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Protecting the cellular energy state during contractions: role of AMP deaminase

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AMP deaminase activity (AMPIMP+NH3) is the entry reaction to the purine nucleotide cycle. In skeletal muscle, excessive energy demands during contractions leads to a net production of ADP, because ATP hydrolysis exceeds ADP rephosphorylation. Elevations in ADP increase AMP, via the myokinase reaction. This accumulation of ATP hydrolysis products should lead to a catastrophic reduction in the energy state of the myocyte. The removal of AMP to IMP in times of excessively high energy demands have been hypothesized as essential to protect the energy state of the cell. While AMP deamination leads to a net loss of adenine nucleotides (principally, as ATP), the viability of the myocyte is preserved. Following these demanding contraction conditions, the concentration of IMP of fast-twitch muscle is rapidly reduced, typically with the return of the muscle adenine nucleotide content (ATP + ADP + AMP) to pre-contraction levels. While these observations are generally observed for fast-twitch skeletal muscle and consistent with the hypothesis, there has been no direct experimental evaluation. In the AK1-/- mouse, there is a markedly reduced accumulation of AMP, during conditions of excessive contractile activity. Rather, there is a high ADP concentration, approaching 1.5 mM, that remains unbound 'free' within the muscle. This contributes to an inordinate reduction in the ATP/ADP ratio. At the same time, PCr hydrolysis is nearly complete leading to a large increase in orthophosphate. In combination, this leads to an exceptional decline in the free energy of ATP hydrolysis. This is projected to impair Ca2+ handling by the sarcoplasmic reticulum and slow cross-bridge cycling rate. The outcome should be slowed contraction characteristics and possible contracture. While some contractile changes were observed, there was a remarkable ability of the muscle to function under these challenging energetic conditions. Thus, it is not essential that the AMP deaminase reaction be operating during intense contraction conditions. This helps explain why patients deficient in AMP deaminase do not always exhibit an impaired muscle function.
Although many countries now have programs to lower the levels of lead in the environment, human exposure to Pb remains of concern to public health officials worldwide. The mechanisms of lead toxicity are still not fully understood, but recent findings have recognized the significance of the lead-induced impairment of the cell energy metabolism. This review outlines recent hypotheses and evidence on the role of nucleotide purines in erythrocyte metabolism regulation. It also describes the resynthesis and decomposition of purine nucleotides in erythrocytes, lead distribution in blood and its influence on purine conversion pathways and both glycolytic and pentosophosphate pathway enzymes in erythrocytes.
The influence of ischemia on purine nucleotide and their catabolite concentration in human myocardium was investigated during surgery of acquired and congenital heart defects. This was compared with the influence of ischemia on rat heart. Concentrations of adenine and guanine nucleotides and their catabolites were measured in the extracts of heart biopsies taken at the onset of ischemia and at the time of reperfusion. The content of myocardial ATP in human heart decreased from the initial value of 223 ± 1.1 to 14.6 ±1.5 nmol/mg protein and total adenine nucleotide pool decreased from 34.2 ± 1.8 to 27.6 ± 1.5 nmol/mg protein during the operation. Significant increases in myocardial concentrations of purine catabolites were also observed with the most prominent rise in inosine from below 0.5 at the onset of the ischemia to 3.0 ± 0.5 nmol/mg protein at the time of reperfusion. A positive correlation was demonstrated between the concentration of purine catabolites in the heart at the end of ischemia with the decrease of both ATP and the total nucleotide pool. An interesting metabolic specificity of the ischemic human heart appeared to be only a small accumulation of inosine monophospahate (IMP). The increase of IMP in the rat heart after ischemia was several-fold higher.
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