Metabolism of Fructose and Galactose and for the Pentose Phosphate Pathway Flashcards
Which two enzymes perform the task to modify and trap glucose inside the hepatocyte?
Glucokinase uses glucose and ATP and forms glucose 6-phosphate.
[glucokinase is an isozyme of hexokinases but is not product inhibited]
*Aldose reductase uses glucose and NADPH and forms sorbitol in the polyol pathway.
[note: aldose reductase is wanted to trap glucose in hepatocytes but it will also act on accumulated galactose in patients with classic galactosemia or galactokinase deficiency. Galactose is used in these patients to form galactitol which accumulates and leads to severe liver damage. Aldose reductase acts on aldoses, like glucose (forming sorbitol) or galactose (forming galactitol). The enzymes does not act on ketoses, like fructose]
The liver has a central role in metabolizing dietary fructose and dietary galactose. Which enzymes use these monosaccharides as substrates and what is formed, respectively?
Fructokinase uses fructose and ATP and forms fructose 1-phosphate.
Galactokinase uses galactose and ATP and forms galactose 1-phosphate.
[note: hexokinases, including glucokinase, phosphorylate the sugar in position-6,
fructokinase and galactokinase phosphorylate their sugar in position-1.]
A genetic defect of fructokinase leads to high fructose levels in the blood. This defect is also referred to as Essential Fructosuria. Is this a benign or a severe condition? Explain!
Fructose is normally trapped in the liver by fructokinase. When this normally abundant enzyme is deficient, then fructose levels in the blood increase which leads also to fructose in urine. Fructose in urine can be detected as reducing sugar with the dipstick test which in addition shows that it is not glucose or galactose.
Essential Fructosuria is a benign condition as no harmful intermediates of fructose metabolism is formed.
After phosphorylation of fructose to fructose 1-phosphate, how can this molecule join glycolysis in the liver? Compare it to fructose 6-phosphate.
In glycolysis, PFK-1 phosphorylates fructose 6-P to fructose 1,6-bisphosphate which then will be cleaved into two triose phosphates.
There is no enzyme that phosphorylates fructose 1-phosphate.
Fructose 1-phosphate is cleaved by aldolase B to glyceraldehyde and dihydroxyacetone phosphate (DHAP). Glyceraldehyde is phosphorylated, and both triose phosphates join glycolysis.
. Which enzyme is deficient in Hereditary Fructose Intolerance and which intermediate accumulates in the liver?
Aldolase B is deficient. Aldolase B is mainly found in hepatocytes. The hereditary deficiency of aldolase B leads to accumulation of fructose 1-phosphate in the hepatocyte after ingestion of fructose
Why is the disease Hereditary Fructose Intolerance also named “fructose poisoning”?
Aldolase B deficiency leads to liver damage and severe hypoglycemia.
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When fructose 1-phosphate accumulates, it traps inorganic phosphate in its structure. Which enzymatic reactions need “free” inorganic phosphate? Why do these patients suffer from severe hypoglycemia? Can aldolase B be used in both, glycolysis or gluconeogenesis in the liver?
Inorganic phosphate is needed for example for ATP synthase in oxidative phosphorylation and for glycogen phosphorylase (phosphorolytical cleavage of glycogen using Pi).
Lack of ATP in the liver reduces liver functions including gluconeogenesis in general. Increased AMP allosterically inhibits fructose 1,6-bisphosphatase, one of the key regulated enzymes of gluconeogenesis. Aldolase B is also an enzyme used in gluconeogenesis, it catalyzes a reversible reaction.
Both, gluconeogenesis and glycogen degradation are reduced which can lead to severe hypoglycemia
Why can dietary fructose, sucrose and sorbitol cause hepatic failure and death in patients with Hereditary Fructose Intolerance?
These patients are deficient in aldolase B and the dietary uptake leads to fructose 1-P accumulation in the liver after ingestion of
dietary fructose
dietary sucrose which is cleaved to glucose and fructose by intestinal mucosal cells
dietary sorbitol which is substrate for hepatic sorbitol dehydrogenase which forms fructose from sorbitol.
Why is sorbitol dehydrogenase found in seminal vesicle cells but this enzyme is low or absent in retina, lens, kidney and nerve cells?
Seminal vesicle cells release fructose for spermatozoa metabolism (via GLUT-5). Glucose is the sugar that is always available in the blood, and aldose reductase and sorbitol dehydrogenase lead eventually to fructose formation in these cells.
The retina, lens, kidney and nerve cells form only minor amounts of sorbitol at normal blood glucose levels catalyzed by aldose reductase. The generation of fructose is not needed in these cells and sorbitol dehydrogenase is low or absent.
Under which conditions is sorbitol formed in the eye (cornea, retina, lens), kidney and myelin sheath of peripheral nerve cells? What results from sorbitol in these cells?
The chronic high blood glucose level in untreated diabetic patients leads to uptake of larger amounts of glucose into these cells, the uptake is via GLUT-1 or GLUT-3 which are insulin-independent.
At these elevated glucose levels, aldose reductase is activated by substrate availability and forms sorbitol. This sugar alcohol was not meant to be formed in these cells and it accumulates and attracts water into the cells. This can lead to cataracts in the lens and to damage of peripheral nerve cells and of renal cells.
Which enzyme is deficient in classic galactosemia and which molecule accumulates? What is the product of aldose reductase acting on galactose? Is this leading to liver damage?
The enzyme galactose 1-P uridyl transferase (GALT) is deficient in patients with classic galactosemia and galactose 1–P accumulates in the hepatocyte.
This leads to less availability of inorganic phosphate (similar to Hereditary Fructose Intolerance where fructose 1-P accumulates) and ATP synthesis and glycogen degradation are reduced.
Galactokinase is product inhibited by galactose 1-P and “free” galactose is now substrate for aldose reductase in the liver. This leads to the abnormal formation of galactitol in the hepatocytes.
Galactose is also found now abnormally in the blood and reaches other cells and aldose reductase in other cells forms galactitol using galactose and NADPH
Why do you find cataracts in patients with classic galactosemia and why is the liver damaged?
Galactose blood levels are abnormally high in these patients, and aldose reductase is activated by substrate availability. Galactitol is like sorbitol trapped in the cell and attracts water which leads to cataracts in the lens and damages nerve endings.
The liver is damaged as galactitol was not meant to be formed by the abundant aldose reductase activity found in hepatocytes. There is no enzyme available that can use this sugar alcohol as substrate. Also, the accumulation of galactose 1-P depletes the available inorganic phosphate. Hypoglycemia occurs after ingestion of galactose as ATP formation and glycogenolysis are reduced
Is classic galactosemia and Hereditary fructose intolerance inherited?
yes they both are
what is the enzyme that is deficient in classic galactosemia?
galactose 1-P uridyl transferase (GALT)
What enzyme is deficient in hereditary fructose intolerance?
aldolase B
