Metabolic Pathways of Glutathione and Uronic Acid

Glutathione and Glucose-6-Phosphate

• Glutathione removes H2O2 in a reaction catalyzed by glutathione peroxidase, which contains selenium analog of cysteine (selenocysteine) at the active site.
• This reaction is important to prevent the accumulation of H2O2, which can decrease the life span of erythrocytes by causing oxidative damage to the cell membrane, leading to hemolysis.

Uronic Acid Pathway

• In the liver, the uronic acid pathway converts glucose to glucuronic acid, ascorbic acid, and pentoses.
• This pathway is an alternative oxidative pathway for glucose that doesn't lead to ATP formation.
• Glucose-6-P is isomerized to glucose-1-P, which then reacts with uridine triphosphate (UTP) to form uridine diphosphate glucose (UDPGlc) in a reaction catalyzed by UDPGlc pyrophosphorylase.
• UDPGlc is oxidized at carbon 6 by NAD-dependent UDPGlc dehydrogenase in a two-step reaction to yield UDP-glucuronate.

Fructose Metabolism

• Fructose can be degraded by glycolysis or lead to excessive fatty acid synthesis and cholesterol synthesis in the liver.
• The liver packs these lipids into VLDL and releases them into the circulatory system, resulting in hypertriglyceridemia.
• VLDL will turn into LDL in the circulation, resulting in hypercholesterolemia.
• Fructose can also be a substrate for gluconeogenesis, which is the fate of much of the fructose metabolized in the liver.
• Excessive glucose-6-phosphate production activates the pentose phosphate pathway, increasing ribose-5-phosphate and consequently increasing nucleic acid synthesis, leading to hyperuricemia and gout.

Galactose Metabolism

• Galactose is needed for the synthesis of lactose, glycolipids, proteoglycans, and glycoproteins.
• Galactokinase catalyzes the phosphorylation of galactose.
• UDPGal is produced by galactose-1-phosphate uridyl transferase enzyme.
• UDPGal is then converted to UDPGlc by UDPGal 4-epimerase enzyme.
• UDPGlc is incorporated into glycogen.
• The epimerase reaction is freely reversible, so glucose can be converted to galactose, and galactose is not a dietary essential.

Membrane Lipids

• Glycosphingolipids (GSLs) have a sphingosine backbone and are ceramide derivatives.
• Cerebrosides are a type of glycosphingolipid, with a monosaccharide part (glucose or galactose).
• Gangliosides are complex glycosphingolipids derived from glucosylceramide, containing one or more molecules of sialic acid bound to galactose or N-acetyl galactosamine.
• Neuraminic acid is the principal sialic acid found in human tissues.

Clinical Aspects

• Impairment of the pentose phosphate pathway leads to erythrocyte hemolysis due to genetic defects of glucose-6-phosphate dehydrogenase, resulting in hemolytic anemia.
• Glutathione peroxidase is dependent on a supply of NADPH, which in erythrocytes can only be formed via the pentose phosphate pathway.
• Measurement of erythrocyte glutathione reductase and its activation by FAD is used to assess vitamin B2 (riboflavin) nutritional status.
• Loading of the liver with fructose may disrupt serum lipid profile and cause high uric acid concentrations, leading to hypertriacylglycerolemia and hypercholesterolemia.
• Fructose and sorbitol are associated with diabetic pathologies, including cataract, neuropathy, and renal insufficiency.