BMB 462 Lecture 14 Outline of Last 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 Outline of Current Lecture I Continuation of the Urea Cycle II Connections between the Urea Cycle and the TCA Cycle III Regulation of the Urea Cycle IV Metabolism of Carbon Skeletons from amino acids V Carbon Transfers VI Phenylalanine Degradation VII The Nitrogen Cycle VIII Nitrogen Fixation Current Lecture Concepts to remembers from previous courses lectures Vitamin B12 function I Continuation of the Urea Cycle a In the last steps of the cycle urea is produced via 2 cleavages The first cleavage produces fumarate and the second gives urea i Start with argininosuccinate Break off four Carbon atoms that originally came as aspartate they get broken off as fumarate ii Cleavage is done by argininosuccinase iii fumarate goes to TCA cycle iv Arginine one of the 20 common Amino Acids but humans don t use it much as a source of Carbon for protein synthesis mostly it is just used for urea cycle Is considered essential because you don t produce enough of it 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 b Arginine goes to cleavage 2 i Cut off 2 nitrogen atoms a carbon and an oxygen for urea the waste ii Regenerate ornithine to act as acceptor for next round of urea cycle iii Cleavage done by arginase II Connections between the Urea Cycle and the TCA Cycle a The 2 cycles can run independently but have important relationships b Oxaloacetate made in TCA cycle add Nitrogen to it amino group to get aspartate i Aspartate is the donor of the 2nd N group in the urea cycle c Fumarate generated from the arginosuccinase reaction in the urea cycle i It is converted to malate which is then converted back to oxaloacetate This results in oxidation of Carbon producing NADH which produces 2 5 ATP equivalents via a redox reaction which allows us to generate ATP by the ETC d Energetics urea requires 4 ATP to make but when you couple it with the TCA cycle oxidation produces 2 5 ATP equivalents III Regulation of the Urea Cycle a Regulation is needed under conditions where you eat excess protein and so have excess Nitrogen or under starvation conditions where you re breaking down muscle mass and therefor have excess Nitrogen that way b Allosteric control of CPSI i Short term control is based on conditions in the particular cell N acetylglutamate is created particularly for regulation it s not an intermediate in any other pathway produced purely for regulatory purposes ii Made from glutamate and acetyl CoA High levels of glutamate is indicative of high levels of N since glutamate is a key N carrier iii Acetylglutamate synthase triggered by arginine makes nacetylglutamate This then allosterically activates carbomyl phosphate synthetase which makes carbamoyl phosphate for the urea cycle c Transcriptional Control of Enzymes i This acts as longer term control based on demand if you eat a big meal with a lot of protein you get more of the enzymes and the urea cycle runs better If there s less protein fewer enzymes are made and therefor the urea cycle doesn t run as much IV Metabolism of Carbon Skeletons from amino acids a Overview i General plan remove nitrogen by transamination convert remaining carbon skeleton into intermediate from TCA cycle so then you can oxidize the Carbons and generate Energy from it b Amino acids are classified by how they re broken down oxidized and whether or not the carbons can be used to make glucose i Ketogenic Amino Acids 1 Only used to make ketones cannot be used to make glucose 2 i e Lysine Leucine 3 Breakdown the amino acids either into acetoacetyl CoA or acetylCoA a Acetoacetyl CoA is a ketone body and acetyl CoA can be made into one ii For acetyl CoA to make glucose the cell needs to take the oxaloacetate and put it through gluconeogenesis If you take the acetyl CoA away from TCA cycle it could not keep running and Energy would not be produced c Glucogenic Amino Acids i i e alanine Carbon is used to make glucose the 13 amino acids that aren t ketogenic or both are glucogenic Amino Acids ii Puts 3 Carbons into pyruvate which will either be used to make oxaloacetate or acetyl CoA One alanine can t do both so it s considered glucogenic d Both Ketogenic and Glucogenic i Carbon from 1 amino acid is used to make both ketone bodies and glucose a ketone body and a glucose ii i e Isoleucine tyrosine phenalalanine tryptophan threonine 1 When phenalalanine is broken down part of the carbons becomes fumarate and part becomes acetoacetate e Know Amino acid ketone pairs i e glutamate and alpha ketoglutarate V Carbon Transfers a Cofactors for One Carbon transfers i The cell needs to rearrange Carbon skeletons to get them to be intermediates in the TCA cycle 1 Not all molecules immediately break down into an intermediate so have to move Carbons around add or subtract them ii These do 1 Carbon transfers iii Activated biotin adds CO2 to some substrate using ATP CO2 is most oxidized form of carbon iv Tetrahydrofolate THF adds Carbons in intermediate oxidation states at either N5 or N10 or both 1 THF picks up the carbon and brings it elsewhere 2 Partially reduced v SAM methyl donor Adds CH3 groups most reduced form of Carbon b Methionine Synthesis and the SAM cycle i 1 THF donates Carbons still donates it in intermediate oxidation state 1 The one exception to that is in making SAM when you donate carbon in the most reduced state ii Add methyl to homocysteine to get methionine Requires coenzyme vitamin b12 iii To move the carbon to somewhere else the cell needs to activate to make transfer more favourable 1 Activate using ATP remove all 3 Phosphate groups and attach adenosine instead of the phosphates to the molecule to activate it iv Activates molecule by producing a sulfonium ion the positive charged sulfur makes the methyl a great leaving group 1 This makes a very high transfer potential so it s very easy to transfer methyl to something else v Next reaction Methyl transferases i e those used in making choline move the methyl group from SAM to the acceptor 1 Now back to s adenosyl homocysteine so the last step is to regenerate the homocysteine receptor a Do this by hydrolyzing off adenosine c Tetrahydrofolate i Donates Carbons in the intermediate oxidation state one
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