Uronic Acid Pathway Overview

Uronic Acid Pathway

• An alternative pathway for glucose oxidation
• Does not produce ATP
• Occurs in the liver
• Converts glucose to glucuronic acid, ascorbic acid (vitamin C - except in humans), and pentoses
• UDPGlc is oxidized to UDP-glucuronate (active form) by NAD-dependent UDPGlc dehydrogenase
• Glucuronate is highly polar
• Glucuronate is used in the synthesis of:
  • Proteoglycans
  • Glucuronide conjugates (steroids, bilirubin, drugs)
  • More soluble and excretable in urine or bile
• Glucuronate is reduced to L-gulonate, a precursor for ascorbate (vitamin C) in animals
• Humans lack L-gulonolactone oxidase, so ascorbic acid cannot be synthesized
• Enzyme deficiencies and some drugs can disrupt the uronic acid pathway
• Essential pentosuria: rare, benign hereditary condition due to a lack of xylulose reductase
  • High levels of xylulose in the urine
• Drugs that activate the uronic acid pathway:
  • Barbital
  • Chlorobutanol
  • Aminopyrine
  • Antipyrine

Fructose Metabolism

• Source: Sucrose, high-fructose syrups (HFS)
• Fructose metabolism is rapid in the liver due to bypassing the regulatory step catalyzed by phosphofructokinase
• Leads to an increase in:
  • Fatty acid synthesis and esterification
  • Serum triacylglycerols
  • LDL cholesterol concentrations
• Fructokinase in the liver, kidney, and intestines converts fructose to fructose-1-phosphate
• Fructokinase activity is not affected by fasting or insulin, explaining why fructose is cleared from the blood of diabetic patients at a normal rate.
• Aldolase B in the liver cleaves fructose-1-phosphate to D-glyceraldehyde and dihydroxyacetone phosphate
• D-Glyceraldehyde enters glycolysis via phosphorylation to glyceraldehyde-3-phosphate by triokinase
• Dihydroxyacetone phosphate and glyceraldehyde-3-phosphate can be degraded by glycolysis or used as substrates for aldolase and gluconeogenesis

Conversion of Glucose to Fructose (Polyol Pathway)

• Aldose reductase converts D-glucose to D-sorbitol
• Sorbitol dehydrogenase in the liver converts sorbitol into fructose
• These reactions are important in the seminal vesicles for sperm cells, which utilize fructose as a primary carbohydrate energy source.
• Loading the liver with fructose can exacerbate:
• Hypertriacylglycerolemia
• Hypercholesterolemia
• Hyperuricemia
• Depletion of inorganic phosphate, accumulation of fructose-1-phosphate, and decreased ATP levels can cause adenine to be converted to uric acid, leading to hyperuricemia.
• Decreased ATP availability affects gluconeogenesis and can result in hypoglycemia.
• If fructose is not removed from the diet, liver failure and death can occur.
• Essential fructosuria: Benign and asymptomatic condition due to a lack of hepatic fructokinase.
  • High oral doses of fructose can lead to osmotic diarrhea as it is passively absorbed by small intestine
• Hereditary fructose intolerance:
  • Due to aldolase B deficiency

The Effect of Hyperglycemia on Sorbitol Metabolism

• Increased activity of the polyol pathway in tissues that are not insulin-sensitive (lens, peripheral nerves, renal glomeruli) as glucose concentration rises
• If sorbitol dehydrogenase is deficient, sorbitol accumulates.
  • This causes osmotic damage as sorbitol does not pass through cellular membranes.
  • Contributes to cataract formation, peripheral neuropathy, and vascular problems leading to nephropathy and retinopathy

Galactose Metabolism

• From lactose
• Galactose is converted to glucose in the liver
• Galactose is synthesized from glucose in the lactating mammary glands
• Required for the synthesis of:
  • Glycolipids
  • Proteoglycans
  • Glycoproteins