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Lecture

Lecture 24, 31-10-12.doc

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Department
Biochemistry
Course
BIOC 311
Professor
Jean Genest
Semester
Fall

Description
BIOC 311, Lecture 24, 31-10-2012 Ketogenesis - excess a-CoA is converted into acetoacetone, acetone and β-hydroxybutyrate “ketone bodies” - ketone bodies are water soluble Ketolysis - Process by which ketone bodies are converted into E that fuels extrahepatic tissues Ketone Bodies in a Nutshell... Glycolysis FA Oxidation 3 acetyl CoA’s Some Amino Acids HMG-CoA acetyl CoA β-hydroxybutyrate acetoacetate acetone Liver Tissue Peripheral Tissues Blood excreted exhaled by kidneys from lungs Peripheral Tissues β-hydroxybutyrate acetoacetate Peripheral 2 acetyl CoA’s FA Synthesis or TCA Cycle 2 E.A.DENNIS©010 - glycolysis, Fa ox and some aa ox makes a-CoA, which are turned into ketones - a-CoA will accumulate in liver and become HMG-CoA, which will then lose a acetyl-CoA and be coverted into 3 ketone bodies - only liver and kidney can accumulate ketone bodies - acetone is useless - TCA is also somewhere where a-CoA can go - Generation of ketone bodies happens normally at low levels, a-CoA normally shunted into it and its source is glucose Production of ketone bodies is in response to low blood glucose - glucose levels in specific tissue remain constant (brain, RBC) while the rest of the body increase in [ketones] due to lipolysis - FA major source of ketone bodies due to its ox Ketogenic a-CoA from β-oxidation of fatty acid Beta Oxidation In a Nutshell... Fatty Acid One iteration of β-Oxidation: Acyl CoA Make fatty acyl CoA. (1) Step 1: Oxidize the β-carbon (C3) Enoyl CoA (2) Step 2: Hydrate the β-carbon L-hydroxyacyl CoA (3) Step 3: Oxidize the β-carbon, again! Ketoacyl CoA Step 4: Thiolyze α−β bond, releasing acetyl CoA (4) Acyl CoA REPEAT from step 1, w/ 2 fewer carbons (shorter) Acetyl CoA TCACycle E.A.DENNI©2010 - when blood glucose is low, oaa in liver is used for gluconeogenesis - ooa in liver is used to make glucose in the liver, meaning that FA derived A-CoA in the liver cannot be used in the TCA cycle Synthesis of a-CoA - same pathway as cholesterol biosynthesis  biosynth shuts down in starvation  location is diffent (mito vs cyto) - made during starvation  initially feeds other organs so the brain can get all the glucose  after a few weeks, the brain uses ketone bodies too - step 1: thiolase takes two acetoCoA and makes acetoacetyl-CoA - step 2: aa-CoA another a-CoA and water is taken by HMG-CoA synthetase to make 3- hydroxy-3-methylglutaryl CoA - step 3: HMG-CoA lyase forms acetoacetate and a-CoA from HMG β-hydroxybutyrate and acetone - made from D-3-hydroxybutyrate which undergoes dehydrogenation with NAD+ (reversible) Which direction is goes is dependent on amount of NAD+ and NADH - makes acetoacetate, which is unstable and spontaneously decarboxylates into acetone Peripheral use of ketone bodies - acetoacetate is taken by 3-ketoacyl transferase with a succinyl-CoA, this transfers the CoA onto the acetoacetate and makes succinate - one additional C
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