Pentose Phosphate Pathway

What is the first reactant of the PPP?

Glucose-6-phoshate

Which two end products of the PPP reconnect with glycolysis as intermediates?

Glyceraldehyde-3-P

Fructose-6-P

Why is the PPP referred to as a shunt?

It creates products that further glycolytic processes

In what kinds of tissues does the oxidative phase of PPP occur?

Rapidly dividing tissues such as

- bone marrow

- skin

- oral and intestinal mucosa

- tumors

What is a requirement of the tissues where oxidative PPP occurs?

Ribose-5-phosphate

Needed for DNA synthesis

In what kinds of tissues do both the oxidative and nonoxidative phases of PPP occur?

1. Tissues that are synthesizing fatty acids, cholesterol, or steroid hormones

2. Tissues that are exposed to high levels of oxygen

Tissues that are synthesizing fatty acids, cholesterol, or steroid hormones

Liver, adipose, lactating, mammary, adrenal cortex, gonads

Tissues that are exposed to high levels of oxygen

Erythrocytes

Cornea & lens

What is a requirement of the tissues where both oxidative and nonoxidative phases of PPP occur?

NADPH

What phase(s) of the PPP does DNA synthesis require?

Oxidative only

How many NADPH are produced from a molecule of glucose-6-P?

2

What is the purpose of cycling the oxidative and non-oxidative phases?

Producing lots of NADPH

What is NADPH used for?

NADPH is a reducing carrier, used for...

1. biosynthetic pathways

2. detoxification

3. reduced glutathione as antioxidant

4. generation of superoxide

What biosynthetic pathways require NADPH?

Fatty acid synthesis

cholesterol synthesis

steroid hormone synthesis

What system is an example of detoxification that uses NADPH?

Cytochrome P-450 in the liver

Characteristics of oxidative phase of PPP

- produce NADPH from 2/4 steps

- irreversible

Characteristics of non-oxidative phases of PPP

- starts with ribose-5-P

- reversible reactions feed to glycolysis or generate hexose-6-P

Which reactions from the PPP produce NADPH?

1. Glucose-6-phosphate dehydrogenase

2. 6-phosphate-gluconate dehydrogenase

1st reaction to make NADPH

Glucose 6-phosphate converted to 6-phosphocucono-delta-lactone

enzyme: Glucose-6-phosphate dehydrogenase

2nd reaction to make NADPH

6-phospho-gluconate converted to D-ribulose 5-phosphate

enzyme: 6-phosphate-gluconate dehydrogenase

What is the rate-limiting step in oxidative PPP?

Glucose-6-phosphate dehydrogenase

also the first step

What kind of regulation does Glucose-6-phosphate dehydrogenase have?

Allosteric;

Feedback inhibition by NADPH

Which molecule can induce Glucose-6-phosphate dehydrogenase?

Insulin

What is a consequence of feedback inhibition in Glucose-6-phosphate dehydrogenase reaction?

Glucose-6-phosphate can proceed to glycolysis and produce ATP

What do free radicals of oxygen do?

Cause oxidative damage to lipids, proteins, and DNA

Damage cell membranes

Hemolysis

Superoxide dismutase (SOD)

an enzyme that destroys superoxide

How are free radicals produced?

1. Cellular respiration

2. External sources (less commonly)

What external sources can create free radicals?

ionizing radiation, sulfa drugs, herbicides, antimalaria, divicine

Catalase and peroxiredoxin 6

Enzymes catalyzing redox reactions to inhibit the negative effects of free radicals

Reduction of glutathione

GSSG -> 2GSH

enzyme: glutathione reductase

Role of 2GSH

Acts as reducing agent to help conversion of hydrogen peroxide to water, catalyzed by glutathione peroxidase

in this reaction, 2GSH is oxidized back to GSSG

Glutathione reductase

Converts Oxidized Glutathione to the reduced form (antioxidant). This REQUIRES NADPH, which is generated from G6PD.

Glutathione is reduced and NADPH is oxidized

What is coupled to glutathione reduction?

Oxidation of NADPH

glutathione peroxidase, catalase, and peroxiredoxin 6

convert peroxide to water and inhibits activity of free radicals

What molecules can form free radicals?

O2-• and H2O2

What two molecules maintained by PPP in the RBC are important for repairing oxidative damage?

NADPH and GSH

Antioxidant Defense enzymes

Superoxidase dismutase

Glutathione peroxidase

Catalase

Peroxiredoxin 6

Glutathione reductase

What amino acids make up GSH?

Glu, Cys, Gly

T/F: GSH can serve as a H+ donor to reduce proteins that have been oxidized

True. This is how it helps to get rid of free radicals

T/F: GSH has normal peptide bonds

False. There is a nonstandard peptide bond between beta-Glu and Cys

What is a negative consequence of autoimmune diseases?

They produce cytokines and free radicals that damage DNA

Role of EGCG (found in green tea) in regulating autoimmunity

Keeps damaged cells from replicating

What exocrine glands have antioxidant enzymes?

Salivary glands and pancreatic glands

How does green tea affect saliva?

Extracts create antioxidants and stimulants to protect the salivary gland, normalize cellular signals, and produce more saliva without negative side effects

What is the key result from Hsu's study about MighTeaFlow?

The green tea formula significantly increased unstimulated saliva flow

What is the effect of MighTeaFlow (green tea) on pH?

Restores pH of salivary glands

What is a way to measure decreased salivary production?

Vertical loss of enamel