Pentose Phosphate

CH339K

Pentose Phosphate

• • An example of a pathway that can be both: – – Anabolic Generates ribose-5-phosphate for nucleotide synthesis Metabolizes dietary pentoses into glycolytic/gluconeogenic intermediates.

– – – Catabolic Generates reducing power (NADPH) Can completely oxidize glucose Can carry on into glycolysis Aka

Hexose Monophosphate Shunt

NADH vs NADPH

As a general rule of thumb: • NAD + /NADH is used in catabolic processes • NADP + /NADPH is used in anabolic processes

G3P to Glycolysis

Oxidative Phase 1) Lose a carbon 2) Reduce 2 NADP +

lactonase H 2 O

Better Picture 1) H CH 2 OPO 3 -2 O H OH H H H O OH H OH Glucose- 6-phosphate Glucose- 6-Phosphate dehydrogenase H CH 2 OPO 3 -2 O OH H H H O NADP + NADPH, H + H OH O 6-Phosphpgluconolactone 2) H CH 2 OPO 3 -2 O OH H H H O H OH O 6-Phosphpgluconolactone 6-Phosphogluconolactonase H 2 O H + O C OH HC OH H O CH HC OH HC OH CH 2 OPO 3 -2 6-Phosphogluconate 3) O C OH HC OH H O CH HC OH HC OH CH 2 OPO 3 -2 6-Phosphogluconate Phosphogluconate Dehydrogenase NADP + NADPH, H + H 2 C C OH O HC OH HC OH CH 2 OPO 3 -2 + CO 2 Ribulose- 5-phosphate

Glutathione

-SH containing tripeptide Glu-Cys-Gly Amino of Cysteine linked to g -carboxyl of glutamate Commonly used for reducing agent in cells Oxidizes to for disulfide-linked GSSG Rereduced to GSH using NADPH

2 NADP + NADPH + H +

GSH Glutathione Reductase GSSG

Making Glutathione

• For the Reaction to form GSH:

GSSG + 2e NADPH + H + + 2H + GSSG + NADPH + H +

⇄ ⇄ ⇄

2GSH NADP + + 2e 2GSH + NADP + + 2 H + -0.23 V +0.32 V +0.09 V

We can figure out D G o redox reactions from what we learned about o' -1 -1 -1

For what it’s worth…

Divicine

is found in fava beans and some other legumes Favas (broad beans) are common foodstuffs in the old world.

Largest production in Europe and China.

The parent plant,

Vicia faba

, is among the oldest cultivated plants ~6,000 years.

Glucose-6-P Dehydrogenase Deficiency

• Effects ~ 4*10 8 people worldwide • Most common human genetic disease • X-linked • Lack of G-6PD means lack of NADPH • Lack of NADPH means lack of GSH • Lack of GSH means excess of peroxides • RBC membranes particularly susceptible to peroxides • Hemolytic Anemia

Glucose-6-Phosphate Dehydrogenase Deficiency

Cappellini, M.D., and Fiorelli, G. (2008) Glucose-6-phosphate dehydrogenase deficiency, Lancet 371 : 64-74.

Harmful Agents for G6PDD Sufferers

Antimalarials

Primaquine Pamaquine Chloroquine

Analgesics

Aspirin Bufferin Anacin Excedrin Empirin APC Tablets Darvon Compound Coricidin

Antibiotics

Sulfanilamide Sulfapyridine Sulfadimidine Sulfacetamide Glucosulfone sodium Nitrofurantoin Furazolidone Nitrofurazone Dapsone Sulfoxone Sulfisoxazole

Anthelmintics

B-Naphthol Stibophen Niridazole

Miscellaneous

Probenecid Thiazide Diuretics Phenothiazine Chloramphenicol Orinase Dimercaprol Methylene blue Naphthalene (moth balls) Vitamin K Fava beans

G3P to Glycolysis

Non-oxidative phase H 2 C C OH O HC OH HC OH CH 2 OPO 3 -2 Ribulose- 5-phosphate H 2 C C OH O H O CH HC OH Epimerase CH 2 OPO 3 -2 Xylulose- 5-Phosphate + Isomerase HC O HC OH HC OH HC OH CH 2 OPO 3 -2 Ribose- 5-Phosphate Transketolase H 2 C OH C O H O CH HC HC OH OH HC OH CH 2 OPO 3 -2 Sedoheptulose- 7-Phosphate O CH HC OH CH 2 OPO 3 -2 Glyceraldehyde- 3-Phosphate HC OH HC OH HC OH CH 2 OPO 3 -2 Erythrose- 4-Phosphate O CH HC OH CH 2 OPO 3 -2 Glyceraldehyde- 3-Phosphate Transketolase H 2 C OH C O H O CH HC OH HC CH 3 OH Fructose- 6-Phosphate Transaldolase H 2 C OH C O H O CH HC OH HC OH CH 2 OPO 3 -2 Fructose- 6-Phosphate

Ribulose can be used to make ribose • enediol intermediate

phosphopentose isomerase

Transketolase moves 2-carbon units

Transaldolase moves 3-carbon units

Lack of transketolase can cause hepatosplenomegaly and liver cirrhosis in childhood.

Verhoeven, N. M. et al (2001) Transaldolase Deficiency: Liver Cirrhosis Associated with a New Inborn Error in the Pentose Phosphate Pathway ,

Amer. J. Hum. Gen

.

68

(5): 1086-1092.

Transketolase uses a TPP cofactor 1.

2.

Transaldolase forms a protonated Schiff base

Control

• Conversion of glucose-6-Pi to the lactone is essentially irreversible. • The enzyme, glucose-6-phosphate dehydrogenase, controls the rate of the pathway. – NADPH competes with NADP for binding in he active site; – ATP competes with glucose-6-phosphate. • At high [NADPH] and/or high [ATP], entrance into the pathway is restricted.

Multiple Functions of Pentose Phosphate Pathway

Products in the pathway can be withdrawn at several points