Fructose, Galactose, and Pentose Posphate Lecture Sep 18 Flashcards
What are the dietary sources of fructose?
Main source is from fruit, although it’s indirect–fruit contains sucrose which is a dissacharide of glucose and fructose.
We can get direct fructose form honey and high fructose corn syrup
What pathway will synthesize fructose int he body?
Where does it happen?
What does it use?
The polyol pathway will take glucose and make fructose.
This occurs in seminal vesicles for sperm production and within the eye.
What enzyme will cleave sucrose into glucose and fructose?
Sucrase
(also called isolmaltase)
How can the polyol pathway lead to pathology in the eye?
Cataracts:
In cases of uncontrolled diabetes (hyperglycemia), the polyol pathway can lead to elevated sorbitol and fructose levels in the eye. This leads to water influx and high fluid pressure.
The excess sugar also results in non-enymatic glycosylation of lens proteins. The high pressure and glycolsylated lens proteins make an opaque spot on the lens.
Where is fructose primarily metabolized?
How does it get into the cell?
Fructose is primarily metabolized in the liver
It enters the hepatocyte through GLUT V receptors (which are symporters with Na+)
What is the first step in fructose metabolism? WHat enzyme does it?
Fructose is phosphorylated by fructokinase to yield fructose 1-phosphate.
This traps the fructose in the cell.
Why is fructose metabolism mainly in the liver?
THe liver is the only tissue that expresses aldolase B.
Aldolase in the res tof the body works on fructose 1,69bisphosphate
Only aldolase B can act on fructose 1 phosphate, which is the substrate we have in fructose metabolism.
What does aldolase B cleave frustose 1 phosphate into?
dihydroxyacetone phosphate
and
glyceraldehyde (which can then be converted to glyceraldehyde 3 phosphate)
What enzyme will convert the glyceraldehyde produces by aldolase into glyceraldehyde 3 phosphate (which is what we want)?
triose kinase
What can the glyceraldehyde 3 phosphate be used for?
What is it usually used for?
It can enter glycolysis to create pyruvate that can enter the TCA cycle to be oxidized (or generate intermediates for fatty acid sythesis)
Or it can enter the gluconeogenesis/glycogenesis pathway.
Since fructose levels are high in the fed state only (hardly any fructose is synthesized in the body), it usually enters the glyconeogenesis/glycogenesis pathway.
It’s converted to glucose 6 phosphate which can be used to make glucose or further worked on to make glycogen.
If the glyceraldehyde 3 phosphate from fructose metabolism enters glycolysis, what important regulatory step is bypassed?
Phosphofructokinase 1
(inhiibited by ATP and citrate: excess energy to work)
(activated by AMP and fructose 2,6 bisphosphate: excess work to fuel)
Even if the glyceraldehyde 3 phosphate from fructose metabolism enters glycolysis instead of gluconeogenesis/glycogenesis, there is still a way for it to be stored instead of burned in the TCA. How is it stored?
THe citrate is diverted out for fatty acid synthesis
EVen though fructose is mainly metabolized in the liver, some of it can be metabolized in other tissues. How is this possible when none of the other tissues have aldolase B?
Hexokinase (which usually acts on glucose) can also act on fructose at a slower rate. This causes the phosphorylation of fructose to fructose 6 phosphate.
THis can either enter glycolysis (in which it DOES NOT bypass the PFK regulatory step) or glycogenogenesis
What causes essential fructosuria?
What are the symptoms?
prognosis?
A mutation in fructokinase results in the inability to ocnvert frutose to fructose 1 phosphate.
This causes a buildup of fructose which is excreted in the urine - fructosuria.
THis is benign - people won’t even knwow they have it unless they have a positive reducing sugar test for diabetes. The glucose specific test will then be negative.
What results from an aldolase B deficiency?
What are the symptoms?
Prognosis?
Treatment?
Hereditary fructose intolerance
This means you can’t convert fructose 1 phosphate into DHAP or G3P.
THe frustose 1 phosphate therefore has no metabolic fat and it accumulate in the liver.
THe bigger issue is that all the phosphate in the liver then gets traped as fructose 1 phosphate! But we need phosphate groups for almost every process! So the condition is quite serious.
It can be asymptomatic until fructose is ingested and if untreated it will cuase recurrent hypolgycemia episodes, FTT and heaptic failure.
Treat by avoiding fructose.
What is the primary dietary souce of galactose?
It’s from the dissacharide lactose (milk sugar) which is galactose and glucose.
What enzyme is used to cleave lactose into galactose and glucose?
lactase
where does galactose metabolism mainly occur?
the liver
Lactase deficiency or lactose intolerance comes in three forms. What are they?
Primary lactase deficiency - an autosomal recessive condition in which lactase activity declines over many years, usually beginning in acolescence. THis is the most common.
Secondary lactase deficiency i due to damage of brush border of intestinal anterocytes due to intestinal disease.
Congeintal lactase deficiency, a very rare genetic conditions, is the complete abscence of lactase
What is the first step in galactose metabolism?
Galactokinase phosphorylates galactose to galactose 1 phosphate to trap it in the cell.
Which enzyme works on galactose 1 phosphate?
WHat is the produce?
Galactose 1 phosphate uridyl transferase
It takes the UDP off UDP-Glucose and adds it to galactose, making UDP galactose
What enzyme will interconvert UDP-galactose and UDP-glucose?
epimerase
What is the end produce of galactose metabolism?
Glucose 1-phosphate for glycogenesis or gycolysis
What causes nonclassical galactosemia?
symptoms?
treatment?
A galactokinase deficiency
You can’t convert galactose to galactose 1-phosphate
The galactose accumulates and is then converted to galactitol through the polyol pathway
This causes cataracts
The treatment is to eliminate lactose form the diet
good prognosis
WHat causes classical galactosemia?
This is a galactose 1-phosphate uridyl transferase deficiency
This means that the conversion of galactose 1-phosphate to UDP galactose cannot occur. This is similar to the hereditary fructose intolerance in that all the phosphate in the liver gets stuck as galactose 1 phosphate and you have major issues.
It’s autosomal recessive and VERY serious
Early onset (1-2 weeks) of jaundice, hepatomegaly, hypoglycemia, lethargy, and FTT
Treatment: try to eliminate galactose from the diet; prognosis is poor.
What results from an epimerase deficiency?
It comes in two forms:
The benign form affects only leukocytes and erythrocytes and is not that awful
The serious form affects all tissues and has syptoms similar to transferase deficiency/classical galactosemia.
You get a buildup of UDP galactose which pushes back to lead to an increase in galactose 1 phosphate, again trapping the liver’s phosphate.
The treatment for this is a galactose restricted diet.
Why is classical galactossemia treated with an elimination of galactose form the diet, while epimirase deficiency is treated with a reduction in diet galactose?
In transferase deficiency, any dietary galactose that comes in will result in phosphate trapping, but the body will still be able to synthesize some galactose by the interconversion of UDP glucose with epiminerase to form UDP galactose.
In epimerase deficiency, the body can’t do the comversion from UDP glucose to UDP galactose, so the only way you can get UDP galactose is thorugh DIETARY galactose. So you still need to eat some of it - just not soo much that it builds up and pushes back into galactose 1 phosphate.
What percentage of the body’s glucose is metabolized throuh the pentose phosphate pathway?
10%
What are the two main purposes of the pentose phosphate pathway?
generates NADPH to provide reducing power for a number of reactions in the body
Generation of 5 carbon sugars for the synthesis of nucleotides
What is the reducing power of NADPH used for in the body?
Biosynthesis/detoxification:
fatty acid synthesis
cholesterol synthesis
nucleotide synthesis
oxidation of toxins by Cyt P450 enzymes
regeneration of reduced glutathione
In what tissues is the pentose phosphate pathways very active?
liver
adipose
lactating mammary gland
adrenal cortex
RBCs
What are the two phases of the PPP?
Which phase is reversible?
The oxidative phase (converts glucose to ribulose 5 phosphate and generates NADPH - NOT reversible)
THe regenerative phase: (converts ribulos 5 phosphate to the glycolysis intermediates fructose 6 phosphate and glyceraldehyde 3 phosphate. This IS reveresible - the glycolysis intermediates can then be used to regenerate 5 carbon sugars for nucleotide synthesis.
What are the two key enzymes of the regenerative phase in the PPP?
transketolase
transaldolase
What is the key metabolic regulator of the PPP?
xylulose 5 phosphate
What are the three steps of the oxidative phase of the PPP?
- glucose 6 phosphate is acted on by G6P dehydrogenase to give 6-phosphoglucano delta-lactone (reducing NADP to NADPH)
- 6 phosphoglucano delta-lactone is acted on by gluconolactonase to form the linear version = 6 phosphogluconate
- 6 phosphogluconate is aced on by 6-phosphogluconate dehydrogenase to oxidize and decarboxylate it to form ribulose 5 phosphate (a 5 carbon sugar with a phosphate group). This reduces another NADP to NADPH
So you start with a 6 carbon sugar, you get a a 5 carbon sugar and two reduced NADPH.
WHat comprises glutathione?
What is glutathione important for?
What form does glutathione need to be in in order to carry out this function?
What is required to keep glutathione in that form?
Glutathione is a tripeptide of glutamic acid, cytsein and glycine (with glutamic acid bound in an atypical peptide bond through glutamid acid’s side chain and cystein’s amine)
It’s role is to neutralize free radicals sot hey do not damage the cell. It especially takes care of hydrogen peroxide
glutathione can either be dimerized through a disulfide bond GS-SG, or in the reduced, unbound form or GSH.
In order to neutralize free radicals, it needs to be able to accept electrons so the unbound, reduced GSH is required.
NADPH’s reducing power is used to maintain glutathione in a reduced state so that it can remove hydrogen peroside from the cell
How is bound GS-SG reduced to 2 GSH?
Through the enzyme glutathione reductase, which uses NADPH as a cofactor
Through what reaction does GSH take care of H2O2?
WHy is this so important for the body?
Through glutahione peroxidase.
This is very important because hydrogen peroxide can dissociate to form the hydroxyl radical, which is the worse one to have in the cell in terms of its ability to cause damage to DNA and proteins
What results from glucose 6 phosphate dehydrogenae deficiency?
When does it manifest?
What are the symptoms?
With G6P dehydrogenase deficiency (favism), you do not have a functional PPP, thus you don’t generate NADPH for biosynthesis, detoxification, or oxidative protection.
THe enzyme is not completely inactive, so patients will still be able to produce NADPH to maintain GSH in the reduced form to some extent, but if they are suddenly put in conditions of high oxodative stress, they will not be able to keep enough GSH int he reduced form and the oxidative stress on their RBCs in particular results in hemolysis and hemolytic anemia.
Men with this condition are typically asymptomatic until they are put on anything that will cause high oxidative stress, such as xenobiotics, sulfa drugs, fava beens, nalidixic acid, TNT, primaquine, methylene blue
What are the functions of transketolase and transaldolase?
transketolase transfers two carbon groups.
transaldolase transfers 3 carbon groups.
THe goal of these reactions is to allow the 5 carbon sugar to be turned into glcolysis intermediates in situations when nucleotide synthesis not requires (needs to turn the 5 C into either a 6C or 3C molecule)
WHen nucleotide synthesis is required, the reverse reactions convert the glycolysis intermediates into fie carbon sugars.
What two things can happen to rubulose 5 phosphate after the oxidative phase of the PPP?
It can either be isomerized into ribose 5-phosphate for nucleotide synhtesis
or it can be epimerized to xylulose 5 phosphate, which is a transcriptional regulator
What are the two fates of xyluluose 5 phsophate?
It can either be acted on by transaldolase and transketolase for glycolytic intermediates. OR it can act as a transcription regulator.
How does X5P act as a transcripition regulator?
It acts indirectly on the charbohydrate response element binding protein (ChREBP), which is a transcription factor
ChREBP is inhibited by phosphorylation through PKA and AMPK and activated by by Phosphatase 2A, which removes the phosphate groups.
X5P allosterically activates PP2A.
Once ChREBP is dephosphorylated, it will translocate ot the nucleus and influence gene transcription.
Specifically, it turns on transcription of genes that are involved in the storage of sugar as fat.
WHat genes are upregulated by ChREBP?
genes involved in the storage of sugar as fats in the body
pyruvate kinase
malic enzyme
citrate lyase
acetyl CoA carboxylase
fatty acid synthase
