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G.Y.W. Ma S.L. Macaulay Judy A. Maggs J.McD. Armstrong J. Bornstein 《Biochimica et Biophysica Acta (BBA)/General Subjects》1982,716(3):400-409
Synthetic part sequences of human pituitary growth hormone (hGH 176–191 and hGH 177–191) corresponding to residues 176–191 or 177–191 of the hormone have been tested for their effects on glycogen and pyruvate metabolism in the rat, both in vivo and in vitro. When injected, the peptides caused transient increases in blood glucose and lactate, while decreasing the activity ratio of glycogen synthase in muscle, adipose tissue and liver and of pyruvate dehydrogenase in muscle and adipose tissue, but not in liver. These decreases were associated with the conversion of the enzymes from their active to their inactive forms, since the peptides did not affect the total amount of either the synthase or the dehydrogenase. The time course of the effect on the enzymes was similar to that for the effect on blood metabolites, and responses for synthase were produced over the range 0.07–7 nmols hGH 177–191/kg body weight. Phosphorylase activity was not affected by the peptides, nor was the capacity to dispose of injected L-lactate. Experiments with adipocytes and hepatocytes showed that the peptides also affected glycogen synthase and pyruvate dehydrogenase activities in vitro. The peptides had no effect on the overall rate of gluconeogenesis from lactate by hepatocytes. However, at times corresponding to those at which glycogen synthase was inactivated, the peptides caused increased incorporation of lactate into free glucose and decreased incorporation into glycogen. It was concluded that the peptides acted directly on their target tissues, and that the observed hyperlactataemia was the result of the inactivation of pyruvate dehydrogenase. The addition lactate increased the flux through the gluconeogenic pathway, and appeared as glucose because the peptide also inactivated glycogen synthase. Thus, the hyperglycaemia produced by hGH 177–199 and related peptides is explicable in terms of a modified Cori Cycle. 相似文献
43.
Abstract Amino acid sequence alignment of the Cephalosporium acremonium isopenicillin N synthase (cIPNS) to similar non-heme Fe2+ -containing enzymes from 28 different sources (bacterial, fungal, plant and animals) revealed a homologous region of high sequence conservation containing an invariant histidine residue at position 272 in cIPNS. The importance of this histidine residue in cIPNS was investigated through site-directed mutagenesis by replacing the histidine residue with leucine. The mutated gene was verified by DNA sequence analysis and expressed in Escherichia coli . When analyzed by denaturing gel electrophoresis and immunoblotting, the mutant cIPNS had identical mobility as that of the wild-type enzyme. Enzyme studies on the mutant enzyme showed loss of enzymatic activity indicating that His272 is essential for the catalytic function of cIPNS, possibly as a ligand for iron binding. 相似文献
44.
Zeyan Zhang Qianfu Gao Shanchao Wang 《Journal of cellular and molecular medicine》2021,25(5):2655-2665
Colorectal carcinoma (CRC) poses heavy burden to human health and has an increasing incidence. Currently, the existing biomarkers for CRC bring about restrained clinical benefits. GSK3β is reported to be a novel therapeutic target for this disease but with undefined molecular mechanisms. Thus, we aimed to investigate the regulatory effect of GSK3β on CRC progression via FTO/MZF1/c-Myc axis. Firstly, the expression patterns of GSK3β, FTO, MZF1 and c-Myc were determined after sample collection. Lowly expressed GSK3β but highly expressed FTO, MZF1 and c-Myc were found in CRC. After transfection of different overexpressed and interference plasmids, the underlying mechanisms concerning GSK3β in CRC cell functions were analysed. Additionally, the effect of GSK3β on FTO protein stability was assessed followed by detection of MZF1 m6A modification and MZF1-FTO interaction. Mechanistically, GSK3β mediated ubiquitination of demethylase FTO to reduce FTO expression. Besides, GSK3β inhibited MZF1 expression by mediating FTO-regulated m6A modification of MZF1 and then decreased the proto-oncogene c-Myc expression, thus hampering CRC cell proliferation. We also carried out in vivo experiment to verify the regulatory effect of GSK3β on CRC via FTO-mediated MZF1/c-Myc axis. It was found that GSK3β inhibited CRC growth in vivo which was reversed by overexpressing c-Myc. Taken together, our findings indicate that GSK3β suppresses the progression of CRC through FTO-regulated MZF1/c-Myc axis, shedding light onto a new possible pathway by which GSK3β regulates CRC. 相似文献
45.
TS (thymidylate synthase) is a key enzyme in the de novo biosynthesis of dTMP, and is indispensable for DNA replication. Previous studies have shown that intracellular degradation of the human enzyme [hTS (human thymidylate synthase)] is mediated by the 26S proteasome, and occurs in a ubiquitin-independent manner. Degradation of hTS is governed by a degron that is located at the polypeptide''s N-terminus that is capable of promoting the destabilization of heterologous proteins to which it is attached. The hTS degron is bipartite, consisting of two subdomains: an IDR (intrinsically disordered region) that is highly divergent among mammalian species, followed by a conserved amphipathic α-helix (designated hA). In the present report, we have characterized the structure and function of the hTS degron in more detail. We have conducted a bioinformatic analysis of interspecies sequence variation exhibited by the IDR, and find that its hypervariability is not due to diversifying (or positive) selection; rather, it has been subjected to purifying (or negative) selection, although the intensity of such selection is relaxed or weakened compared with that exerted on the rest of the molecule. In addition, we have verified that both subdomains of the hTS degron are required for full activity. Furthermore, their co-operation does not necessitate that they are juxtaposed, but is maintained when they are physically separated. Finally, we have identified a ‘cryptic’ degron at the C-terminus of hTS, which is activated by the N-terminal degron and appears to function only under certain circumstances; its role in TS metabolism is not known. 相似文献
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47.
Valérie Collot Jana Sopkova-de Oliveira Santos Pascale Schumann-Bard Nathalie Colloc'h Eric T. MacKenzie 《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):195-199
The synthesis, pharmacological evaluation and modelisation of 7-methoxyindazole (7-MI) and related alkoxy-indazoles as novel inhibitors of neuronal nitric oxide synthase are presented. 7-MI remains the most active compound of this series in an in vitro enzymatic assay of neuronal nitric oxide synthase activity. Modeling studies of the interaction of 7-substituted indazole derivatives complexed with nNOS and the relationship with their respective biological activities suggest that a bulky substitution on position-7 is responsible for a steric hindrance effect which does not allow these compounds to interact with nNOS in the same way as 7-NI and 7-MI. 相似文献
48.
Mitochondria are found in all nucleated human cells and generate most of the cellular energy. Mitochondrial disorders result from dysfunctional mitochondria that are unable to generate sufficient ATP to meet the energy needs of various organs. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a frequent maternally inherited mitochondrial disorder. There is growing evidence that nitric oxide (NO) deficiency occurs in MELAS syndrome and results in impaired blood perfusion that contributes significantly to several complications including stroke-like episodes, myopathy, and lactic acidosis. Both arginine and citrulline act as NO precursors and their administration results in increased NO production and hence can potentially have therapeutic utility in MELAS syndrome. Citrulline raises NO production to a greater extent than arginine, therefore, citrulline may have a better therapeutic effect. Controlled studies assessing the effects of arginine or citrulline supplementation on different clinical aspects of MELAS syndrome are needed. 相似文献
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