BMB 462 Lecture 13 Outline of Last Lecture I Overview of Cholesterol Synthesis II Mevalonate pathway for IPP synthesis III Regulation of Cholesterol Synthesis IV Lipoprotein Transport of Cholesterol Lipids V Apolipoprotein Function Outline of Current Lecture I Review of cholesterol lipid transport via lipoproteins II Overview of Amino Acid catabolism III Ammonia collection in hepatocytes IV Pyridoxal Phosphate V Introduction to the Urea Cycle Current Lecture Concepts to remembers from previous courses lectures The Cori Cycle I Review of cholesterol lipid transport via lipoproteins a Lipids enter from diet ACAT makes cholesterol esters TAG synthesized i TAG and cholesterol are packaged into chylomicrons which enter circulatory system They pass through extrahepatic tissue ii Lipoprotein lipase activated by APOCII breaks off FA from TAG iii Remnants from chylomicron move into liver so most cholesterol is taken to the liver 1 Liver makes Fatty Acids and packages them as TAGs Cholesterol esters are packaged using ACAT iv TAGs and Cholesterol esters are transported using VLDLS VLDL IDL remnants either go to liver or to receptors in extrahepatic tissue In extrahepatic tissue use APOB100 receptors as LDLs or LDLs go to liver b When working in reverse the cell uses HDLs These notes represent a detailed interpretation of the professor s lecture GradeBuddy is best used as a supplement to your own notes not as a substitute i Take empty HDLs and pick up cargo in extrahepatic Get Fatty Acids from LCAT ii APO A1 packages up cholesterol to take back to liver iii Cholesterol can t be broken down to Energy in the liver so either it is turned into bile salts or it gets removed as waste c LDL is bad cholesterol because it moves excess cholesterol into extrahepatic tissues where it builds up HDL is good because it scavenges remnants and removes them as waste or processes them takes it out of circulation and into liver d LDL Uptake LDL uptake is regulated by receptor mediated endocytosis ApoB100 is a protein on the surface of lipoproteins It s recognized by the LDL receptor i Binding causes endocytosis of LDL in endosome Everything but the LDL receptors is broken down receptors are recycled back to surface ii Cholesterol is stored in cholesterol ester droplets Use ACAT to form the esters for storage The other components i e amino acids are shuttled off for use elsewhere iii Cholesterol could also be used in membrane Cells that use lots of hormones need a lot of cholesterol as building blocks II Overview of Amino Acid catabolism a Catabolic situations i Too much protein in diet and the protein exceeds the ability to break it down there is more uptake than construction of new proteins then body will break down amino acids and get rid of extra nitrogen and oxidize Carbon for Energy or store it as fat sugar ii Protein turnover if rate of breakdown exceeds need of materials for biosynthesis then again catabolize extra Amino Acids iii Starvation Loss of muscles mass though no Energy is stored as protein so during starvation the body will break down muscle for carbon for Energy as well as nitrogen for amino acids Mostly break down oxygen for oxidation Energy source b General Strategy i Remove Nitrogen from amino acids and get rid of it using the urea cycle via secretion ii Convert the Carbon skeletons the backbones into intermediates for central metabolism these feed into the citric acid cycle for oxidation for Energy iii If you remove nitrogen from an alpha aminoacetate you get an alphaketoacetate III Ammonia collection in hepatocytes a Using Glutamate i Transamination take amino group from amino acid and move it to alphaketoglutarate That produces glutamate and alphaketo acid w whatever side chain the amino acid had The enzyme is amino transferase or transamerase ii Glutamate Dehydrogenase used to release free Amino Acids Does oxidation reduction reactions here it allows for amino group to be hydrolyzed off NAD P accepts e1 Water breaks off amino group in oxidative deamination 2 Produces ammonia and alphaketoglutarate from glutamate b Using Glutamine i Glutamine Synthetase Takes glutamate ammonia to give glutamine Glu NH4 Gln 1 Requires ATP purpose is to pick up free nitrogen as ammonia Activate gamma Carbon by attaching Pi from ATP Makes a good leaving group and takes e so that Nitrogen can come in and attack carbon ii Glutaminase Does hydrolysis to 1 Produce Glu and free ammonia 2 Brings in water and cleaves off ammonia c Using Alanine alanine and pyruvate are alphaketo acid amino acid pair i Pyruvate glutamate transfer amino group to get alanine and alphaketoglutarate ii In muscles goes towards alanine in liver goes towards glutamate iii Break it down in glycolysis transfer amino group from protein to alphaketoglutarate iv Then alanine amino transferase transfers amino to pyruvate for alanine In reverse the regenerated pyruvate goes to create glucose in glycolysis d Relationship between alpha keto groups glutamate and glutamine all have the same Carbon backbone it s the amine groups that differ the number of nitrogen atoms IV Pyridoxal Phosphate aka PLP a Cofactor very flexible can participate in many reactions b Facilitates reactions involving alpha beta or gamma carbons of amino acids i Does this by helping during heterolytic cleavage at one of those carbons making a carbanion PLP stabilizes this acting as an e sink c As a transaminase Can go in either direction i Bring in PLP initially attached to enzyme by covalent bond Bond is broken and PLP is attached to initial amino acid through a Schiff base Bring in a general base and remove H which causes a change in shape and alphaketoglutamate breaks off ii Amino Acid 1 leaves as alphaketo acid 1 Alphaketo acid 2 goes back in other direction and picks up amino group to create Amino Acid 2 This is made possible by PLP d Racemization interconverts L and D amino acids e Decarboxylation Remove CO2 via decarboxylation and wind up releasing biological amine PLP stabilizes it through quininoid intermediate f Side chain elimination Same thing could happen with side chain removal as with decarboxylation side chain is removed instead of carboxylate group V Introduction to the Urea Cycle a Overview convert toxic NH4 to urea for excretion urea consists of almost completely oxidized c aka waste and the 2 nitrogen amino groups When breaking down Amino Acids you get too much Nitrogen in the system If it accumulates it could be toxic so need to remove it b Reactions
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