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Biomedical subjects

E D Bransome

Publications and source records attributed to E D Bransome.

At least 19 recordsLinked to original sources
PubMed1998

The ligand insertion hypothesis in the genomic action of steroid hormones.

Gene regulation by steroids is tightly coupled to hormone concentration and stereochemistry. A key step is binding of hormones to receptors which interact with consensus DNA sequences known as hormone response elements (HREs). The specificity and strength of hormone binding do not correlate well with hormonal activity suggesting an additional step involving recognition of ligand by the gene. Stereospecific fit of hormones between base pairs and correlation of fit with hormonal activity led to the proposal that such recognition involves insertion of hormone into DNA. Here, the feasibility of insertion was investigated using computer models of the glucocorticoid receptor DNA binding domain bound to its HRE. The site reported to accommodate glucocorticoids was found in the HRE and was exposed to permit unwinding at this locus. The resulting cavity in the unwound DNA/receptor interface fit cortisol remarkably well; cortisol formed hydrogen bonds to both the receptor and DNA. Current experimental evidence is generally consistent with ligand binding domains of receptors undergoing a conformational change which facilitates transfer of the ligand into the unwound DNA/receptor interface. We propose this step is rate limiting and alterations in receptor, DNA or hormone which attenuate insertion impair hormonal regulation of gene function.

Computer Simulation↗
PubMed1997

Metyrosine and pheochromocytoma.

BACKGROUND: Severe hemodynamic instability may occur during surgery for removal of pheochromocytoma, unless there is preoperative pharmacological treatment. OBJECTIVE: To evaluate the effects of metyrosine (alpha-methyl-p-tyrosine), a catecholamine synthesis inhibitor, and alpha-blockade with prazosin or phenoxybenzamine on cardiovascular morbidity during surgery for pheochromocytoma. METHODS: A retrospective analysis was made of patients followed up at the Medical College of Georgia, Augusta, during 28 years who received metyrosine and prazosin (n = 6), metyrosine and phenoxybenzamine alone (n = 14), phenoxybenzamine alone (n = 6), or no medication (n = 7) during 3 weeks before tumor removal. The percentage of patients not requiring pressors or phentolamine during the intraoperative period as well as the perioperative peak systolic pressures and peak heart rates were estimated in each group. RESULTS: There was a significant (P < .05) increase in intraoperative peak systolic pressures without preoperative treatment (mean +/- SD, 243 +/- 40 mm Hg) vs metyrosine (mean +/- SD, 168 +/- 27 mm Hg). Ninety-five percent of patients who received metyrosine did not require pressors intraoperatively vs 50% with phenoxybenzamine alone. Eighty-one percent of patients pretreated with metyrosine did not require intraoperative phentolamine vs 33% with phenoxybenzamine alone and 29% without medications. Two patients in the no medication group died as a results of hypertensive crisis. CONCLUSIONS: The combination of alpha-metyrosine and alpha-blockade results in better blood pressure control and less need for use of antihypertensive medication or pressors during surgery, compared with the classical method of single-agent adrenergic blockade. Preoperative treatment with metyrosine along with an alpha-blocker is a useful strategy for decreasing the surgical morbidity in patients with pheochromocytoma and assumes greater importance as long as the availability of phentolamine for intraoperative use is a problem.

Adolescent↗
PubMed1994

Hypoglycemia caused by selegiline, an antiparkinsonian drug: can such side effects be predicted?

Treatment with selegiline produced profound hypoglycemia in a 70-year-old man with Parkinson's disease. The hypoglycemia was accompanied by hyperinsulinemia and persisted for 1 week after selegiline was discontinued. Although this side effect of antidepressant monoamine oxidase inhibitors was well documented in 1959-1968 publications, it was not known to the manufacturer of selegiline. Effects of drugs on glucose metabolism may be predictable through a novel molecular modeling technique developed in our laboratories, which shows that glucose exhibits stereochemical complementarity to a specific site in partially unwound DNA. Selegiline and other molecules affecting glucose metabolism fit into the same DNA base sequence. It therefore should be possible to employ this technique to identify pharmaceutical agents that possess hypoglycemic or hyperglycemic effects in vivo.

Aged↗
PubMed1993

Recent developments in drug design: computational chemistry and models of the interaction of ligands with receptors.

Recent articles and advertisements suggest that drug design is within the reach of any chemically oriented scientist who obtains the latest three-dimensional computer graphics programs for his personal computer. This sort of "rational" drug design has however had limited success. When it has been successful, it has required the rigorous application of computational chemistry. Bowen et al. in their accompanying paper provide a summary of a number of approaches and the assumptions involved. The papers by McDonnell et al. and Hendry describe two different approaches: utilizing molecular genetics to test the effective interaction in vitro of ligands with their receptors and utilizing the model structure of DNA as a blueprint for the structure of the intracellular targets of drugs.

Computer Graphics↗
PubMed1987

Initial studies of a phytoestrogen-deoxyribonucleic acid interaction.

Molecular modeling studies show that estrogens such as estradiol complement the topography of spaces between base pairs in unwound DNA and simultaneously hydrogen bond phosphate moieties on opposite strands. We demonstrate here that the phytoestrogen coumestrol has this capability, in addition to its documented properties of UV absorbance at lambda greater than 300 nm and fluorescence. The latter properties enable spectroscopic examination of interactions with DNA by methods not possible with estrogenic steroids. On exposure to calf thymus DNA, the UV spectrum of coumestrol displays a bathochromic shift and simultaneous hypochromic effect with an isosbestic point at 370 nm, suggesting a shift between coexisting free and bound states. Similar results are observed with the intercalating agents adriamycin, ethidium bromide, and acridine. The fluorescence spectrum of coumestrol is quenched on exposure to DNA as are those of adriamycin and acridine. Coumestrol differs from the intercalators in that denatured DNA does not affect its UV spectrum or alter its relative fluorescence yield. Unlike classical intercalators, coumestrol has no influence on the thermal stability of calf thymus DNA. Preliminary electrophoretic analysis of DNA plasmid conformers indicates that coumestrol is incapable of significantly altering DNA superhelical density, in contrast to ethidium bromide. These initial physicochemical data provide evidence for the DNA base-estrogen electronic and/or hydrophobic interactions suggested by modeling studies, yet tend to rule out classical intercalation as an explanation for these phenomena.

Animals↗
PubMed1986

The stereochemical complementarity of DNA and reproductive steroid hormones correlates with biological activity.

Modeling studies revealed that progesterone, testosterone, and estradiol are stereochemically complementary to the cavity formed between base pairs in the DNA sequence, 5'-dTdG-3' X 5'-dCdA-3'. Each steroid aligned precisely with the topography of the cavity and formed 2 stereospecific hydrogen bonds linking phosphate oxygens on adjacent DNA strands. Hydrogen bonding donor-acceptor relationships were different for each hormone. The remarkable stereochemical specificity of the hormone-DNA complexes was demonstrated by the lack of complementarity of steroid enantiomers and steroid analogs having alternate ring systems and/or changes in the position of functional groups. Fit of molecules into DNA in the manner of the parent hormone correlated with biological activity. Antagonists also fit into the cavity but differed from agonists in their hydrogen bonding linkages to DNA and/or extended out of the cavity beyond the helix. Unlike flat intercalating agents which form stable complexes with DNA, wedge shaped steroids may thus be capable of forming reversible sequence-specific complexes with DNA. We conclude that the stereochemistry of DNA can be used to predict hormonal activity.

Animals↗
PubMed1985

Apparent stereochemical complementarity of estrogens and helical cavities between DNA base pairs: implications for the mechanism of action of steroids.

The shape of the space occupied by a model of the estrogenic steroid hormone estradiol-17 beta conforms closely to a helical cavity between neighboring base pairs in partially coiled B-DNA. The orientation of estradiol-17 beta when fitted into DNA allows stereochemically complementary hydrogen bonding of both the 3- and 17 beta-hydroxyl groups to phosphate oxygens of the deoxyribose-phosphate backbone on adjacent strands. Changes in the chirality (handedness) of the steroid skeleton or in the absolute stereochemistry of hydrogen bonding groups prevent formation of complementary fits in the DNA. Synthetic estrogens can also adopt conformations which are stereochemically complementary to the cavities between base pairs. The complementary relationships between active estrogens and nucleic acids may be related to constraints on the evolution of the structure and the biological function of steroids.

Base Composition↗
PubMed1983

Effect of CO2 induced pH changes on the response of isolated guinea pig tracheas to theophylline.

The effect of CO2 induced pH changes on the response of airway smooth muscle to theophylline was studied. Our data show that simulated respiratory acid-base disturbances (pH range 7.0 to 7.8) have no significant effect on the response of isolated guinea pig tracheal cylinders at basal tone to theophylline. On the other hand, tracheal cylinders precontracted with histamine showed a diminished sensitivity to theophylline at pH values above 7.40, and an enhanced sensitivity at pH values below 7.40.

Animals↗
PubMed1981

Are there structural analogies between amino acids and nucleic acids?

Space-filling molecular models have been used to examine structural analogies between amino acids and nucleic acids. The three-dimensional structures of amino acid R groups appear to be stereochemically related to cavities formed by removal of single bases in double helical nucleic acids. The common L amino acids may thus be complementary to their codons.

Adenine↗
PubMed1981

First approximation of a stereochemical rationale for the genetic code based on the topography and physicochemical properties of "cavities" constructed from models of DNA.

To examine the question of whether or not the genetic code has a stereochemical basis, we used artificial constructs of the topography and physicochemical features of unique "cavities" formed by removal of the second codon base in B-DNA. The effects of base changes on the stereochemistry of the cavities are consistent with the pattern of the genetic code. Fits into the cavities of the side chains of the 20 L amino acids involved in protein synthesis can be demonstrated by using conventional physicochemical principles of hydrogen bonding and steric constraints. The specificity of the fits is remarkably consistent with the genetic code.

Amino Acids↗