L17: Gluconeogenesis/CHO metabolism III Flashcards
Describe the synthesis of lactose.
Describe/Draw the oxidative/non-oxidative phase reactions of the pentose phosphate pathway.
What pentose phosphate pathway deficiency(ies) seen in human? What is/are the clinical presentation(s)?
- Beriberi: result of thiamine deficiency that in addition to affecting PDH and alphaKGDH, also affects the transketolase reactions of the non-oxidative phase of the PPPathway preventing rearrangement of carbon structures and leading to an imbalance in the CHO pool. Prevalent in low income communities, but most especially in alcoholic patients. Alcoholism reduces thiamine uptake and storage.
Why is gluconeogenesis not a reversal of glycolysis? Explain. Explain what reactions occur to circumvent this issue.
- Glycolysis has 3 irreversible reactions: hexokinase, phosphofructokinase 1 and pyruvate kinase. In order for glucose to be synthesized, ie. gluconeogenesis, 4 new enzymes not seen in glycolysis are seen: Pyruvate carboxylase, PEP carboxykinase, Fructose-1,6-bisphosphatase and glucose-6-phosphatase.
How can oxaloacetate initiate gluconeogenesis?
- Malate-oxaloacetate shuttle. Oxaloacetate can be moved from the mitochondria to the cytoplasm via this shuttle and gluconeogenesis can occur.
How do high levels of NADH prevent gluconeogenesis from proceeding?
- Malate-oxaloacetate shuttle. When levels of NADH are high, it will donate its electrons to oxaloacetate to form malate, which moves into mitochondria and reconverts to oxaloacetate and NADH in the matrix. This ensures low oxaloacetate in the cytosol and inhibition of gluconeogenesis.
How does acetyl-CoA affect regulation of gluconeogenesis?
- Acetyl-CoA stimulates pyruvate carboxylase stimulating gluconeogenesis
What pentose phosphate pathway deficiency(ies) are seen in humans? What is/are the clinical presentation(s)?
- G6PD deficiency: defect that lowers the activity of PPPathway and cells have lower NADPH levels. These levels impair glutathione reduction and deprive RBCs of antioxidant protection. Affected pts are very sensitive to hydrogen peroxide, which are produced in infections (by macrophages), by drugs (eg. Primaquine that is used to treat malaria and pneumocystis pneumonia) and during consumption of fava beans (known as favism) as these cause oxidatie stress and trigger hemolytic crisis and hemolytic anemia. Most prevalent in African and Mediterranean Americans. It is x-linked recessive.
Which enzymes of gluconeogenesis are regulated? What factors inhibit and stimulate these enzymes? Which is the main regulated step? Which are reversible/irreversible?
- Pyruvate carboxylase: +: acetyl-CoA; -: insulin - PEP carboxykinase: +: glucagon via cAMP; -: insulin, AMP - Fructose-1,6-bisphosphatase: +: citrate; -: F26BP, AMP (main regulated step) - Glucose-6-phosphatase: +: glucagon; -: insulin
What are the precursors for gluconeogenesis?
- Lactate, - Amino acids - Glycerol
What is the purpose of the pentose phosphate pathway? What are the products from this pathway used for?
- Way for generating pentoses and NADPH - Pentoses are used for synthesis of: DNA, RNA, ATP, NADH, FADH, Coenzyme A - NADPH are used for synthesis of: FAs, cholesterol, NTs, nucleotides and reduction of oxidized glutathione and P450 monooxygenases
Describe/draw the synthesis of glucose from non-CHO precursors (gluconeogenesis).
Do muscles respond to glucagon?
- No
What are the products of the non-oxidative phase of the pentose phosphate pathway? Why are these important?
- 2 F6P and 1 glyceraldehyde-3-phosphate - These are intermediates in the glycolytic / gluconeogenic pathways and can be synthesized from pentoses depending on the need of the cell.
How is the pentose phosphate pathway regulated?
- Glucose-6-Phosphate Dehydrogenase is inhibited by NAPDH. When NADPH is high, G6P can be used elsewhere.
What are the products of the oxidative phase of the pentose phosphate pathway?
- Ribose-5-phosphate, 2 NADPH and CO2
Can glucose be synthesized from fat?
- No. Fatty acid chains do not contribute to glucose synthesis. Glycerol from triglycerides can, but chains cannot.
Explain what reaction(s) the cell can perform when there is a need for NADPH and glucose. ATP is not required.
Briefly explain the role of F26BP in gluconeogenesis and glycolysis.
- High F26BP concentrations: glycolysis is stimulated, gluconeogenesis is inhibited - Low F26BP concentrations: glycolysis is inhibited; gluconeogenesis is stimulated
How does AMP affect regulation of gluconeogenesis?
- AMP stimulates PFK2, causing increased concentrations of F26BP, which causes inhibition of gluconeogenesis
Explain what reaction(s) the cell can perform when there is a need for NADPH and ATP. Ribose is not required.
Explain what reaction(s) the cell can perform when there is a need for both NADPH and ribose. ATP is not required.
Why is gluconeogenesis important?
- To avoid a coma, blood glucose concentrations must be kept constant by coordinating glucose storage, synthesis and degradation. Hypoglycemia during periods of non-eating is not normal. We don’t have to always be eating.
What is the energy difference between the theoretical reversal of glycolysis and gluconeogenesis? Why?
Theoretical reversal of glycolysis would cost 2 ATP, while gluconeogenesis costs 6 ATP. Difference = 4.
Contributing to this difference: Gluconeogenesis requires 4 enzymes not used in glycolysis. The pyruvate carboxylase enzyme uses one ATP – cycles twice = 2. The PEP carboxykinase enzymes uses one GTP – cycles twice = 2. 3PG to 1,3 BPG via phosphoglycerate kinase uses 1 ATP – cycles twice = 2. This accounts for 6 energy equivalents.
Note: F16Bisphosphatase and G6Phosphatase do not give your energy back when they dephosphorylate
