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Role of Ascorbate and Dehydroascorbic Acid in Metabolic Integration of the Cell
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Gábor Bánhegyi, András Szarka, József Mandl
ε-N-trimethyl-l-lysine hydroxylase and β-butyrobetaine hydroxylase, enzymes necessary for synthesis of carnitine, seem to be localized to the mitochondria and cytosol. Carnitine is essential for the transport of fatty acids into mitochondria for β-oxidation and consequent ATP generation [66]. However, the subcellular localization of 4-hydroxyphenylpyruvate dioxygenase, the enzyme that participates in the catabolism of tyrosine, is less known. In the nucleoplasm Fe(II)/2-oxoglutarate–dependent dioxygenases are involved in the epigenetic regulation of gene expression by demethylating histones and DNA [55]. Enzymes that demethylate histones mainly belong to the Jumonji protein family conserved from yeast to humans with a common jmjC functional domain [82]. DNA demethylation occurs at the methyl group of 5-methylcytosine via subsequent oxidative steps catalyzed by the dioxygenases of the ten-eleven translocation (TET) family [35,45].
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Normal feeds should be stopped and the hepatorenal dysfunction and rickets treated as indicated. Prior to 1991, the only successful long-term treatment of tyrosinaemia type I was liver transplantation but, with the advent of NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione) – a potent inhibitor of the up-stream enzyme 4-hydroxyphenylpyruvate dioxygenase – effective treatment is now available. NTBC prevents the toxic metabolites forming and is effective in both the acute and chronic forms of the disease. A dose of 1 mg/kg/d is recommended. Because the children still have a ‘metabolic block’, they require a low phenylalanine and tyrosine diet with a supplementary phenylalanine-/tyrosine-free amino acid formula. Growth, tyrosine levels and residual liver damage all need to be monitored, including regular liver imaging for hepatoma.
Metabolic Disorders II
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
Hypertyrosinemia in a pediatric patient is a nonspecific finding, and can be associated with all forms of liver failure as well as with a diverse group of conditions involving the pathway of tyrosine catabolism: Hepatocellular dysfunction due to acute or chronic liver disease.Transient tyrosinemia of the newborn.Hereditary genetic enzymatic deficiencies: – HT1- fumarylacetoacetate (FAA) deficiency.– HT2 – Tyrosine aminotransferase deficiency.– HT3 – 4-hydroxyphenylpyruvate dioxygenase (HPD) deficiency.Scurvy.Hyperthyroidism.
Uncover diagnostic immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation-related CCR5, CD86, CD8A, ITGAM, and PTPRC in kidney transplantation patients with allograft rejection
Published in Renal Failure, 2022
Long He, Boqian Wang, Xueyi Wang, Yuewen Liu, Xing Song, Yijian Zhang, Xin Li, Hongwei Yang
WGCNA was used to identify genes related to allograft rejection after the kidney transplant. First, samples were clustered and four abnormal samples were deleted. When the parameter value of the weight coefficient is 24, the scale-free topology is approximate (Figure 2(A)). After building the cluster tree, the minimum number of genes in modules was set to 100, which separate seven modules (gray modules were not included). The dynamic cutting tree method was utilized to merge the modules with the dissimilarity degree <25%. Finally, five modules were identified (Figure 2(B,C)). As shown in Figure 2(D), the red module had the highest positive correlation with allograft rejection after kidney transplant (Pearson’s r = 0.45; p = 3E–41). Some up-regulated genes in the red module were identified, such as C-C motif chemokine receptor 5 (CCR5), CD86 molecule (CD86), CD8a molecule (CD8A), integrin subunit alpha M (ITGAM), and protein tyrosine phosphatase receptor type C (PTPRC). The blue module had the highest negative correlation with allograft rejection after kidney transplant (Pearson’s r = −0.2; p = 1E–08). Some down-regulated genes in the blue module were identified, such as 4-hydroxyphenylpyruvate dioxygenase (HPD) and afamin (AFM). Therefore, red and blue modules were chosen as hub modules, which involved 1066 genes.
The potential of nitisinone for the treatment of alkaptonuria
Published in Expert Opinion on Orphan Drugs, 2019
Nitisinone is a naturally occurring herbicide discovered when observations were made of the reduction in the number of other plants growing in close-proximity to the bottlebrush plant (Callistemon) [39]. The absence of other species from around the bottlebrush suggested an effect from inhibition of pathway(s) affiliated with growth. It was discovered that the chemical known as Leptospermone, which is present in the soil around the plants had a bleaching effect, amongst others, on neighboring plants. Leptospermone belongs to the triketone family and impedes chloroplast development by 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition; HPPD is an enzyme involved in the catabolism of tyrosine and is integral to the production of a number of natural plant products [40,41]. The discovery of the triketone family, of which Leptospermone was an early finding, led to the discovery and development of nitisinone. The initial work in understanding how nitisinone worked was undertaken by Zeneca Agrochemicals following indications that it inhibited the actions of another enzyme which uses tyrosine as a substrate; tyrosine hydroxylase. Further work on nitisinone by Zeneca Central Toxicology Laboratories clarified that Nitisinone did not inhibit tyrosine hydroxylase or tyrosine aminotransferase, but in fact, was a potent inhibitor of HPPD [38].