Term
| What are the primary functions of the pentose phosphate pathway? |
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Definition
1. Generation of NADPH for reductive biosynthesis
2. Generation of ribose (5-C) sugar for nucleotide synthesis
Also involves:
Interconversion of C3, C4, C5, C6, C7 sugars; connection with glycolysis or gluconeogenesis. (5C sugars are converted to 6C and 3C sugars) |
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Term
| What is the function of NADPH? |
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Definition
| It is an electron (proton) donor in reductive biosynthesis |
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Term
| What is the first phase of the PP pathway? |
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Definition
oxidative phase (non-reversible):
glucose 6-phosphate (6C) is converted to ribulose-5 phosphate (5C), generating two NADPH molecules for each molecule of glucose 6-phosphate oxidized |
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Term
| What is the second phase of the PP pathway? |
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Definition
non-oxidative phase (reversible):
3 ribulose 5-phosphate is converted by a series of rearrangements to produce
2 fructose 6-phosphate + glyceraldehyde 3-phosphate |
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Term
| What is the rate limiting step in the PP pathway? |
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Definition
Glucose 6-phosphate is oxidized to 6-phospho-gluconolactone by glucose 6-phosphate dehydrogenase (G6PD). NADP+ is a cofactor, and NADPH is produced. This is the rate-limiting step for the pentose phosphate pathway
This is the 1st step in the oxidative phase |
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Term
| What reaction in the PP yields ribulose 5-phosphate? |
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Definition
| 6-phosphogluconate is oxidized and decarboxylated by 6-phosphogluconate dehydrogenase, yielding ribulose 5-phosphate. Both NADPH and CO2 are produced |
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Term
| What are the two re-arrangements that ribulose 5-phosphate is subject to? |
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Definition
pentose phosphate isomerase catalyzes rearrangement of ribulose 5-phosphate to form ribose 5-phosphate.
pentose phosphate epimerase catalyzes rearrangement of ribulose 5-phosphate to form xyulose 5-phosphate.
both reactions are reversible |
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Term
| What is the 1st interconversion catalyzed by transketolase? |
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Definition
transketolase catalyzes the transfer of a 2-carbon fragment from xylulose 5-phosphate to ribose 5-phosphate to form glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate.
This enzyme requires thiamine pyrophosphate (TPP) as cofactor - same cofactor as PDH |
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Term
| What role does transaldolase play in the PP pathway? |
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Definition
| Transaldolase catalyzes the transfer of a 3-carbon fragment from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate, thus generating fructose 6-phosphate and erythrose 4-phosphate |
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Term
| What is the 2nd interconversion that transketolase catalyzes? |
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Definition
Transketolase* catalyzes the transfer of a 2-carbon fragment from xylulose 5-phosphate to erythrose 4- phosphate, generating fructose 6-phosphate and glyceraldehyde 3-phosphate.
this step requires TPP as well |
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Term
| What is the net reaction of the non-oxidative phase of the PP? |
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Definition
3 ribulose 5-phosphate ------>
2 fructose 6-phosphate + glyceraldehyde 3-phosphate
3 5C sugars are converted to 2 6C sugars and 1 3C sugar |
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Term
| What is the overall PP reaction? |
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Definition
3 Glucose 6-phosphate + 6 NADP+ + 3 H2O ----->
2 fructose 6-phosphate + glyceraldehyde 3-phosphate + 6 NADPH + 6 H+ + 3CO2 |
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Term
| How is the PP pathway regulated? |
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Definition
Not regulated by hormones – flow thru this path determined by:
Ratio of NADPH to NADP+ - the need for NADPH
Need for ribose 5-phosphate
Lack of hormone regulation makes it different from glycolysis, gluconeogenesis, and glycogen metabolism. |
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Term
| What will happen in the PP pathway if the cell needs ribose 5-phosphate but not NADPH? |
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Definition
fructose 6-phosphate and glyceraldehyde 3-phosphate are diverted from glycolysis, converted to ribose 5-phosphate.
The oxidative phase is skipped because the cell doesn't need NADPH and the non-oxidative phase is run in reverse to generate ribose 5-phosphate |
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Term
| What happens in the PP if the cell needs for NADPH and ribose 5-phosphate are balanced? |
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Definition
oxidative branch and pentose isomerase are active,
little flow through non-oxidative branch.
there is little flow in the non-oxidative branch because ribose 5-phosphate is needed and can't undergo interconversions |
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Term
| What happens in the PP if the cell needs NAPDH but not ribose 5-phosphate? |
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Definition
oxidative and non-oxidative branch make fructose 6-phosphate and glyceraldehyde 3-phosphate, which are converted by gluconeogenesis to glucose 6-phosphate.
The ribose 5-phosphate is not needed so it is used to make products that can be used in gluconeogenesis |
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Term
| What is the importance of PP for RBC's? |
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Definition
The PP pathway generates NADPH
NADPH is necessary for glutathionine reduction.
Reduced glutathione protects cellular proteins from oxidative damage (glutathione peroxidase is used)
NADPH is required for reduction of oxidized glutathione by glutathione reductase
Therefore, deficiency of NADPH in RBCs leads to hemolysis |
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Term
| What does glucose 6-phosphate dehydrogenase deficiency cause? |
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Definition
Reduced activity of G6PD leads to oxidative stress and drug-induced hemolysis (because there is a reduced amount of NADPH)
This is manifested as increased sensitivity to:
- drugs that increase cellular protein oxidation
- many infectious diseases
- fava beans, which contain pro-oxidants (“favism”)
Note there are over 3000 variants of G6PD gene with reduced activity and it is X-linked |
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Term
| Why might Glucose 6-phosphate dehydrogenase deficiency be prevalent in some areas? |
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Definition
The parasite P. falciparum requires a high concentration of reduced glutathione for optimal growth. Thus, persons with low-activity G6PD variants are more resistant to infection with P. falciparum, a fact which may explain higher prevalence of G6PD mutations in tropical regions.
Heterozygote advantage similar to sickle cell and malaria |
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Term
| How does fructose enter the body and get transported into cells? |
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Definition
Fructose is derived from sucrose.
Sucrase breaks down sucrose into glucose and fructose and fructose enters cells through the fructose transporter (GLUT 5) which is expressed in the small intestine, liver, and kidney medulla |
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Term
| Explain fructose phosphorylation |
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Definition
D-Fructose is phosphorylated by fructokinase to generate D-Fructose-1-phosphate
- this enzyme is found primarily in liver, but is also
present in small intestine and kidney medulla
- fructose metabolism is not regulated by insulin |
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Term
| What happens to D-fructose-1-phosphate? |
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Definition
D-Fructose-1-phosphate is cleaved by aldolase B to generate Dihydroxyacetone phosphate (a glycolytic intermediate) and D-glyceraldehyde
- this enzyme is also known as fructose aldolase
- expressed in mammalian liver (cytosol)
D-glyceraldehyde is then phosphorylated by triokinase (kinase is specific for trioses) to form glyceraldehyde 3-phosphate (another glycolytic intermediate)
Fructose can eventually be used in glycolysis or gluconeogenesis but its almost always glycolysis considering fructose is ingested as part of a meal |
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Term
| What is the rate limiting step of fructose metabolism? |
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Definition
The cleavage of D-fructose-1-phosphate by aldolase B is the rate limiting step.
the activity of fructokinase exceeds the activity of aldolase B |
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Term
| What does aldolase B deficiency cause? |
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Definition
Severe aldolase B deficiency = fructose intolerance
- Can lead to intracellular accumulation of fructose-1-phosphate
-this traps Pi as fructose 1-phosphate which can lead to depletion of ATP in the liver cells |
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Term
| How does galactose metabolism work? |
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Definition
Lactose is cleaved by lactase to release galactose and glucose
galactose is phosphorylated by lactokinase to form galactose-1-phosphate
UDP is added to galactose-1-P by galactose-1-P uridyltransferase (UDP-glucose is donor)
UDP-galactose is a substrate for UDP-glucose: galactose 4-epimerase, which regenerates UDP-glucose
glucose-1-phosphate is a substrate for phosphoglucomutase, which yields glucose-6-phosphate
Thus galactose can be used in glycogen synthesis or glycolysis |
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Term
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Definition
results from deficiency of either galactokinase or galactose uridyl transferase
accumulation of galactose-1-P causes liver failure (lack of transferase) - because of the trapped Pi
accumulated galactose (lack of kinase) can be reduced to galactitol, cause cataract formation if severe |
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Term
| How is fructose synthesized in the body? |
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Definition
Through the sorbitol (polyol) pathway
D-glucose converted to D-sorbitol by aldolase reductase. Uses NADPH.
D-sorbitol is converted to D-fructose by sorbitol dehydrogenase and generates NADH
In seminal plasma it serves as the major energy source for spermatozoa. |
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Term
| What is the role of sorbitol in diabetes? |
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Definition
The polyol pathway plays a role in diabetic pathology
Due to induction of aldose reductase by elevated glucose in tissues of diabetic patients, it exceeds the capacity of sorbitol dehydrogenase.
Accumulation of sorbitol crystals in various tissues causes pathology: lens (eye), glomerulus (kidney)
Sorbitol is less soluble than glucose so it precipitates out of cells and can accumulate |
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Term
| What is the glucoronic pathway? |
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Definition
Glucose can be converted to glucoronic acid which is a component of GAG's and proteoglycans.
It also can lead to other things like the PP and most animals (NOT HUMANS) use it (through the gulonic acid intermediate) to make Vitamin C |
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Term
| What is essential pentosuria? |
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Definition
absence of L-xylulose reductase (enzyme 6)
benign condition results in excretion of L-xylulose in urine
formerly misdiagnosed as diabetes in some cases
(“old” test for reducing sugars, “new” test specific for glucose) |
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Term
| How can glucose lead to amino sugars? |
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Definition
Glucose is changed to fructose 6-phosphate.
Glutamine donates an amino group to fructose 6-phosphate and through a series of reactions amino sugars are produced |
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Term
| What are the different fates of glucose? |
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Definition
ribulose 5-phosphate
glycogen
pyruvate
glucuronic acid
UDP-glucosamine
UDP-N-acetylglucosamine |
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Term
| What are the three types of regulation of carbohydrate metabolism? |
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Definition
1) Allosteric modification – ratio [ATP]/[AMP] is critical, and concentration of metabolites such as acetyl CoA and citrate are important - the most rapid form of regulation
2)Covalent modification – kinases and phosphatases modify enzyme activity (hormone-regulated) - slower but more important. PP pathway is the exception because it's not affected by hormones
3)Enzyme synthesis – receptor-mediated hormone-sensitive regulation of mRNA synthesis |
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Term
| What are the two regulatory themes of carbohydrate metabolism? |
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Definition
Coordinate regulation within a pathway (e.g., glycolysis)
Reciprocal regulation of opposing pathways (e.g., glycolysis vs. gluconeogenesis |
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