Transcript Pentose Phosphate - Michael P. Ready
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