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FA synthesis + PPP
Biochem and medical genetics
| Question | Answer |
|---|---|
| Pentose Phosphate Pathway | Occurs in cytosol 2x irreversible oxidative reactions then series of reversible sugar-phosphate interconversion No ATP directly used Releases CO2 and NADPH NADPH for reductive biosynthesis Pentose sugars for nucleotide biosynthesis |
| Functions of PPP | Synthesis of 5 carbon sugars - biosynthesis of ATP, CoA, DNA, RNA, FAD, NAD Synthesis of NADPH - Antioxidant and lipogenesis |
| Irreversible oxidative reactions of PPP | G-6-P to 6-phosphoglucnolactone by G-6-P dehydrogenase - generates NADPH Then to 6-phosphogluconic acid by 6-PGL hydrolase - requires water Then to Ribulose 5 phosphate by 6-PG dehydrogenase - releases CO2 and NADPH |
| Fate of Ribulose 5-phosphate | Converted to xylulose 5 phosphate by phosphopentose epimerase Converted to ribose 5 phosphate by phosphopentose isomerase These then enter further reversible reactions |
| Non-oxidative reactions of the PPP | X5P + R5P - sedoheptulose 7 phosphate and glyceraldehyde 3 phosphate by transketolase Then to erythrose 4 phosphate and fructose 6 phosphate by transaldolase E4P and X5P then to fructose 6 phosphate and glyceraldehyde 3 phosphate by transketolase |
| Transketolase | Moves 2 carbon units Requires thiamine pyrophosphate as a prosthetic group Similar in structure to E1 subunit of pyruvate dehydrogenase |
| Transaldolase | Moves 3 carbon units Forms a Schiff base between the enzyme and one of the sugars Similar in mechanism to aldolase in glycolysis |
| Regulation of PPP | Oxidative - by Glucose 6 phosphate dehydrogenase - stimulated by NADP+ and inhibited by NADPH Non-oxidative - freely reversible so flux through is controlled by levels of substrates and products - availability of sugars |
| Mode 1 of PPP | Need lots of ribose sugars - RNA production etc G6P through glycolysis to F6P and G3P Transketolase and transaldolase rearrange these to ribose 5 phosphate |
| Mode 2 of PPP | Equal need for NADPH and ribose sugars e.g. rapidly dividing cells for DNA G6P proceeds through oxidative reactions generating NADPH and ribose 5 phosphate |
| Mode 3 of PPP | Need NADPH - FA synthesis G6P through oxidative reactions to form NADPH and R5P Through non oxidative reactions to F6P and G3P Can go into glycolysis to make ATP or return through gluconeogenesis to make G6P for more NADPH - loops through |
| NADPH as an antioxidant | Elevated peroxides and free radicals can damage components of the cell This an be reduced by reduction of peroxides to water via glutathione oxidation NADPH used to power this through glutathione reduction |
| Glucose 6 phosphate dehydrogenase deficiency | Most common human enzyme defect Most people are asymptomatic Presents as drug induced or infection induced acute haemolytic anaemia Haemolysis also seen after ingesting fava beans |
| Why does G6PD deficiency lead to anaemia | Drugs/infection/fava beans lead to oxidative stress Less able to generate NADPH, so cannot overcome oxidative stress RBCs are particularly susceptible as they lack mitochondria so have no other method of NADPH production |
| Why is G6PD deficiency so common | Distribution of sufferers matches very closely with distribution of malaria This may therefore offer a level of protection against malaria |
| Basics of fatty acid synthesis | Excess carbohydrates and protein are converted to lipids for energy storage Incorporates acetyl CoA into FA chain Powered by ATP and NADPH Occurs in cytoplasm Site is species dependent - in liver and lactating mammary gland in humans |
| Fatty acid synthesis vs oxidation | Elongation by malonyl CoA vs degradation to acetyl CoA Intermediates linked to ACP vs CoA Reductant = NADPH vs Oxidants = HAD and FADH Enzymes in one polypeptide chain vs separate enzymes Cytosol vs mitochondria |
| Elongation by Malonyl CoA | Acetyl CoA converted to malonyl CoA by acetyl CoA carboxylase Requires ATP |
| Intermediates linked to ACP | Acyl carrier protein Different binding site but similar linkage to CoA Acetyl CoA - Acetyl ACP by acetyl transacylase Malonyl CoA - Malonyl ACP by malonyl transacylase |
| Chemistry of FAS | Reverse of FAO FAO - oxidation, hydration, oxidation, cleavage FAS - reduction, dehydration, reduction, condensation |
| Reductant use in FAS | NADPH is used At the two reduction steps |
| Mechanism of FAS | Acetyl ACP + malonyl ACP to acetoacetyl ACP by b-ketoacyl-ACP synthase To d-b-hydroxybutyryl ACP by b-ketoacyl ACP reductase To a,b-trans-butenoyl ACP by b-hydroxyacyl ACP dehydratase To butyryl ACP by enoyl-ACP reductase |
| Continuation through synthesis pathway | Growing fatty acid chain goes through synthesis process 7 times, extending by 2 carbons each time At palmitoyl ACP, palmitoyl Thioesterase hydrates this to palmitate |
| Synthesis of other fatty acids | Odd chain - introduction of propionyl ACP not acetyl ACP LCFA - produced by enzymes on cytoplasmic face of SER Unsaturated - ER systems also introduce double bonds into LCFAs |
| Fatty Acid synthase | A multifunctional dimeric enzyme - only functional as the dimer Each FAS monomer has multiple catalytic properties 7 different enzymatic activities and phosphopantetheine binding domain |
| Domain 1 of FAS | Substrate entry domain MAT - malonyl/acetyl transacylase KS - the ketoacyl ACP synthase DH - dehydratase |
| Domain 2 of FAS | Reduction unit ER - enol ACP reductase KR - ketoacyl ACP reductase ACP - acyl carrier protein |
| Domain 3 of FAS | Palmitate release unit TE - thioesterase |
| Takes place in cytosol | Acetyl CoA is in mitochondria and cannot pass through inner membrane Citrate is exported - Acetyl CoA goes through initial TCA cycle Turned back into acetyl CoA by ATP citrate lyase This consumes ATP |
| Production of NADPH by mitochondria | OAA converted to malate by malate dehydrogenase Malate to pyruvate by malic enzyme - this step produces NADPH Pyruvate then converted to acetyl CoA or OAA to be fed into TCA cycle |
| Allosteric regulation of FAS | Acetyl CoA carboxylase Activated by citrate - feed forwards mechanism Inhibited by long chain fatty acyl CoA - feed back mechanism Active in polymer form |
| Intracellular covalent regulation of FAS | Acetyl CoA carboxylase Inactivated by AMPK, which is activated by AMP Signals low energy - dont want to consume energy |
| Hormonal regulation of FAS | Acetyl CoA carboxylase Activated by insulin - protein phosphatase 2A dephosphorylates to activate Inactivated by glucagon and adrenaline - PKA phosphorylates |
| Reciprocal regulation of synthesis and oxidation of FA | Citrate, which activates synthesis also inactivates oxidation Malonyl-CoA inhibits CPT-1 which blocks transfer of FAs into mitochondria, thus inhibiting their oxidation |
| TAG synthesis | FAs primarily stored as TAGs Glycerol backbone with 3 FAs via ester bonds |
| FA esterification | Fatty acyl CoA + G3P - lysophosphatidic acid by G3P acyltransferase To phosphatidic acid by acylG3P acyltransferase To diacylglycerol by phosphatidic acid phosphatase To TAG by diacylglycerol acyltransferase Each step requires fatty acyl CoA |
| Production of glycerol 3 phosphate | Can be synthesised from the glycolytic intermediate DHAP Part of glycerol phosphate shuttle mechanism to get NADH into mitochondria Glycerol from TAG breakdown can be phosphorylated during starvation |
| Transport of TAG | Exported from the liver inside very low density lipoprotein particles These are made of TAGs, cholesterol and proteins Similar to chylomicrons |
| TAGs in adipose tissue | VLDL particles recognised by LPL on luminal surface of endothelial cells in adipose and muscle capillaries Hydrolyses TAG into FA and glycerol Adipose - taken up and re-esterified (insulin) Muscle- FA used in oxidation (glucogon) |
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