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Glycolysis (Summary (1) The 6C sugar Glucose is broken down to two 3C…
Glycolysis
Summary
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2) 2ATP are used up early on, 4ATP are generated in the later phases. (net gain 2)
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4) 3 steps are essentially irreversible, the majority are reversible
5) ADP, ATP, NAD+ & inorganic phosphate Pi are required for glycolysis to proceed
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Molecules are broken down in stages:
- 1 - Large molecules into smaller ones
- 2 - Small molecules are broken down to simpler compounds that play a key role. Major end product is Acetyl-CoA
- 3 - 2 carbon fragment of Acetyl CoA is oxidised in the Kreb cycle (TCA cycle) during this process
- electron are released from oxidation of acetyl group
- electron transferred via carriers (eg NADH) to the inner mitochondrial membrane
- Electrons passed down the electron transport chain to the final electron acceptor oxygen. Oxygen is reduced to water
- This process will drive the generation of ATP (oxidative phosphorylation)
- Glucose is the central role in metabolism
- Rich in potential energy
- complete oxidation of glucose to carbon diocide and water has delta G = -2840kj/mol (standard free energy change)
- Storing glucose as a high molecular weight polymer (starch or glycogen) a cell can stockpile large quantities of hexose unit while maintaining a relatively low cytosolic osmolarity
- When energy demands suddenly increase, glucose can rapidly released from these storage polymers to produce ATP
- Glycolysis almost a universal central pathway of glucose catabolism
- Sole source of metabolic energy for some tissues like the brain, erythrocytes and some anaerobic microbes
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Sequential enzyme reaction
- Breaks down glucose to two 3 carbon compounds
- Some of released free energy conserved in the form of ATP and NADH
- Phase I - reaction steps 1-5 free energy content of intermediates is raised using ATP
- Phase II - reaction steps 6-10 - the payoff phase - energy is liberated.
- Glucose found in blood
- Breakdown of polysaccharides (glycogen & starch)
- Enters cells cytosol by specific transporter proteins
- Enzymes for glycolysis are located in cytosol
- Other hexose sugars like fructose, mannose, galatose, get converted into intermediates of the glycolytic pathway
Glycolytic Pathway
- 3 steps are irreversible, majority are reversible
- Irreversible steps = key control points
- Reactions will have a negative deltaG change under physiological
- Control points due to the enzymes involved and how regulated:
- Hexokinase - step 1
- Phosphfuctokinase - step 3
- Pyruvate kinase - step 10
Hexokinase
- Glucose + ATP ------> Glucose-6-phosphate + ADP
- Hexokinase is an enzyme which will phosphorylate hexose sugars
- Glucose is the preferred substrate; but it can phosphorylate other hexose sugars - fructose and mannose
- Kinase enzymes add a phosphate group (comes from ATP)
- Muscle hexokinase is allosterically inhibited by its product glucose-6-phosphate (G6P) making it an important control point
- An allosteric inhibitor binds at a site other than the active site
Isoenzymes: Hexokinase and Glucokinase
- Liver cells (hepatocytes) contain a form of hexokinase called glucokinase
- Glucokinase is more specific for glucose and differs in its regulation from hexokinase
- It is an isoenzyme (a different protein that carries out the same reaction) of hexokinase
- Need 2 as muscle and liver cells have different roles; muscles consume glucose and the liver produces it
- Glucokinase Km = 10 mM; Hexokinase Km = 0.1 mM
Phosphofructokinase
- Fructose-6-phosphate + ATP Fructose-1,6-bisphosphate + ADP
- Converts fructose-6-phosphate (F6P) to fructose-1,6-bisphosphate (F1,6P or FBP)
- First irreversible reaction that is unique to glycolysis.
- The commitment step - often an important control point in a pathway
- ATP allosterically inhibit the phosphofructokinase
- A high level of ATP in the cell means the cell does not need any more so glycolysis is slowed down
- Citric acid (intermediate of Krebs cycle) is also an allosteric inhibitor
- The Krebs cycle also provides intermediates for biosynthese. As it is a cycle the overall level of the intermediates is reflected in the level of citrate. If the cell has enough there is no need for anymore citrate and so glycolysis slows down.
Pyruvate kinase
- Phosphoenolpyruvate + ADP Pyruvate + ATP
- Reaction is essentially irreversible; a key control point
- Pyruvate kinase converts phosphoenolpyruvate (PEP) to pyruvate
- Generates second ATP by substrate level phosphorylation
- Glycolysis will produce 2x pyruvate from 1 glucose molecule
- Fate of pyruvate can vary
Catabolism of other sugars
- Glycogen loses glucose residues in the form of glucose-1-phosphate. This is converted to glucose-6-phosphate by phosphoglucomutase
- Other hexose sugars - fructose, mannose, galalctose get converted into intermediates of the glycolytic pathway
- Galactose ends up as glucos-1-phosphate and then glucose-6-phosphate
- Fructose can end up as either fructose-6-phosphate or glyceraldehyde-3-phosphate. Varies by tissues and enzymes
Glycolysis generates pyruvate: Then what?
- Fate of pyruvate depends on presence or absence of oxygen and the type of cell
- Oxygen is present the environmental conditions for the cells are aerobic - cells use the enzyme pyruvate dehydrogenase to convert pyruvate to acetyl-CoA - this happens in the mitochondira.
- Glycolysis can generate 2 molecules of pyruvate (from one glucose molecue) so can generate 2 NADH
- NADH will then be oxidised via the electron transport chain in mitochondria to regenrate NAD+
- Acetyl-CoA can enter the krebs cycle
- If oxygen is absent the environmental conditional for the cell are anaerobic
- Under anaerobic conditions the cells carry out fermentaion
- Oxygen is not present and so cannot act as the final electron acceptor
- Pyruvate acts as an organic electron acceptor
- In muscle cells pyruvate is reduced to lactate
- In yeast pyruvate is reduced to ethanol
- Function of fermentation is to regenerate NAD+ so it can be used again in glycolysis
- If NADH (oxidised form of the electron carrier)(NADH) is not regenerated glycolysis will stop
Gluconeogenesis
- Synthesis of glucose from simpler precursors such as pyruvate or lactate
- Gluconeogenesis occurs in liver and provide glucose for export to other tissues when other sources of glucose are exhausted
- Uses some of the enzymes of glycolysis (the reversible ones)
- Other enzymes used for non-reversible glycolysis reaction steps
Allows control of metabolism
Replacement enzymes for gluconeogenesis
- Pyruvate to phosphoenol pyruvate
- Pyruvate kinase replaced by pyruvate carboxylase (pyruvate to oxaloacetate and phosphoenolprytuvate carboxykinase
- Fructose-1-6-bisphosphate to fructose-6-phosphate:
- Phosphofructokinase replaced by fructose-1,6-bisphosphatase
- Glucose-6-phosphate to glucose
- Hexokinase replaced by glucose-6-phosphatase
Summary
- Glycolysis requires 'energy; initially, will then generate energy
- Glycolysis has a net yield of 2x ATP, 2xNADH and 2X pyruvate
- Many of the enzymes of glycolysis are reversible.
- Some enzymes are not reversible - key control points
- Aerobic conditions allow pyruvate to enter krebs cycle as Acetyl CoA
- Anaerobic conditions pyruvate is fermented to lactate or ethanol to regenerate NAD+ to continue glycolysis
- Gluconeogenesis uses the reversible enzymes of glycolysis and different enzymes for the irreversible/control steps