CFB 10: Pentose Phosphates

What is the pentose phosphate shunt?

Alternate pathway of glucose catabolism that also

is involved in the biosynthesis of pentose sugars (especially ribose) and NADPH2 through

the production of ribulose 5-P.

Ribulose 5-P is converted to ribose 5-P and other phosphorylated carbohydrates

What are the aliases of the pentose phosphate shunt?

Hexose monophosphate shunt

Phosphogluconate pathway

Why is it a shunt?

Because it starts with a glycolytic intermediate and can end with the production of other glycolytic intermediates

2 important products of the pentose phosphate pathway

Ribose-5-phosphate

NADPH

What is needed for nucleotide synthesis?

Ribose-5-phosphate

What is needed to reduce glutathione to synthesize fatty acids, NO, and steroids/sterols, to detoxify drugs, and is part of the respiratory burst?

NADPH

Pentose phosphate pathway accounts for what % of liver glucose metabolism?

5-10%

More in adipocytes

What does the first oxidative portion of the shunt produce? While converting what?

2 NADPHs while converting G6P to the pentose ribulose-5-phosphate and CO2

What is the first enzyme of the pentose phosphate pathway?

Glucose-6-phosphate dehydrogenase

What is the key regulated step of the pentose phosphate pathway?

Glucose-6-phosphate dehydrogenase

What does oxidative decarboxylation produce?

Another NADPH, a pentose, and CO2

NADP/NAPDH uses the same chemistry as NAD+/NADPH, but in the opposite ________.

Opposite polarity (i.e. reduction reactions)

Is there more NADPH or NADP?

NADPH

Is there more NADH or NAD+?

NAD+

T/F: The phosphate provides a "handle" to allow enzymes to select the coenzyme and functions in the chemistry.

False; does NOT function in the chemistry

What is the NADPH-mediated reaction in fatty acid synthesis?

Uses for NADPH: synthesis

Fatty acid synthesis

Cholesterol synthesis

Neurotransmitter synthesis

Nucleotide synthesis

Uses for NADPH: detoxification

Reduction of oxidized glutathione

Cytochrome P450 monooxygenases

What happens to pentoses in the second, non-oxidative phase?

Pentoses are interconverted

What happens to carbon skeletons in the second, non-oxidative phase?

Carbon skeletons rearranged

What transfers 2 carbon units using thiamine?

Transketolase

What is the disease associated with a thiamine deficiency?

Wernicke-Korsakoff (alcohol abuse)

Wet or dry beriberi (neurological or bodily)

What transfers 3 carbon units?

Transaldolase

What reaction does transketolase do first?

Xylulose 5-P + Ribose 5-P →Sedoheptulose 7-P + Glyceraldehyde 3-P

What reaction does transaldolase do?

Sedoheptulose 7-P + Glyceraldehyde 3-P → Erythrose 4-P + Fructose 6-P

What reaction does transketolase do second?

Xylulose 5-P + Erythrose 4-P → Glyceraldehyde 3-P + Fructose 6-P

Reversible interconversion of Pentose-P and glycolytic intermediates:

3 Pentose-P → 1 Triose-P + 2 Hexose-P

What are the different modes of the pentose phosphate pathway?

NADPH ~ Ribose

Ribose > NADPH

NADPH > Ribose

When is the ribose > NADPH mode used?

When nucleotides, but not NADPH are needed

No oxidation

When is NADPH > ribose mode used?

Dump ribose back to glycolysis

The non-oxidate portion of the pentose phosphate shunt:

Can lead to synthesis of pentose phosphates from glycolytic intermediates

3 multiple choice options

What is the rate-limiting step of the pentose phosphate shunt?

Glucose-6-phosphate dehydrogenase

What does G6P Dehydrogenase catalyze?

G6P → Phosphogluconolactone

G6P dehydrogenase is inducible by _______.

Insulin

Allosteric feedback of G6P Dehydrogenase is inhibited by _____.

NADPH

What is the coenzyme of G6P Dehydrogenase reaction?

NADP+

What inhibits the G6P Dehydrogenase reaction?

NADPH

How does the actual V compare with the potential Vmax?

1% of actual activity

Highly restricted

What reaction does 6-P Gluconate Dehydrogenase do?

6-P Gluconate → Ribulose 5-P + CO2

What enzyme is active in many cancers and may be important for some T cells?

6-P Gluconate Dehydrogenase

When is oxygen bad for you?

Hydroxyl radical is very active; can damage DNA and RNA

The _________ of oxygen yields highly reactive speies.

Reduction

What can O2- produce?

H2O2

What can O2- and H2O2 produce?

Hydroxyl radicals

What is the Haber-Weiss Reaction?

Production of hydroxyl radical, water, and oxygen from hydrogen peroxide and superoxide

What is the Fenton Reaction?

Production of hydroxyl radical and hydroxyl ion from hydrogen peroxide with the oxidation of ferrous (II) ion

Iron of hemoglobin and O2 react to give...

Superoxide

When is generation of radicals good?

"Respiratory burst" in neutrophils

What is defective in Chronic Granulomatous Disease (CGD)?

Respiratory burst

Injury of what is thought to be important in many disease states?

Atherogenesis (oxidation of LDL)

Ischemia/reperfusion injury

Alcoholism

Neurodegenerative disease (ALS)

Acute renal failure

Emphysema

Free radical injury

What can inactivate radicals?

Antioxidants

Vitamins A, C, and E

What converts superoxide to hydrogen peroxide for protection from radicals?

Superoxide dismutase (SOD)

What is required for the reduction of peroxides by peroxidase?

Glutathione (GSH)

What maintains the supply of reduced glutathione needed to destroy peroxide?

NADPH produced by G6P Dehydrogenase

What is responsible for maintaining the intracellular environment in a reduced state so that disulfide bonds in proteins stay reduced?

Glutathione

What is the most reactive oxygen species?

Hydroxyl radical

Which of the following enzymes used NADPH as the coenzyme?

Glutathione reductase

3 multiple choice options

What is characterized by "Heinz bodies" in RBCs when the cells are exposed to an oxidizing chemical in vitro?

G6PDH deficiency

What are immature RBCs that are usually 1% of circulating RBCs?

Reticulocytes

What is an elevation of reticulocytes indicating active erythropoiesis in bone marrow?

Reticulocytosis

What does G6PD deficiency track with?

Malaria and sickle cell

What do these drugs/foods cause?

Sulfonamides

Aspirin

Quinadine and quinine

Napthylene (mothballs)

Fava beans

Hemolytic anemia

You are doing a substantial procedure on a patient. Out of concern for infection, you prescribe prophylactic antibiotics. Two days later, the patient calls complaining that his urine has turned a very dark color. What is going on?

G6P Dehydrogenase deficiency

In G6P dehydrogenase deficiency, what change from normal in red blood cells leads to hemolytic anemia?

Decreased concentrations of NADPH

Why are red cells particularly sensitive to oxidative damage?

Other cells have alternative pathways to produce NADPH, for example malic enzyme (malate dehydrogenase)

Red cells don't do this but other cells in the body do!

The pentose phosphate shunt produces _________________ used for nucleotide synthesis and _____ used in reductive biosynthesis.

Ribose-5-phosphate for nucleotide synthesis

NADPH for reductive biosynthesis

Why is NADPH>>NADP and NAD+>>NADH in oxidative reactions?

Since NADPH is mostly used for biological reduction

What does the pentose phosphate shunt start with?

Oxidative portion that generates NADPH, CO2 and pentose phosphate

What is the major regulatory point?

G6P dehydrogenase (first PPS enzyme)

Deficiencies in G6PDH are _-linked. How may unsuspected deficiency manifest?

X-linked

Anemia after oxidative challenge

What does the non-oxidative part of the shunt interconvert?

Pentoses (ribose-5-P) and converts them to glycolytic intermediates by transketolase (2 carbon transfer) and transketolase (3 carbon transfer) activity

The pentose phosphate pathway can make ribose directly from what?

Glycolytic intermediates without oxidation

What is reduced to water in single electron steps?

Molecular oxygen

What reactive intermediates are formed?

Superoxide, peroxides, and hydroxyl radicals

What can the reactive intermediates be used to do?

Inactivate pathogens

T/F: All intermediates cause tissue damage.

True

Formation of atherosclerotic plaques

What reduces superoxide to peroxide?

Superoxide dismutase (SOD)

What reduces peroxide to water and oxidizes glutathione?

Glutathione peroxidase (contains selenium)

What uses NADPH to regenerate reduced glutathione needed by glutathione peroxidase?

Glutathione reductase