6 shuttles
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The document discusses two shuttles - the malate-aspartate shuttle and glycerol-phosphate shuttle - that balance redox potential between the cytosol and mitochondria during gluconeogenesis. The malate-aspartate shuttle transports metabolites and NADH between compartments, while the glycerol-phosphate shuttle transports only NADH. Both shuttles are required to balance redox states and transport metabolites lacking dedicated transporters between subcellular locations during gluconeogenesis.
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6 shuttles
- 1. Shuttles Balancing the Redox potential between the cytosol and mitochondria • Malate - Aspartate Shuttle • Glycerol-Phosphate-Shuttle 1
- 2. Shuttles • For gluconeogenesis: Metabolites must be transported between cytosol and mitochondria. There is no transporter for OAA. • The redox potential requires balancing between cytosol and mitochondria. Malate-Aspartate Shuttle cytosol pyruvate Mitochondrion pyruvate Malate Malate OAA OAA Aspartate Aspartate Gluconeogenesis Malate-Aspartate Shuttle for 'transport' of NADH and metabolites. Glycerol-3-Phosphate Shuttle for 'transport' of NADH 2
- 3. Glycerol Metabolism H–C = O | C–OH | C–OPO3 C–OH | C–OH | C–OH glycerol GA3P ATP Glycerol kinase TPI ADP C–OH | C=O | C–OPO3 DHAP NADH NAD+ G3P-DH C–OH | C–OH | C–OPO3 G3P Can be used in glycerol-phosphate Shuttle 3
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- 6. Pentose Phosphate Pathway (PPP) or Hexose Monophosphate Shunt 6
- 7. Glucose nucleotide biosynthesis ( se a 6P G l ) er iv G6P R5P Glycogen gly co NADPH Pyruvate Energy Storage lys is Energy Production Generates reducing equivalents for reductive biosynthesis and reduction of glutathione. R5P = ribose-5-phosphate X5P = xylulose-5-phosphate 2 NADP+ 2 NADPH R5P G6P ---> ---> ---> Ribulose-5-Phosphate X5P Reductive portion 7
- 8. Important Facts about the PP-Pathway 1. Generates 2 NADPH for every G6P oxidized. Needed for: • Reductive biosynthesis • Reduction of glutathione 2. It produces R5P for nucleotide synthesis. 3. It produces X5P – an allosteric effector of carbohydrate metabolism. 4. Pathway is not a dead-end. It generates metabolites that can feed back into glycolysis. 5. G6P-DH catalyzes the 1st step: • Inhibited by high NADPH. • Induced in liver by high carb diet. 8
- 9. Importance of Hexose Monophosphate (HMP) Shunt in Red Blood Cells • Role in maintaining viability of red blood cell. • Provides NADPH to protect against oxidative damage. – NADPH is needed for reduction of glutathione. – Glutathione can reduce reactive oxygen species (H2O2, organic peroxides). – Reducing conditions are necessary for keeping Fe+2 in hemoglobin from being oxidized. 9
- 10. Glutathione • A tri-peptide (γ-glutamyl-cysteinylglycine) • Important for destroying harmful oxidants. 2 GSH + R–O–O–R GSSG + R–OH + H2O Glutathion peroxidase 2 GSH GSSG Glutathione reductase NADP+ NADPH + H+ Pentose Phosphate Pathway (G6P-DH) 10
- 11. Glutathione in Red Cell • Helps to maintain sulfhydryl groups of proteins such as hemoglobin. These groups can undergo spontaneous oxidation to disulfides. 2 protein–SH + 1/2 O2 ---> protein–S–S–protein + H2O GSSG 2 GSH Glutathione reductase NADPH NADP+ 11
- 12. Important Facts about the PP-Pathway 1. Generates 2 NADPH for every G6P oxidized. Needed for: • Reductive biosynthesis • Reduction of glutathione 2. It produces R5P for nucleotide synthesis. 3. It produces X5P – an allosteric effector of carbohydrate metabolism. 4. Pathway is not a dead-end. It generates metabolites that can feed back into glycolysis. 5. G6P-DH catalyzes the 1st step: • Inhibited by high NADPH. • Induced in liver by high carb diet. 12
- 13. Role of Metabolites in PPP 2 NADP+ 2 NADPH + CO2 G6P Ribulose-5-P X5P Ribose-5-P F6P + GA3P Intermediates in glycolysis Allosteric activation Nucleotide synthesis + PP2A (phosphoprotein phosphatase 2A) Bifunctional Enz ChREBP (transcription factor) 13
- 14. Remember the BiFunctional Enzyme F6P kinase Ptase BiF-Enz F-2,6BP Allosteric activator PFK-1 Allosteric inhibitor F-1,6BPase 14
- 15. Carbohydrates to Fats ChREBP = Carbohydrate response element binding protein • A transcription factor • Highly expressed in liver, kidney, & adipose tissues. • Inactive state: present in cytosol & specific ser/th sites are phosphorylated. • Activated by dephosphorylation. PP2A = Phosphoprotein phosphatase 2A • Function = it dephosphorylates: – Bifunctional Enzyme – ChREBP • Activated by Xylulose-5-Phosphate (X5P) 15
- 16. ChREBP • When dephosphorylated by PP2A it translocates to nucleus, gets dephosphorylated again, binds DNA, and upregulates transcription of: – pyruvate kinase – acetyl-CoA carboxylase – FA synthase proteins P P P ChREBP ChREBP PP2A cytosol nucleus PP2A ChREBP DNA Response Elements P ChREBP mRNA transcripts 16
- 17. Allosteric Effects of X5P in Liver Glucose G6P NADPH X5P Allosteric activation + PP2A Bifunctional E Which activity? Effect? Activates PFK-2 ↑[F2,6-BP] Activates Glycolysis ChREBP Effects Transcription: • Pyruvate kinase • Acetyl-CoA carboxylase • FA synthase Protein Induction Promotes Carbs ---> Fats 17