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Inborn Errors of Metabolism
Published in Praveen S. Goday, Cassandra L. S. Walia, Pediatric Nutrition for Dietitians, 2022
Surekha Pendyal, Areeg Hassan El-Gharbawy
To be used for energy, galactose needs to be converted to glucose via the Leloir pathway in the liver (Figure 23.2). Defects in three different enzymes: galactose-1-phosphate uridyl transferase (GALT), galactokinase, and galactose epimerase (GALE) can occur in this pathway that can result in galactosemia. Of these, GALT deficiency is the most common and has significant genotype-phenotype correlation based on residual enzyme activity.
Metabolic Disorders II
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
Galactose is a monosaccharide, predominantly derived from hydrolysis of lactose or ‘milk sugar’, the main type of sugar found in milk and dairy products. The Leloir Pathway of galactose metabolism is depicted in Figure 41.1. In addition to formation of glucose-1-phosphate, the main end-product galactose may be phosphorylated for further integration into glycoproteins or glycolipids, (up to 5% of the GALT metabolic capacity), reduced to galactitol, or oxidized to galactonate.
Hexokinase in Health and Disease
Published in Rivka Beitner, Regulation of Carbohydrate Metabolism, 1985
The in vivo activity of hexokinase can be regulated by the intracellular compartmentation, as discussed in Section IV. In hepatomas a considerable amount of hexokinase activity is associated with the mitochondria. This important phenomenon was originally reported by several workers111–113 and studied in detail by Bustamante and Pedersen.53,55,110 In a series of hepatomas the amount of bound hexokinase appeared to correlate with the growth rate and the glycolytic activity of the tumors.55 The tumor mitochondrial hexokinase was directly coupled to oxidative phosphorylation, because addition of glucose to respiring hepatoma mitochondria (after a burst of ATP synthesis) resulted in stimulation of respiration,53 whereas glucose had no effect on the respiration of mitochondria from control and regenerating liver, which bear no hexokinase on their membranes. Addition of tumor mitochondria to normal rat liver cytosol produced a stimulatory effect on glycolysis, while tumor mitochondria devoid of hexokinase activity did not.55 From these studies it has been concluded that mitochondrial bound hexokinase might be responsible, at least in part, for the high aerobic glycolytic flux in hepatomas. This conclusion was further supported by the finding that substitution of glucose in the culture medium, by galactose, which can enter the glycolytic chain by the Leloir-pathway bypassing the hexokinase step, produced a marked decrease in lactic acid production. Remarkably, the cells grew equally well in both conditions.53 However, it was not established unequivocally whether mitochondrial bound hexokinase or increased hexokinase activity per se was stimulatory for tumor glycolysis. Moreover, the possibility that the high glycolytic rate in tumor cells was provoked by an ineffective Na-K-ATPase, as stated by others,123 is bypassed by the use of rather high concentrations of inorganic phosphate in some crucial experiments.
Molecular regulation of adhesion and biofilm formation in high and low biofilm producers of Bacillus licheniformis using RNA-Seq
Published in Biofouling, 2019
Faizan Ahmed Sadiq, Steve Flint, Hafiz Arbab Sakandar, GuoQing He
Lipid and sugar metabolism seemed to play an important role in the matrix production. Genes (BLi01117, BLi03508, BLi02826, and BLi03500) responsible for the production of key enzyme, FabG, (3-oxoacyl-[acyl-carrier protein]) involved in fatty acid biosynthesis were upregulated in the biofilm state of both strains. In terms of sugar metabolism, the role of nucleotide sugars (UDP-glucose and UDP galactose), produced by the Leloir pathway enzyme (GalE), and their conversion into polymeric chains by different glycosyltransferases like (glycogen synthase) and glycosyltransferase EpsJ was evident.
Repurposing drugs for the treatment of galactosemia
Published in Expert Opinion on Orphan Drugs, 2019
Galactosemia is a term which describes four diseases resulting from mutations in the genes encoding enzymes of galactose metabolism [1,2]. The Leloir pathway facilitates the conversion of galactose to the glycolytic intermediate glucose 6-phosphate (Figure 1) [3]. It is also important in the synthesis of UDP-sugars, which are important precursors for the synthesis of glycolipids and glycoproteins. The disaccharide lactose is a significant source of galactose in the diets of babies and Caucasian adults. This disaccharide, which occurs in milk, is hydrolyzed releasing d-glucose and β-d-galactose. In aqueous solution, the two anomers of d-galactose (α-d-galactose and β-d-galactose) interconvert at an appreciable rate [4]. However, this rate is not enough to supply the Leloir pathway whose first enzyme, galactokinase (GALK1; EC 2.7.1.6), only recognizes the α-anomer of d-galactose. Galactose mutarotase (aldose 1-epimerase, GALM; EC 5.1.3.3) catalyses the interconversion of the d-galactose anomers [5,6]. Mutations in the GALM gene can result in the most recently discovered form of the disease, Type IV galactosemia, which appears to behave more like a complex genetic disorder than a simple, Mendelian disease [7,8]. The Leloir pathway is generally considered to begin with the phosphorylation of α-d-galactose at the expense of ATP in a reaction catalyzed by galactokinase [9,10]. Type II galactosemia (OMIM #230200) is caused by mutations in the GALK1 gene [11,12]. The product of this reaction α-d-galactose 1-phosphate participates in an exchange reaction with UDP-glucose, generating α-d-glucose 1-phosphate and UDP-galactose. This reaction is catalyzed by galactose 1-phosphate uridylyltranferase (GALT; EC 2.7.7.10) and mutations in the corresponding gene are associated with type I galactosemia (or classic galactosemia; OMIM #230400) [13–15]. UDP-glucose is regenerated in an isomerization reaction catalyzed by UDP-galactose 4ʹ-epimerase (GALE; EC 5.1.3.2). This enzyme can also catalyze the epimerisation of the N-acetyl derivatives of d-glucose and d-galactose [16]. Type III galactosemia (OMIM #230350) is caused by mutations in the GALE gene [17,18]. The production of α-d-glucose 1-phosphate is generally considered to complete the Leloir pathway. However, one final reaction is required before the carbon atoms in the original galactose molecule can enter glycolysis: α-d-glucose 1-phosphate is isomerized to d-glucose 6-phosphate in a reaction catalyzed by phosphoglucomutase (PGM; EC 5.4.2.2) [19]. To date, no form of galactosemia has been associated with this enzyme. However, congenital disorder of glycosylation, type It (OMIM #614921) is associated with PGM1 deficiency. The glycosylation disorders have some similarity with those seen in galactosemia types I and III [20].