China
Africa
Explore chapters and articles related to this topic
Metabolism of Glutamine and Glutamate in the Liver — Regulation and Physiological Significance
Published in Elling Kvamme, Glutamine and Glutamate in Mammals, 1988
Glutamate is a poor primary substrate for gluconeogenesis in the liver,” and has been assumed to penetrate the liver membrane relatively slowly (but see Section V). Glutamate is formed from the transamination of a number of amino acids with 2-oxoglutarate, and also by the metabolism of histidine, ornithine, and proline, as well as glutamine. Glutamate is also formed by the reductive amination of 2-oxoglutarate via glutamate dehydrogenase, and this reaction is of importance in urea synthesis from exogenous ammonia. Glutamate degradation proceeds either via the aminotransferase pathway as described above, or via the glutamate dehydrogenase reaction, producing ammonia and 2-oxoglutarate. A feature of glutamine and glutamate metabolism in the liver is the important role of mitochondrial enzymes in these pathways.6 Thus, glutaminase, glutamate dehydrogenase, 2-oxoglutarate dehydrogenase, glutamate-oxoaloacetate aminotransferase, ornithine transcarbamylase, proline dehydrogenase, and carbamoyl phosphate synthetase are all located in the mitochondrial matrix. A reaction of particular importance in liver mitochondria is the conversion of glutamate to N-acetylglutamate via the enzyme N-acetylglutamate synthetase. N-Acetylgluta-mate is the essential activator of carbamoyl phosphate synthetase, an enzyme which is important in the regulation of urea synthesis.
Thyroid function analysis after roxadustat or erythropoietin treatment in patients with renal anemia: a cohort study
Published in Renal Failure, 2023
Xiaomeng Zheng, Yiyi Jin, Tao Xu, Hongbin Xu, Suyan Zhu
Chronic kidney disease (CKD) is a serious public health challenge wordwide. In China, approximately 10.8% of patients with CKD are affected by renal anemia [1]. Renal anemia is most commonly associated with CKD and may affect the quality of life of patients with CKD, increasing the morbidity and mortality associated with cardiovascular disease and the risk of hospitalization [2]. Abnormal iron metabolism in the kidney and impaired kidney erythropoietin are the main causes of renal anemia [3]. The current standard of care for renal anemia focuses on the above two causes including the use of iron, recombinant human EPO (rHuEPO), and their combinations [3]. Nevertheless, the use of rHuEPO requires intravenous or subcutaneous injections, which may increase pain for the patient and needle sticks for the nurse. Hypoxia inducible factor (HIF) increases endogenous erythropoietin in CKD patients [4] and is rapidly degraded by HIF proline dehydrogenase (HIF-PH). Therefore, HIF-PH inhibition can stabilize HIF, which is considered a new strategy for the treatment of renal anemia. Clinical trials have shown that roxadustat, a novel orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, can be used to treat anemia in dialysis or nondialysis patients and is noninferior to EPO [5,6].
Phenyl-substituted aminomethylene-bisphosphonates inhibit human P5C reductase and show antiproliferative activity against proline-hyperproducing tumour cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Giuseppe Forlani, Giuseppe Sabbioni, Daniele Ragno, Davide Petrollino, Monica Borgatti
Tumour development implies a deep reprogramming of cell metabolism, often inducing some additional or differential metabolic dependencies. These can be exploited for the identification of new therapeutic strategies based on substances able to target specific requirements of malignant cells1. Among the changes in the metabolic fluxes undergone by tumoral cells to satisfy a larger demand for carbon skeletons, ATP and reducing power, increasing rates of the so-called proline-P5C cycle seem to play a significant role in several cancer types2–3. Although some other mechanisms have been also hypothesised, such as an increase of collagen synthesis and maturation and the acquisition of cancer cell plasticity and heterogeneity4, the main contribution of proline metabolism to tumorigenesis seems to rely upon the consequently augmented redox cycling and maintenance of pyridine nucleotides5. Proline is synthesised from glutamate or ornithine in short pathways sharing the last step, the NAD(P)H-dependent reduction of the common intermediate δ1-pyrroline-5-carboxylic acid (P5C) by P5C reductase (EC 1.5.1.2)6. P5C is also formed during the mitochondrial degradation of proline to glutamate, which involves two oxidative steps catalysed in sequence by proline dehydrogenase (ProDH; EC 1.5.5.2)7 and P5C dehydrogenase (P5CDH, also known as aldehyde dehydrogenase 4; EC 1.2.1.88)8. The former is believed to feed electrons directly to the respiratory ubiquinone pool,9 whereas the latter uses NAD+ as the electron acceptor10. The occurrence of a shortcut in which the P5C released by ProDH is not further oxidised by P5CDH, but is reduced back to proline by P5C reductase, has been early hypothesized11. Such apparently futile proline-P5C cycle (Figure 1) may provide the cell with a mechanism for transferring reducing equivalents from the cytosol to the mitochondrion11–12, and to fuel the respiratory chain13. Moreover, ProDH activity may alternatively lead to ROS production14, which can trigger in turn the apoptotic mechanism15, or increased ATP synthesis for protective autophagy16. Although in plants the occurrence of the proline-P5C cycle is still a matter of debate due to the physical separation of P5C reductase and ProDH17, its role in human cell is now well established18. Consistently, high levels of expression of both ProDH and P5C reductase have been reported in a series of cases in which cell metabolism needs to be enhanced, for instance during nutrient stress19 or metastasis formation20.