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Maple syrup urine disease (branched-chain oxoaciduria)
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The fundamental defect is in the activity of the branched-chain oxoacid dehydrogenase multienzyme complex (Figures 19.1 and 19.2) [1, 6, 7]. The components are E1 (a decarboxylase), E2 (an acyl transferase), and E3 (a flavoprotein lipoamide dehydrogenase (dihydrolipoyl dehydrogenase)). E1 is composed of two proteins in an α2β2 structure. The enzyme complex, which was purified to homogeneity by Pettit and colleagues [7], is analogous to the pyruvate and the 2-ketoglutarate dehydrogenase complexes; in fact, the E3 component of the three complexes is the same protein, and in E3 deficiency (Chapter 50) defective activity of each dehydrogenase enzyme results. Expression studies have shown that the complex does not assemble spontaneously; the E1 α and β proteins require chaperonins for folding and assembly [8].
Evolution
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Developing further the theoretical replication problems, Dobkin et al. (1979) turned with the MDV-1 variant to the unsolved problems of the Qβ enzyme-driven replication. They intended to answer the following intrinsic questions: Are the multistranded structures required intermediates in the replicative process? Can a single replicase molecule complete the entire replicative cycle, and in particular, can it dissociate from the complex? To determine whether a multienzyme complex was a necessary intermediate, they performed experiments under conditions of the template excess, in which only monoenzyme complexes were present. The results demonstrated that a single replicase molecule was competent to carry out a complete cycle of the MDV-1 replication and that the multistranded structures were not required intermediates in RNA replication. These experiments also suggested that, at the end of each replicative cycle after the completion of chain elongation, the complex released the product RNA before the replicase dissociated from the template (Dobkin et al. 1979).
Pharmacokinetic-Pharmacodynamic Correlations of Corticosteroids
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Helmut Möllmann, Stefan Baibach, Günther Hochhaus, Jürgen Barth, Hartmut Derendorf
The liver and kidney are the main organs for glucocorticoid metabolism.12 Predominantly, hydroxylation and coupling with sulfate or glucuronic acid to water-soluble, inactive derivatives take place, which are renally excreted.13 Circadian variations in metabolism and clearance have been observed.14–16 Some compounds, especially P and PR, undergo an 11-keto to hydroxy interconversion17 that is catalyzed by the 11β-hydroxysteroid dehydrogenase in various tissues.12 Renal and hepatic metabolism, as well as liver, significantly contribute to the conversion of HC to cortisone.18,19 Recent studies indicate that the converting enzyme consists of multiple enzymes or a multienzyme complex.20
The protective role of jervine against radiation-induced gastrointestinal toxicity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Selvinaz Yakan, Tuba Aydin, Canan Gulmez, Ozkan Ozden, Kivilcim Eren Erdogan, Yusuf Kenan Daglioglu, Fundagul Andic, Onur Atakisi, Ahmet Cakir
Impaired mitochondrial function is the result of overexpression of HIF-1-induced PDH which inactivates pyruvate dehydrogenase multi-enzyme complex (PDC) by adding a phosphate group to the TCA cycle by converting the pyruvate into acetyl-CoA33. HIF-1-induced PDH is caused by overexpression. HIF-1 stimulates enzymes and lactate dehydrogenase in glycolysis and induces pyruvate dehydrogenase kinase-1 (PDK1) in the mitochondria. PDK1 inhibits the activity of the pyruvate dehydrogenase multienzyme complex (PDH or PDC), which provides acetyl-CoA to the TCA cycle, and thus oxidative phosphorylation slows down. The slowing of oxidative phosphorylation also reduces the formation of reactive oxygen species (ROS). With this mechanism, HIF-1 in hypoxic conditions keeps ROS formation in balance. Otherwise, ROS-induced apoptosis may occur. The use of PDH inhibitors is a novel treatment strategy that directs oxidative phosphorylation from glycolysis of cancer cells, thus stimulating apoptosis34–37. In our study, cytoplasmic PDH enzyme activity was shown to decrease in intestinal tissues in groups receiving J (J + RT and J + RT + J) (Figure 6). This result indicates that J can be a chemotherapeutic agent with PDH inhibition and antitumour activity.
New discoveries in progressive myoclonus epilepsies: a clinical outlook
Published in Expert Review of Neurotherapeutics, 2018
Shweta Bhat, Subramaniam Ganesh
N-acetyl-α-neuraminidase is a constituent enzyme in the lysosomal enzyme complex along with enzymes cathepsin A, b‐galactosidase, and N‐acetylgalactosamine‐6‐sulfate sulfatase. It plays a central role in biological processes by catalyzing the removal of terminal sialic acid attached to glycolipids, glycoproteins, oligosaccharides, and polysaccharides [105]. Mutation in gene NEU1 structurally affects the normal folding, as well as its active site and results in disruption of the functional multienzyme complex in lysosomes [106]. The severity of the disease phenotype correlates with the mutation pathogenicity. Loss of function mutations leading to severe disease phenotype and mutations leaving residual activity of the enzyme can have milder symptoms [103]. In the absence of proper functioning of this enzyme, there is lysosomal storage of sialic acid overloaded macromolecules. Knockout mice of Neu1 (Neu1-/-) survive and develop sialidosis that is reminiscent of human type II sialidosis [107]. Mice model for mimicking type I sialidosis was also reported [108]. Together these models have contributed to our understanding of NEU 1 function at the molecular level and pathogenesis of sialidosis [105].
Safety and Efficacy of N-SORB®, a Proprietary KD120 MEC Metabolically Activated Enzyme Formulation: A Randomized, Double-Blind, Placebo-Controlled Study
Published in Journal of the American College of Nutrition, 2019
Qiurong Wang, Rui Guo, Sreejayan Nair, Derek Smith, Bledar Bisha, Anand S. Nair, Rama Nair, Bernard W. Downs, Steve Kushner, Manashi Bagchi
N-SORB is a novel KD120 multienzyme complex (MEC) containing a range of protease, amylase, and lipase enzymes including glucoamylase and alpha-galactosidase. These enzymes have been engineered to be activated in pH ranging from 6.5 to 8.5 and, contrary to popular belief, it is directed to be taken in an empty stomach. We have encapsulated this novel formulation in a proprietary SK713 SLP (Prodosome®) technology, which has been shown to facilitate rapid absorption of the encapsulated ingredients into the blood, increasing their bioavailability (20). Previous clinical studies have demonstrated that intervention with N-SORB improves gastrointestinal and neuroendocrine functions (20,21).