Stable, aglycon-specific inactivators of glycosidases have
considerable potential as tools in the study of
mechanisms of oligosaccharide processing, and possibly as avenues
toward new therapeutics. Glycosidases for which
the rate-determining step with the natural substrate is the hydrolysis
of the glycosyl-enzyme intermediate are shown
to be inactivated by the 2‘-deoxy-2‘-fluoro derivative of this
substrate. Thus Agrobacterium
faecalis
β-glucosidase
is inactivated by 2‘-deoxy-2‘-fluorocellobiose according to
inactivation parameters of k
i = 0.018
min-1 and K
i =
20
mM. Inactivation is shown to occur via the accumulation
of the same 2-deoxy-2-fluoroglycosyl-enzyme intermediate
as that formed using activated 2-deoxy-2-fluoroglycosides by
identification of the labeled peptide in proteolytic
digests. Thus, interactions between the enzyme and the sugar
aglycon provide sufficient transition state stabilization
to allow formation and trapping of the glycosyl-enzyme.
β-Glucocerebrosidase, a β-glucosidase specific for
hydrolysis
of glucocerebrosides, is not inactivated by
2‘-deoxy-2‘-fluorocellobiose, thereby demonstrating the aglycon
specificity
of this class of inactivator.
Changes between 1972 and 1982 in the use of in-hospital services were studied for 164 patients admitted with acute myocardial infarction. Resource use was measured in constant 1982 dollars adjusted for differences in clinical severity of the patients. Although average length of stay decreased by almost 40% during this period, the number of physician services doubled and total physician costs increased almost threefold. The increase in physician costs was due primarily to the use of complex diagnostic technologies and to the provision of coronary artery bypass graft surgery. The results of this study suggest that as hospital costs are constrained by prospective payment, physician costs may continue to rise as new diagnostic and therapeutic services are introduced into practice and as more care is shifted to the outpatient setting.
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