three patients. Here, we present the first reported case of compound heterozygous β zero (β0)-thalassemia and Hemoglobin Minneapolis-Laos in a 46-year-old Thai female. She presented at Siriraj Hospital (Bangkok, Thailand) with chronic microcytic anemia, which is a more severe phenotype than would be expected from either trait alone. Initial hemoglobin electrophoresis via high-performance liquid chromatography and capillary electrophoresis revealed elevated hemoglobin A2 (5.5% and 6.3%, respectively), which is a finding consistent with a β-thalassemia trait, but this finding failed to explain the full extent of her anemia. Next-generation sequencing was then performed to investigate for a congenital red blood cell disorder. The results identified the following two mutations in the β-globin gene (HBB): heterozygous β0-thalassemia codon 41/42 (-TTCT), and HBB c.356T >A, the latter of which is consistent with hemoglobin Minneapolis-Laos. This case highlights the importance of advanced genetic testing to diagnose rare hemoglobin variants that cannot be identified by conventional investigation and further contributes to our understanding of this rare combination's clinical phenotype.

Humans↗
PubMed2001

Chemiluminescence of hemoglobin and identification of related compounds with the hemoglobin chemiluminescence in plasma.

A low level of chemiluminescence by hemoglobin (Hb) was detected in the reaction with H2O2 and hydrogen donors such as gallic acid and catechins. The photon intensity was affected by the ferric state of Hb (methemoglobin > oxyhemoglobin), and was roughly correlated with the radical-scavenging potential of catechins. We hypothesized the reversible activation reaction of Hb as the chemiluminescence mechanism of the H2O2/gallic acid/Hb system. It is indicated that the oxidized-Hb (Hb-OOH) formation was a chemiluminescence-rate-determining step and one-electron reduction by a hydrogen donor of the compound-I-type intermediate ([.XFeIV] = O) proved a chemiluminescence-specificity-determining step. Spectral analysis showed that the photon emission from the H2O2/gallic acid/Hb system was produced without singlet oxygen generation. The concentration dependence of photon intensity suggests a high consumption ratio of H2O2 leading to protection from H2O2 toxicity. Albumin was defined as a hydrogen donor by the isolation of chemiluminescent substance in plasma using this chemiluminescence system.

Catechin↗
PubMed1996

A starch-hemoglobin resuscitative compound.

A resuscitative compound in freeze-dried form has been synthesized between a modified starch and a tetremerically stabilized hemoglobin. In order to complex the hemoglobin, the starch has been prepared in mono-, di-, tri-, and tetra-aldehyde moieties. The hemoglobin was stabilized with low molecular weight diacids. Electrophoretic densitometric patterns indicate compound formation. The resulting polymers were characterized with respect to oxygen transport (biotonometry), Hill constant and P50. The in vivo evaluation indicates that these compounds are effective in exchange-transfusion experiments with rats to a level of about 85% replacement of whole blood. The final product is a cost-effective acellular resuscitative compound which can be stored in freeze-dried form at room temperature for extended periods of time. This artificial blood substitute can be reconstituted upon the addition of water.

Animals↗
PubMed1995

Pharmacologic profile of diaspirin cross-linked hemoglobin in hemodialysis patients.

Various hemoglobin compounds have been evaluated as potential oxygen-carrying, blood volume expanders, but toxicity has prevented clinical application. Diaspirin cross-linked hemoglobin (DCLHb) represents a modified hemoglobin compound that is derived from human red blood cells and maintained in a tetrameric configuration by cross-linkages between the two alpha chains of the hemoglobin molecule. In a randomized, placebo-controlled, single-blind, cross-over trial, DCLHb's safety and pharmacologic parameters were evaluated in 18 subjects receiving chronic hemodialytic therapy. A 30-minute infusion of 25, 50, or 100 mg/kg DCLHb or placebo was given at the start of routine hemodialysis. One week later, the alternate treatment (placebo or DCLHb) was administered. Maximum plasma hemoglobin concentrations and terminal half-life values were calculated for each dosage group. Dialysate was collected and assayed for hemoglobin. Changes in systolic and diastolic blood pressure from baseline and the volume of hypertonic saline administered for treatment of hypotension during hemodialysis were measured. The maximum plasma hemoglobin concentrations increased with DCLHb dose and occurred at the end of DCLHb infusion. The mean (+/- SD) terminal half-life ranged from 2.1 +/- 1.0 hours in the 25 mg/kg DCLHb group to 4.3 +/- 1.4 hours in the 100 mg/kg group, but did not differ significantly between groups. Mean baseline plasma hemoglobin corrected areas under the plasma concentration-time curves increased from 89 to 1,136 mg/hr/dL across the fourfold dose range. Diaspirin cross-linked hemoglobin was not dialyzable as none was detected in dialysate. The maximum increase in systolic blood pressure from baseline increased significantly with DCLHb dose compared with placebo (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2001

Cell culture and animal models to screen for promising fetal hemoglobin-stimulating compounds.

Sickle cell anemia (SCA) and the thalassemias are globally the most common class of inherited single-gene disorders. Current treatment options are limited, especially in developing countries. More practical and cheaper therapies are urgently needed. Since high fetal hemoglobin (HbF) levels ameliorate the clinical symptoms of these diseases, one current approach is to use pharmacological agents to reactivate the gamma-globin genes and stimulate the production of HbF. Several in vitro and in vivo experimental models developed for this purpose are the subject of this review. The models include in vitro established erythroid-like cell lines and primary cultures (both in semisolid and liquid media) of erythroid progenitor cells obtained from normal donors and patients with SCA and beta-thalassemia, as well as in vivo models in genetically modified (transgenic) and unmodified animals. These experimental systems are useful for large-scale screening of compounds for HbF-stimulating potential, for determining the mechanism of action of potent compounds at the cellular and molecular levels, and for studying the pharmacology, pharmacokinetics, and toxicology of the drugs. These models are essential to find, test, and develop new drugs that will be effective and safe for clinical use in adults and children.

Anemia, Sickle Cell↗
PubMed1977

Mutagenicity of benzidine and related compounds employed in the detection of hemoglobin.

Seven compounds commonly used as chromagens for the detection of hemoglobin and its derivatives have been assayed for mutagenicity employing the Salmonella/mammalian microsome test. Three of these compounds, benzidine, o-dianisidine, and o-tolidine, were shown to be mutagenic. Since benzidine and o-tolidine are already known to be carcinogens, there is a high probability that o-dianisidine will also prove to be a carcinogen. Four compounds tested with this system, o-anisidine, diphenylamine, guaicol, and o-toluidine, were not mutagenic.

Animals↗
PubMed1983

Encapsulation of hemoglobin in phospholipid vesicles.

Hemoglobin has been encapsulated in phospholipid vesicles by extrusion of hemoglobin/lipid mixtures through polycarbonate membranes. This technique avoids the use of organic solvents, sonication, and detergents which have proven deleterious to hemoglobin. The vesicles are homogeneous, with a mean size of 2400 A as determined by photon correlation spectroscopy. The encapsulated hemoglobin binds oxygen reversibly and the vesicles are impermeable to ionic compounds. Hemoglobin encapsulated in egg phosphatidylcholine vesicles converts to methemoglobin within 2 days at 4 degrees C. By contrast, when a mixture of dimyristoyl phosphatidylcholine, cholesterol and dicetyl phosphate is used there is no acceleration in methemoglobin formation, and the preparation is stable for at least 14 days at 4 degrees C.

Animals↗