Pentose Phosphate pathway
What are the two major products generated by the pentose phosphate pathway?
*2 NADPH molecules*, and pentose (5 carbon sugar) from one molecule of glucose
Tansketolase and transaldolase create a reversible link btw the pentose phosphate pathway and glycolysis by catalyzing these 3 successive reactions:
*C5* + *C5* --> C3 + C7 C3 + C7 --> C6 + C4 C4 + *C5* --> *C6* + *C3* (both c6 and c3 are used in glycolysis)
What is the significance of Transketolase and transaldolase?
*Many tissues* such as adipose tissue, the liver, and mammary glands *require* large amounts of *NADPH* for fatty acid synthesis rather than ribose 5-phosphate. In these cases, *ribose 5-phosphate is converted into the glycolytic intermediates* glyceraldehyde 3-phosphate and fructose 6-phosphate by transketolase and transaldolase.
What is the second link between the pentose phosphate pathway and glycolysis?
*Transaldolase* = enzyme Glyceraldehyde 3-phosphate + Sedoheptulose 7-phosphate --> *Fructose 6-phosphate (glycolysis)* + Erythrose 4-phosphate
What is the third link between the pentose phosphate pathway and glycolysis?
*Transketolase* = enzyme Erythrose 4-phosphate + Xylulose 5-phosphate --> *Fructose 6-phosphate (glycolysis)* + *Glyceraldehyde 3-phosphate (glycolysis)*
What is the first link between the pentose phosphate pathway and glycolysis?
*Transketolase* = enzyme Xylulose 5-phosphate + Ribose 5-phosphate --> *Glyceraldehyde 3-phosphate (glycolysis)* + Sedoheptulose 7-phosphate both reactants came from ribulose 5-phosphate
How does Transketolase stabilize carbanionic intermediates (mechanism)?
1. Contains a tightly bound thiamine pyrophosphate as its prosthetic group. 2. the enzyme transfers a two-carbon glycoaldehyde from a ketose donor to a aldose acceptor. 3. the site of the addition of the two-carbon unit is the thiazole ring of TPP.
Synthesis pathways requiring NADPH (created by the pentose phosphate pathway)-4
1. Fatty acid biosynthesis 2. Cholesterol biosynthesis 3. Neurotransmitter biosynthesis 4. Nucleotide biosynthesis (RNA/DNA backbone = Ribose/deoxyribose sugars)
What is occurring in the oxidative phase of the pentose phosphate pathway?
1. Glucose 6-phosphate is oxidized to *ribulose 5-phosphate* 2. *2* molecules of NADPH are generated
What is occurring in step 2 of the conversion of Glucose 6-phosphate to ribulose 5-phosphate? (2 parts)
1. Hydrolysis of 6-phosphoglucono-δ-lactone to 6-phosphogluconate 2. *Enzyme: A specific lactonase*
What are the 2 phases of the pentose phosphate pathway?
1. Oxidation generation of *2* NADPH 2. Non-oxidative interconversion of sugars
Detoxification pathways requiring NADPH (created by the pentose phosphate pathway)-2
1. Reduction of oxidized glutathione 2. Cytochrome P450 monooxygenases
Mode 4: What happens when both NADPH and ATP are required?
1. Ribose 5-phosphate from PPP is converted to pyruvate 2. fructose 6-phosphate and glyceraldehyde 3-phosphate enter the glycolytic pathway. 3. Pyruvate formed by these reactions generates ATP. ATP and NADPH are concomitantly generated
What is occurring in step 3 of the conversion of Glucose 6-phosphate to ribulose 5-phosphate? (3 parts)
1. The six-carbon sugar 6-phosphogluconate is oxidatively decarboxylated to yield ribulose 5-phosphate. NADP+ is again the electron acceptor. 2. Enzyme: 6-phosphogluconate dehydrogenase 3. Generation of 5-carbon compound from 6-carbon compound *Second NADPH screamed in this step*
How does Tranaldolase stabilize carbanionic intermediates (mechanism)?
1. Transfers a three-carbon dihydroxy-acetone unit from a ketose donor to an aldose acceptor. 2. Does not contain a prosthetic group. Rather, a Schiff base is formed between the carbonyl group of the ketose substrate and the ε-amino group of a lysine residue at the active site of the enzyme.
What is occurring in step 1 of the conversion of Glucose 6-phosphate to ribulose 5-phosphate? (4 parts)
1. dehydration of glucose 6-phosphate at carbon 1 2. *Enzyme: Glucose 6-phosphate dehydrogenase* 3. Enzyme is highly specific for NADP+ --> *Creates 1st NADPH molecule* 4. 6-phosphoglucono-δ-lactone is an intramolecular ester between the C-1 carboxyl group and the C-5 hydroxyl group.
What is the net result of the previous catalyzed reactions?
3 C5 --> 2 C6 + C3 -The net result is the formation of two hexoses and one triose from three pentoses.
What is Pamaquine and how is it used?
A. an old malarial drug derived from fava beans, which are consumed in Mediterranean countries is an oxidative agent that leads to the generation of peroxides. B. NADPH supply is reduced in people. C. Free radical toxicity is increased. D. Causes a Pamaquine-induced hemolytic anemia as RBCs do not have oxidative phosphorylation.
Mode 3: What happens when more NADPH than ribose 5-phosphate is required?
Adipose tissue requires a lot of NADPH for fatty acids synthesis. Glucose 6-phosphate is completely oxidized to CO2. 1. PPP forms two molecules of NADPH and one molecule of ribose 5-phosphate. 2. Ribose 5-phosphate is converted into fructose 6-phosphate and glyceraldehyde 3-phosphate. 3. Glucose 6-phosphate is resynthesized from fructose 6- phosphate and glyceraldehyde 3-phosphate by the gluconeogenic pathway. *Thus glucose 6-phosphate is completely oxidized and NADPH is generated*
How is the oxidized glutathione reduced back?
By glutathione reductase, using NADPH
What is the net reaction of stage 1 of the pentose phosphate pathway?
Glucose 6-phosphate + 2 NADP+ + H2O --> *Ribulose 5-phosphate* + *2 NADPH* + CO2
What happens to excess ribose 5-phosphate that is formed by the pentose phosphate pathway?
It can be completely converted into glycolytic intermediates
Mode 1: What happens when more ribose 5-phosphate than NADPH is needed?
Most of the glucose 6-phosphate is converted into fructose 6-phosphate and glyceraldehyde 3-phosphate by the glycolytic pathway. -Tansaldolase and transketolase convert them to ribose 5-phosphate (rapidly dividing cells need ribose 5-phosphate for the synthesis of nucleotide precursors of DNA)
Which way does the pentose phosphate pathway run?
Parallel to glycolysis
What is the evolutionary advantage to glucose 6-phosphate dehydrogenase deficiency?
Parasites causing Falciparum malaria require reduced glutathione for optimal growth. Thus the deficiency in some people is a mechanism of protection against malaria.
Ribulose 5-phosphate to Xylulose 5-phosphate: Enzyme
Phosphopentose epimerase
What enzyme controls the isomerization of ribulose 5-phosphate to ribose 5-phosphate?
Phosphopentose isomerase
Mode 2: What happens with equal needs of NADPH and ribose 5-phosphate are needed?
Predominant reaction under these conditions is the formation of: 1) 2 molecules of NADPH and 2) One molecule of ribose 5-phosphate from one molecule of glucose 6-phosphate
What plays a key role in processing the glucose 6-phosphate partitioned between the glycolytic pathway and the pentose phosphate pathway?
The *cytoplasmic concentration of NADP+* plays a key role in determining the fate of glucose 6-phosphate
What happens to RBC's w/o adequate levels of reduced glutathione?
The hemoglobin sulfhydryl groups can no longer be maintained in the reduced form. Membrane damage occurs in RBCs.
What is the most important regulatory factor of the pentose phosphate pathway?
The level of NADP+ -Low levels of NADP+ reduce the dehydrogenation of glucose 6-phosphate b/c it is needed as the electron acceptor. NADPH competes with NADP+ in binding to the enzyme.
What is the location of the nonoxidative phase of the pentose phosphate pathway?
The reaction take place in the *cytoplasm*
What are pentose phosphate pathway and glycolysis linked by?
Transketolase and transaldolase
Is the pentose phosphate considered primarily anabolic or catabolic?
While is does involve oxidation of glucose, its primary role is *anabolic* rather than catabolic
What does the flow of glucose 6-phosphate depend on? (3 molecules)
it depends on the need for NADPH, ribose 5-phosphate, and ATP
What does the enzyme Glutathione peroxidase do?
it detoxifies hydrogen peroxide (H2O2) into 2H2O and takes 2GSH (reduced glutathione) and forms oxidized glutathione GS-SG (creating a disulfide bridge.
Where is ribose 5-phosphate frequently found?
it is the precursor to many biomolecules including RNA (3 sugars- oxidized), DNA (3 sugars- deoxidized), ATP (1 sugar), NADH, FAD (1 sugar), and Coenzyme A (1 sugar)
