BMB 462 Lecture 13 Outline of Last Lecture I. Overview of Cholesterol SynthesisII. Mevalonate pathway for IPP synthesisIII. Regulation of Cholesterol SynthesisIV. Lipoprotein Transport of Cholesterol/LipidsV. Apolipoprotein FunctionOutline of Current Lecture I. Review of cholesterol/lipid transport via lipoproteinsII. Overview of Amino Acid catabolismIII. Ammonia collection in hepatocytesIV. Pyridoxal PhosphateV. Introduction to the Urea CycleCurrent LectureConcepts to remembers from previous courses/lectures:- The Cori CycleI. Review of cholesterol/lipid transport via lipoproteinsa. 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 wastec. 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. ApoB100is 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 blocksII. Overview of Amino Acid catabolisma. Catabolic situationsi. 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/sugarii. Protein turnover - if rate of breakdown exceeds need of materials for biosynthesis then again catabolize extra Amino Acidsiii. 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 foroxidation Energy source.b. General Strategyi. Remove Nitrogen from amino acids and get rid of it using the urea cycle via secretionii. Convert the "Carbon skeletons", the backbones, into intermediates for central metabolism – these feed into the citric acid cycle for oxidation for Energyiii. If you remove nitrogen from an alpha aminoacetate you get an alphaketoacetate.III. Ammonia collection in hepatocytesa. Using Glutamatei. 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 transferaseor transameraseii. 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 e-1. Water breaks off amino group in oxidative deamination 2. Produces ammonia and alphaketoglutarate from glutamateb. Using Glutaminei. 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 attackcarbonii. Glutaminase - Does hydrolysis to:1. Produce Glu and free ammonia2. Brings in water and cleaves off ammoniac. 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 alphaketoglutarateiv. Then alanine amino transferase transfers amino to pyruvate for alanine. In reverse, the regenerated pyruvate goes to create glucose in glycolysisd. Relationship between alpha-keto groups, glutamate, and glutamine - all have the same Carbon backbone, it's the amine groups that differ; the number of nitrogenatomsIV. 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- sinkc. 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 withdecarboxylation (side chain is removed instead of carboxylate group)V. Introduction to the Urea Cyclea. Overview - convert toxic NH4 to urea for excretion (urea consists of almost completely oxidized c aka waste, and the
View Full Document
Unlocking...