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Glycolysis
Biochem and medical genetics
| Question | Answer |
|---|---|
| Key points of glycolysis | Glucose is primary fuel for brain, RBCs and renal medulla Anaerobic process 3 stages Occurs in the cytosol Fate of end products depend on cellular conditions Control is mediated by supply and demand Highly conserved occurring in virtually all cells |
| Na independent facilitated diffusion of glucose | Family of 14 Glucose Transporters (GLUT isoforms) Tissue specific Specialised functions |
| Na monosaccharide co-transporter | Sodium Glucose cotransporter (multiple SGLT isoforms) Energy requiring Against concentration gradient Epithelial cells of intestine, renal tubule and choroid plexus |
| Hormones involved in glucose regulation | Glucagon - signals low blood glucose - produced by alpha cells working to increase release of glucose Insulin - signals high blood glucose - produced by beta cells working to increase glucose uptake Adrenaline - fight or flight - uses any nutrients |
| Where does glucose transport occur | Insulin sensitive facilitated transport - most tissue Insulin insensitive active transport - intestine, renal tubules and choroid plexus Insulin insensitive facilitated transport - RBC, WBC, lens, cornea, liver and brain |
| GLUT transporter mechanism | Conformational change on binding to glucose (flipping) Mediated by diffusion gradients |
| Effects of Km | If Km<<[S] then uptake is independent of [S] - e.g. in GLUT3 - in the brain glucose is immediately taken up If Km>[S] then uptake is dependent on [S] - e.g. in GLUT2 - the liver only takes up glucose at high conc |
| Glucose sensing in the liver | Liver plays a key role in buffering glucose Presence of GLUT2 - with a high Km If conc is high - taken up for storage If conc is low - liver doesn't take it up, sparing it for organs that need it |
| Glucose sensing in the pancreas | Plays a key role in regulation of glucose by production of insulin/glucagon Presence of GLUT2 ensures insulin is released when glucose is high Intake of glucose leads to increased ATP - closes K channels leading to opening of Ca channels and exocytosis |
| GLUT4 | The insulin regulated channel Insulin causes translocation of GLUT4 vesicles to the membrane Leads to increased conc of GLUT4 in the membrane |
| Stages of glycolysis | Glucose priming - Glucose to fructose 1,6 bisphosphate Splitting of phosphorylated intermediate - Fructose 1,6 bisphosphate to glyceraldehyde 3 phosphate and dihydroxyacetone phosphate Ox-red phosphorylation - G3P and DHAP to pyruvate |
| Glucose phosphorylation | Glucose is converted into glucose 6 phosphate by hexokinase or glucokinase This uses ATP Locks glucose inside the cell Activates glucose Maintains conc gradient |
| Hexokinase | Most tissues Regulated by G6P Broad substrate specificity Low Km Low Vmax |
| Glucokinase | Liver, pancreatic islets Similar specificity Different regulation High Km High Vmax |
| Phosphorylation of Fructose 6 phosphate | Glucose 6 phosphate is converted to fructose 6 phosphate by phosphoglucose isomerase Phosphofructokinase-1 then converts this to fructose 1,6 bisphosphate This uses ATP This is easier to split into 2x 3 carbon sugars than glucose |
| Splitting of a 6C intermediate to two 3C intermediates | Fructose 1,6 bisphosphate is broken down by aldolase into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate These are interconverted by triose phosphate isomerase |
| Triose phosphate isomerase | Catalytically perfect enzyme At equilibrium 96% of triose phosphate is DHAP TPI deficiency is rare - autosomal recessive Leads to haemolytic anaemia and cardiomyopathy |
| Oxidation of glyceraldehyde 3 phosphate | Conversion of G3P to 1,3 diphosphoglycerate by glyceraldehyde 3-phosphate dehydrogenase is coupled with production of NADH These are then used to synthesis ATP |
| Why is glyceraldehyde 3 phosphate dehydrogenase a 2 step process | This couples a chemically unfavourable reaction with a favourable reaction Oxidation has a negative free energy Acyl phosphate formation has a positive free energy Overall reaction is negative - can be spontaneous |
| Substrate level phosphorylation | 1,3 diphosphoglycerate is converted to 3-phosphoglycerate by phosphoglycerate kinase to produce ATP Phosphoglycerate mutase converts this to 2-phosphoglycerate Enolase converts this to phosphoenolpyruvate Pyruvate kinase forms pyruvate to produce ATP |
| Produces of glycolysis | 2x pyruvate 2x ATP 2x NADH |
| Fate of pyruvate in aerobic conditions | Transported into mitochondria Converted to Acetyl-coA in link reaction Used in TCA cycle Generated NADH and FADH2 used in ETC |
| Fate of pyruvate in anaerobic conditions | Oxidation reduction by pyruvate dehydrogenase to form lactate Used to regenerate NAD to allow glycolysis to continue |
| Cori cycle | Lactate produced in anaerobically respiring cells Exported into blood and carried to liver Liver converts this back to pyruvate Gluconeogenesis converts this back to glucose |
| Pyruvate - transamination | Pyruvate can be converted into alanine by alanine transaminase This converts an alpha amino acid, often glutamate, into an alpha keto acid, often alpha keto glutamate |
| Cahill cycle | Alanine is produced via transamination of pyruvate in cells Transported to liver via blood Converted back into pyruvate Gluconeogenesis reforms glucose Used in transport of ammonia |
| Re-oxidation of cytoplasmic NADH | Inner mitochondrial membrane impermeable to NADH Shuttle mechanisms transfer reducing equivalents across |
| Malate- Aspartate shuffle | An equivalent amount of NADH is formed in the mitochondrial matrix and then re oxidised by Complex 1 Mostly in liver and cardiac cells NADH used to convert oxaloacetate to malate, which in mitochondria reforms oxa... to give NADH. Then forms aspartate |
| Glycerol phosphate shuffle | Cytoplasmic NADH is converted to FADH2 in the inner mitochondrial membrane and electrons passed to QH2 Only 1.5 ATP produced per NADH More rapid Can work against gradients Occurs mostly in muscle |
| Regulation of hexokinase | Inhibited by its product glucose 6 phosphate Lots of glucose into a cell will block activation of further glucose Particularly in muscle |
| Regulation of glucokinase | Activated by insulin and glucose- activates glucokinase binding protein F 6P causes glucokinase to be stored in the nucleus |
| Control of phosphofructokinase | Inhibited by ATP, citrate and H+ Activated by AMP and F2,6BP Useful to control as it is irreversible, consumes energy and is the point of commitment of glucose to respiration |
| Fructose 2,6BP | Formed from fructose 6 phosphate by phosphofructokinase 2 and converted back by fructose bisphosphatase 2 These are bifunctional enzymes - when not phosphorylated acts as PFK2, when phosphorylated acts as PBP2 Phosphorylated by glucagon activating PKA |
| Regulation of pyruvate kinase | Active when non-phosphorylated Phosphorylated by PKA due to cAMP activation by glucagon Dephosphorylated by protein phosphatase Activated by F1,6BP Inhibited by ATP and alanine |
| Fructose metabolism | Can go through normal glucose process as forms fructose 1,6 bis phosphate Can also be converted to fructose 1 phosphate by fructokinase (absence leads to essential fructosuria) This forms glyceraldehyde by aldolase B (hereditary fructose intolerance) |
| Sucrose metabolism | Broken down into glucose and fructose These are metabolised separately |
| Galactose metabolism | Galactokinase converts it into galactose 1 phosphate This is converted to glucose 1 phosphate which feeds in as glucose 6 phosphate This step converts UDP-glucose to UDP-galactose which is used to form glycolipids, glycoproteins and GAGs |
| Lactose metabolism | Broken down into glucose and galactose These are metabolised separately |
| Evidence for glycolysis - Eduard Buchner | Showed that extracts of yeast could ferment sugars Disproved Louis Pasteur's theory that fermentation can only occur in living cells Showed that enzymes are needed, not cells |
| Evidence for glycolysis - Meyerhof and Embden | Meyerhof - Isolated many of the intermediates of the glycolytic pathway from muscle extracts Embden - proposed the steps of the glycolytic pathway |
| The Warburg effect | Cancer cells produce energy from a high rate of glycolysis followed by conversion of pyruvate to lactose instead of oxidative phosphorylation This occurs even in the presence of oxygen - known as aerobic glycolysis Reason behind this is unknown |
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