Liver Metabolism 2: Fructose And Galactose Flashcards
How does fructose and galactose enter hepatocytes
Via GLUT 2 transporters
Fructose goes straight into glycolysis where as galactose can go into glycolysis or be used to form glycolipids and glycoproteins
Major differences between fructose and glucose metabolism
1) fructose does NOT stimulate insulin
- glucose does
2) gets metabolized by fructokinase in the liver
- glucose gets metabolized by glucokinase
3) fructose can be uptaken by hepatocytes without insulin presence
- glucose can but usually requires insulin presence (requires it if going to be uptaken by GLUT 4 receptors as well)
4) fructose has no negative feedback loop with metabolism (will continue metabolism until all is used up if allowed to)
- glucose has a built in negative feedback regulation built in
Fuctokinase
Enzyme that is irreversible and ONLY found in liver, small intestine cells and kidney
Phosphorylates fructose -> F1P
This enzyme allows metabolism to bypass the PFK-1 regulatory step
- skips F6P -> F 1,6 P step of glycolysis
Rate of phosphorylation is 10x greater than glucokinase (way faster)**
If levels of fructose are insanely high, glucokinase can start to phosphorylate it as well, but it has an exceptionally high Km (low affinity)***
Aldolase enzymes
both A/B/C exist inside the liver
- all 3 can cleave fructose 1,6 BP -> Glyceraldehyde-3-phosphate
- however ONLY aldolase B can cleave fructose 1-P -> glyceraldehyde
The end product of aldolase mechanisms is Dihydroxyacetone Phosphate (DHAP) which enters glycolysis and gluconeogenesis directly and glyceraldehyde.
glyceraldehyde needs to be phosphorylated to glyceraldehyde 3-phosphate first though before being turned into DHAP
Essential fructosuria
An autosomal recessive disorder where there is a deficiency of fructokinase enzymes
Is a benign condition where fructose does accumulate in the urine
- no clinical symptoms show up since glucokinase takes over fuctokinase job since fructose levels end up being so high in the blood
Fructose intolerance
Autosomal recessive disorder where there is a deficiency of aldolase B in hepatocytes
Leads to excess fructose 1-phosphate (since aldolase B is the only enzyme to cleave this)
Symptoms:
- severe hypoglycemia
- vomiting
- jaundice
- hemorrhage
- hepatomegaly
- renal dysfunction
- hyperuricemia
- lactic acidemia
Treatment = NO fructose/sucrose in diet
The polyol pathway in the liver
A pathway used to convert glucose into fructose (usually only in glucose excess though)
1) D-glucose is reduced to sorbitol (polyol) via aldose reductase
- this enzyme is found in pretty much every tissue
- *glucose in excess will spontaneously metabolize into sorbitol
2) sorbitol is then converted to D-fructose via sorbitol dehydrogenase
- this enzyme is only found in liver and seminal vesicles
What is the only endogenous polyol?
Sorbitol
All other polyol (sugar alcohols) are found externally and synthetically
How does sorbitol effect diabetes mellitus
In hyperglycemia conditions, the excess glucose is converted into sorbitol spontaneously
However, excess sorbitol is bad because only liver can metabolize it to fructose, therefore excess sorbitol begins to build-up
- causes high osmotic uptake of water
Symptoms:
- cataracts
- retinopathy
- nephropathy
- peripheral neuropathy
How does D-galactose and D-glucose differ?
D-Galactose carbon 3 is flipped
Lactose synthesis in humans
Produced by lactating mammary glands
- synthesized in Golgi apparatus in these glands
Uses the enzyme: lactose synthase (UDP-galactose:glucose galactosyltransferase)
Which requires two 2 protein complexes to form:
1) = B-D-galactosyltransferase (found in all tissues
2) = a-lactalbumin (found only in mammary glands)
a-lactalbumin is ONLY synthesized in the presence of prolactin
Galactokinase deficency
Rare autosomal recessive disorder where there is little-no galactokinase enzymes
- causes elevation of galactose in blood and urine and elevated galactitol presence
this causes cataracts
Treatment = restrict diet from galactose and lactose
Aldose reductase
Enzyme that converts galactose to galactitol (ONLY in extreme levels of galactose)
- the levels have to be so high that it really only comes into play with galactokinase deficiencies
found in kidneys/retina/lens/nerve tissues and ovaries
Causes conversion of galactose -> galactitol
- excess galactitol = cataracts
Classic galactosemia
Is a autosomal recessive disorder where there is a deficiency of galactose 1-phosphate uridylyltransferase enzymes
Causes accumulation of galactose 1-phosphate and galactitol
Symptoms: (begins at breast feeding ages)
- liver and brain damage symptoms
- cataracts
- Developmental delays
- infertility
screening can be done by chorionic villus sampling
Treatment = remove all galactose and lactose from diet
