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Fructose is released from the disaccharide ______ by the digestive enzyme______ in the _______
- Fructose is released from the disaccharide sucrOSE by the digestive enzyme sucrASE in the intestine
What is the polyol (sorbitol-aldose reductase) pathway? What do aldol reductase and sorbitol dehydrogenase do?
- it's how glucose and fructose can be interconverted
- aldol reductase: glucose <--> sorbitol
- sorbitol dehydrogenase: sorbitol <--> fructose
- sorbitol can't move across cell membranes
- such conversions can occur in seminal vesicles (sperm fuel) and the eye (retinopathy)
- catalyzes the reaction
- Fructose + ATP --> fructose-1-phosphate + ADP
- cleaves BOTH fructose-1-phosphate (fructose metabolism) and fructose-1,6-bisphosphate (glycolysis)
- preferentially expressed in the liver
aldolases A and C act ONLY on ___________, but aldolase B acts on BOTH fructose __________ and ___________
- aldolases A and C act only on fructose 1,6-bisphosphate
- aldolase B acts on both fructose 1,6-bisphosphate and fructose-1-phosphate
- aldolase A: preferentially expressed in the muscle + erythrocytes
- aldolase C: preferentially expressed in the brain
aldolase B cleaves fructose-1-phosphate into:
- 1) dihydroxyacetone-phosphate (DHAP): can enter glycolysis
- 2) glyceraldehyde: must be phosphorylated before entering glycolysis
- caused by a deficiency of fructokinase (fructose --> fructose-1-phosphate)
- not associated with significant clinical abnormalities b/c there's no accumulation of fructose-1-phosphate (or ATP deficiency)
Deficiency of aldolase B results in:
- dietary fructose intolerance and an accumulation of fructose-1-phosphate
- caused by ingestion of fructose, sucrose or sorbitol
- an accumulation of fructose-1-phosphate is associated with depletion of ATP and Pi
Prominent changes in blood concentrations of metabolites as a result of fructose intolerance/malfunctioning aldolase B are:
- 1) a fall in glucose: fructose-1-phosphate inhibits the release of glucose from glycogen
- 2) a fall in free phosphorus: phosphorus becomes trapped in fructose-1-phosphate so Pi can't be used for ATP synthesis
- 3) a rise in uric acid: due to increased synthesis/breakdown of purine nucleotides
hexokinase (does a lot of things)
- 1) catalyzes phosphate transfer to the C6 of the sugar (glucose --> glucose-6-phosphate)
- 2) can ALSO act on fructose in the absence of glucose to form fructose-6-phosphate
- 3) phosphorylates mannose --> mannose-6-phosphate
Which enzyme catalyzes the phosphorylation of mannose --> mannose-6-phosphate?
How does mannose enter the glycolytic pathway?
Mannose is phosphorylated to mannose-6-phosphate by hexokinase, which can then be isomerized to fructose-6-phosphate by phosphomannose isomerase (thing #3 in glycolysis)
mannose-6-phosphate --> fructose-6-phosphate
What is the main source of dietary galactose?
lactose found in dairy products
Galactose in blood is rapidly absorbed by the _____, where it can be converted to ______.
- The LIVER rapidly absorbs galatose and converts it to GLUCOSE
- An increase in blood glucose concentration usually follows the ingestion of galactose or lactose
enzyme that catalyzes the phosphorylation of galactose --> galactose-1-phosphate
- product of phosphorylation of galactose by galactokinase; it can't be isomerized directly to any glucose or fructose derivative, nor is there any aldolase that can cleave it
- in order to use galactose-1-phosphate, the cell must first make a glucose-nucleotide, uridine diphosphoglucose (its metabolism depends on formation of sugar-nucleotide derivatives)
uridine diphosphoglucose (UDP-Glu)
- needed in order to metabolize galactose-1-phosphate
- formed by the isomerization of glucose-6-phosphate --> glucose-1-phosphate by phosphoglucomutase
- UDP-Glu pyrophosphorylase then catalyzes the reaction between glucose-1-phosphate & UTP (uridine triphosphate) to form UDP-Glu + Pi
The reaction catalyzed by phosphoglucomutase (glucose-1-phosphate --> UDP-Glu) is analogous to:
the reversible phosphoglycerate mutase reaction of the glycolytic pathway (3-phosphoglycerate --> 2-phosphoglycerate)
Which enzyme catalyzes the reversible isomerization of glucose-6-phosphate to glucose-1-phosphate?
*Galactose-1-phosphate is toxic to cells when present in excess
- transfers the nucleotide portion of UDP-Glu to galactose-1-phosphate to form UPD-galactose
- this is essential for the metabolism of galactose-1-phosphate
- UDP-glucose + galactose-1-phosphate --> UDP-galactose + glucose-1-phosphate
epimerizes the galactose in UDP-galactose to UDP-glucose
What coenzyme is required for the interconversion of UDP-galactose with UDP-glucose by the enzyme UDP-galactose-4-epimerase?
- it acts as a true coenzyme for the reaction, so NADH is not produced except as a reaction intermediate
Which enzyme permits the glycosylation of proteins and lipids with galactose even in the absence of dietary galactose?
- this enzyme can isomerize UDP-glucose to UDP-galactose, and can therefore produce UDP-galactose even when galactose is absent in the diet
Name three enzymes of galactose metabolism that, when deficient, can lead to galactosemia (accumulation of galactose in the blood)
- 1) Galactokinase
- 2) galactose-1-phosphate uridyltransferase
- 3) UDP-galactose-4-epimerase
- leads to high levels of blood galactose & galactosuria after eating foods with galactose, but isn't associated with disturbance of growth or development
- some of the galactose is reduced to galactitol (sugar alcohol); can cause cataracts if it accumulates in eye lens
- disorder is uncommon
galactose-1-P uridyltransferase deficiency
- galactose-1-phosphate accumulates in the tissues and some is reduced to galactitol-1-phosphate (sugar alcohol)
- these are more toxic than NON-phosphorylated galactose and galactitol
- disease is characterized by lack of growth, vomiting, diarrhea, dehydration & jaundice during newborn period; cataracts and developmental retardation later
- early diagnosis/exclusion of all forms of galactose from diet can prevent these problems
- AR inherited disease that has much more severe consequences than a lack of galactokinase
How can infants with galactose-1-P uridyltransferase deficiency synthesize galactose-containing glycoproteins and glycolipids?
it's still possible for infants to do so even with no galactose in the diet using epimerase, which converts UDP-glucose to UDP-galactose
- unable to interconvert UDP-glucose to UDP-galactose
- leads to high levels of galactose-1-phosphate
- when affecting blood cell epimerase there are no clinical problems
- when affecting liver or other tissue epimerase, it's more severe and looks clinically similar to a galactose-1-phosphate uridyltransferase deficiency
- treatment involves decreasing amount of galactose in the diet; a small amount is still necessary
Accumulation of which metabolite in the lens of the eye can lead to the development of cataracts in individuals with galactokinase deficiency?
Lack of growth in newborns, accumulation of galactose-1-phosphate and accumulation of galactitol-1-phosphate are all associated with the deficiency of what enzyme?
conjugation makes molecules more:
- POLAR, and therefore more excretable, more easily transported out
- eg. UDP-Glucuronic acid: conjugated glucose can be used to make proteoglycans; makes it more water soluble, allows for transport out of cells
- seen in bilirubin & drugs
The longer alcohol remains in the stomach, the ______ it will be absorbed.
SLOWER; this is why food that slows emptying of stomach contents slows absorption and reduces peak blood alcohol levels
Which organ metabolizes the majority of the alcohol absorbed into the bloodstream following ingestion?
The first step in the metabolism of alcohol is:
oxidation of ethanol to acetaldehyde (an oxidation reaction)
What are the two major ways that ethanol is oxidized to acetaldehyde?
- 1) the alcohol dehydrogenase (ADH) pathway in the cytosol
- 2) the microsomal ethanol oxidizing system (MEOS) (attributed to CYP2E1, an isoform of cytochrome P450) in the smooth endoplasmic reticulum
Name the primary enzyme that catalyzes the conversion of alcohol into acetaldehyde:
Alcohol dehydrogenase (ADH)
microsomal ethanol oxidizing system (MEOS)
- MEOS is found in the smooth endoplasmic reticulum and its role in ethanol metabolism is small in non-habitual drinkers
- its activity increases during chronic alcohol consumption, accounting for increased tolerance in heavy drinkers
With which ethanol oxidation system will acetaminophen poisoning more readily occur?
The MEOS system; alcohol can create problems by interfering with the cytochrome P450 system, which is also used to process many drugs (eg. barbiturates)
The build up of which alcohol metabolite makes people ill when consuming too much alcohol?
What two enzymes catalyze the breakdown of acetaldehyde?
- 1) aldehyde dehydrogenase 2 (ALDH)
- 2) acetylCoA synthetase
The genes for both enzyme ___ and _____ occur in two polymorphic forms, affecting their abilities to function
Like ADH (EtOH --> acetaldehyde), the ALDH2 (toxic acetaldehyde --> acetic acid) gene occurs in two polymorphic forms
What is the chemical equation for the reaction catalyzed by aldehyde dehydrogenase?
- Acetaldehyde + NAD+ --> acetate + NADH + H+
- CH3CHO + NAD+ --> CH3COO- + NADH + H+
- acetate can be converted to acetylCoA then CO2 & H2O
- *acetate can also be acetic acid (a carboxylic acid) depending on environment
drug that inhibits acetaldehyde dehydrogenase (enzyme that converts acetaldehyde into acetic acid); causes unpleasant side effects when alcohol is consumed
What are two ways in which alcohol consumption can lead to acidosis?
- 1) only so much acetate can be converted to acetyl CoA; excess may appear in the blood and lead to acidosis
- 2) alcohol metabolism depletes cellular stores of NAD+
- to restore NAD+, an increased conversion of pyruvate to lactate by lactate dehydrogenase is needed, which can lead to lactic acidosis
How does the production of NADH inhibit gluconeogenesis?
- NADH is produced when alcohol is converted to acetaldehyde AND when acetaldehyde is converted to acetate
- this leads to a depletion of NAD+, which is corrected for by converting pyruvate back into lactate
- however now less pyruvate is available for gluconeogenesis
- this could be corrected for using the TCA cycle and converting malate to oxaloacetate
- BUT that conversion produces more NADH
- Malate + NAD+ --> Oxaloacetate + NADH
- the malate side of the reaction is favored, gluconeogenesis fails to occur, and hypoglycemia may result
How does the production of NADH stimulate triglyceride formation?
- excess NADH results in dihydroxyacetone phosphate (DHAP) being converted into glycerol-3-phosphate
- a depletion of NAD+ impairs the ability to oxidize fatty acids into acetyl CoA, therefore an increased number of triglycerides are secreted into plasma or deposited in liver
- can arise from deficiency of vitamin B1 (thiamine) - acute
- C confusion
- O ophthalmoplegia
- A ataxia (difficulty with motor control)
- T thiamine Tx
- can arise from deficiency of vitamin B1 (thiamine) - chronic
- R retrograde amnesia
- A anterograde amnesia
- C confabulation (tall tales)
- K korsakoff's psychosis
methanol metabolism (moonshine)
- can be found in incorrectly made alcoholic beverages & is metabolized by the same enzymes that metabolize ethanol
- however the products of that metabolism is formaldehyde and formic acid which cause metabolic acidosis, neurological problems (eye damage) and death
- metabolism of methanol is slow partly because it's a poorer substrate for the enzymes, so to prevent problems ethanol may be used as an antidote for methanol poisoning
ethylene glycol metabolism (antifreeze)
metabolized to glycoaldehyde by alcohol dehydrogenase and to glycolic acid by aldehyde dehydrogenase; results in severe acidosis that ethanol as a competing substrate can prevent problems
Which enzyme catalyzes the phosphorylation of fructose to fructose-6-phosphate?
What is the reaction catalyzed by fructokinase?
fructose --> fructose-1-phosphate
What is the reaction catalyzed by galactokinase?
galactose --> galactose-1-phosphate