Biomedical subjects
Publications and source records attributed to R Breslow.
The performance of 21 hospitalized depressed patients was compared to a matched group of 21 controls on the Wechaler Memory Scale. The depressed patients showed deficits on Mental Control, Verbal Learning, and Visual Reproduction tasks, which indicate impairment of memory functions in depression. There may be a deficit in the attention and alerting mechanism of depressed patients.
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Hexamethylenebisacetamide is a potent inducer of erythroid differentiation in murine erythroleukemia cells. A series of chemical compounds structurally related to hexamethylenebisacetamide were tested for inducing activity including polymethylene chains terminally substituted with various combinations of carboxylate, amino, amide, or sulfoxide groups. Effective "dimerization" of dimethyl sulfoxide through a linear polymethylene chain increases its inducing activity by a magnitude similar to that observed when N-methylacetamide is effectively dimerized in such a manner. It was found that all potent inducing agents possess both a hydrophilic and hydrophobic portion of the molecule, as well as a planar portion. All are Lewis bases, possessing a free electron pair available for hydrogen bonding. The polymethylene chain joining functional groups must be flexible and must be 5 to 6 carbon atoms in length to achieve maximal activity. Introduction of triple or double (cis or trans) bonds into the polymethylene chain does not alter activity.
The enzyme carboxypeptidase A has been extensively studied and is thus a good candiate for chemical models and imitation. A model system was constructec which combined two of the three catalytic functional groups of the enzyme together with the appropriate substrate group, and cooperative effective catalysis was demonstrated. However, the mechanism which the model system used in enzyme-like conditions was unexpected, and this led to a study of the enzyme itself. Carboxypeptidase A was studied by examination of oxygen-18 exchange reactions and the ability of the enzyme to substitute only lytic agents, such as methanol, forthe water which is normally used. The result of these studies is proposed mechanism of action of this enzyme which accommodates the large amount of information already available, and which indicates that this enzyme uses a mechanism similar to that found in the model system. Approaches have also been made to an artificial enzyme which could hydrolyse amides. Cyclodextrin has been functionalized with two imidazole groups placed on opposite sides of the cavity. This material catalyses the hydrolysis of an amide, which binds to the cyclodextrin cavity and then is hydrolysed with the assistance of one imidazole in its basic form and the other one in its protonated form, acting together in a way reminiscent of the cooperation of some of the functional groups of hydrolytic enzymes.
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We have reported evidence that an anhydride intermediate is not involved in the hydrolysis of typical peptide substrates by carboxypeptidase A (peptidyl-L-amino-acid hydrolase, EC 3.4.12.2), and we describe further evidence here. Recently an anhydride intermediate has been detected in the hydrolysis of an ester substrate by this enzyme. Other evidence also suggests that esters and peptides may not be cleaved by the same type of mechanism. A possible explanation is that the substrate carbonyl and a water molecule are always aligned between glutamate-270 and the zinc atom of the enzyme, but not always in the same sequence. With peptides the carbonyl is coordinated to zinc, and the water is delivered by glutamate acting as a general base. Esters are weaker ligands, and in some cases the ester carbonyl may not displace water from zinc. This would lead to a nucleophilic mechanism, with glutamate-270 forming an anhydride while zinc-aquo serves as a Brönsted acid. This picture is consistent with other evidence on ester cleavage, and resolves the otherwise baffling discrepant data on peptide as compared to ester substrates.
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This report identifies a group of compounds, polymethylene bisacetamides (acetylated diamines), which are potent inducers of erythroid differentiation in murine erythroleukemia cells. A known inducing agent, N-methylacetamide, was dimerized through varying numbers of methylenes in an attempt to increase the local effective concentration at adjacent target sites. The simple dimer was no more effective than N-methylacetamide alone; introduction of five to eight methylenes between acetamide groups substantially increased the effectiveness of these compounds. The hexamethylene bisacetamide was active between 0.5 mM and 5 mM; the percentage of cells induced and the rate at which they were recruited to differentiation was dependent upon the concentration of inducer within this range. At 5 mM hexamethylene bisacetamide essentially the entire population (greater than 99%) was induced to a pathway of erythroid differentiation which was greater differentiation of the cultured cells than with any inducer yet tested.
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Murine-virus-infected erythroleukemia cells cultured in a medium with dimethylsulfoxide or N,N-dimethylformamide are induced to differentiate to erythroid cells. A number of highly polar compounds have a similar effect in inducing erythroid differentiation of the virus-infected cells, as assayed by the appearance of hemoglobin. These compounds are 1-methyl-1-2-piperidone, N,N-dimethylacetamide, N-methylpyrrolidinone, N-methylacetamide, 2-pyrrolidinone, propionamide, pyridine-N-oxide, piperidone, N-methylformamide, acetamide, and triethylene glycol. It has been previously reported that dimethylsulfoxide must be present during DNA synthesis and, possibly, shortly therafter, to induce differentiation. These findings are consistent with the hypothesis that dimethylsulfoxide and related polar compounds act by changing the conformation of DNA or a DNA-protein complex, causing an alteration in transcription that leads to the expression of the program of erythroid differentiation.
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