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  • Title: Hepatic glutamine metabolism.
    Author: Häussinger D.
    Journal: Beitr Infusionther Klin Ernahr; 1987; 17():144-57. PubMed ID: 2891351.
    Abstract:
    The outstanding role of glutamine in hepatic nitrogen metabolism in general has been the subject of extensive research within the past few years. Hepatic glutaminase shows an extraordinary pH sensitivity, is not inhibited by glutamate and is activated by its product ammonium, thereby contrasting the kidney enzyme. In the absence of ammonium virtually no activity can be detected. Control of hepatic glutamine degradation is exerted at the level of glutaminase activity and glutamine transport across the plasma and mitochondrial membranes. These transport systems establish glutamine concentration gradients across the respective membranes: with a physiological extracellular glutamine concentration of 0.6 mM, the cytosolic and mitochondrial concentrations are 7 and 20 mM, respectively, both in vivo and in vitro. Therefore mitochondrial glutaminase is operating in vivo near its Km of 22-28 mM. In the intact liver acinus, glutaminase and the enzymes of the urea cycle are localized in the periportal hepatocytes, whereas glutamine synthetase is restricted to small hepatocyte population in the perivenous area; i.e., at the outflow of the sinusoid. Therefore, following the sinusoidal bloodstream, urea and glutamine synthesis are anatomically switched around. With respect to hepatic ammonium detoxication, this organization represents functionally the sequence of a periportal low-affinity system (urea synthesis) and a perivenous high-affinity system (glutamine synthesis) for ammonium removal. The role of glutamine synthetase is that of a scavenger for ammonium which has escaped periportal urea synthesis before the sinusoidal blood reaches the systemic circulation. The role of glutaminase is seen in a pH-modulated ammonium amplifier inside the mitochondria of the periportal compartment, thereby determining flux through the urea cycle. Periportal glutaminase and perivenous glutamine synthetase are simultaneously active, resulting in the so-called intercellular glutamine cycle. The role of this cycle is to improve the efficiency of hepatic urea synthesis at the physiologically low portal ammonium concentrations, thereby compensating the comparatively low ammonium affinity of carbamoylphosphate synthetase, the rate-controlling enzyme of the urea cycle. Normally, periportal glutamine breakdown is matched by a compensatory perivenous glutamine resynthesis; thus no net glutamine turnover is observed. In addition, intercellular glutamine cycling is an effective means of adjusting flux of portal ammonium into either urea or glutamine according to the needs of systemic pH regulation.(ABSTRACT TRUNCATED AT 400 WORDS)
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