S55: Extracting Energy from Fatty Acids and Amino Acids!Catabolism of Fats and Proteins!- Fats and proteins are used to obtain E (derived from TCA cycle, oxidative phosphorylation)!- CAN NOT provide E under anaerobic conditions!- Fatty acids= major source of E, about 40% of overall E needs met by fatty acid oxidation (skeletal m./heart use primarily)!- When fasting: fatty acids from trigly stores= main E source!Fatty Acid Mobilization!- Most come from triglycerides that we ingest or make!- White adipose tissue= store as lipid droplets!- Release from stores req. lipases in lipolysis <-- stimulated by hormones that respond to fasting (ex. glucagon) or stress (ex. epineph)!- Hydrolysis of triglyceride --> glycerol + 3 fatty acids !- Hormonal control of trigly mobilization in adipose!- lipid droplets coated in protein, perilipin, which gets phosphorylated by HSL, which also P-ed two lipases --> lipases are activate andd can access lipid droplet!- Glycerol (the backbone) released during Trigly hydrolysis can enter glycolysis to provide E (after a few steps)!- Steps in Fatty Acid Oxidation!- Uptake of f.a. into cells by difufusion and carrier-med. transport!- Activation by conjugation w/Coenzyme A --> fatty acyl-CoA!- 2 high E bonds from ATP req. to activated fa's for oxidation!- fatty acid + CoA+ ATP ---> (enzyme= acyl-CoA synthetase) fatty acyl-CoA + AMP + Pi!- Transfer into mitochondria thru a carnitine intermediate!- acyl CoA can pass thru other mm, but not inner mitoch. membrane, is transient transfered to carrier molecule= carnitine (semi-essential nutrient)!- acyl-carnitine transfer across the IMM by a transport protein!- inside mitoch., carnitine is removed and CoA added back on to acyl group!- step is E neutral, but the major control point for B oxidation!- Step wise removal of 2-carbon acetyl-CoA units from carboxy-terminal end of fatty acid chains (B-oxidation)!- get 8 acetyl CoA --> TCA cycle (from 16C molecule)!- each rxn catalyzed by enzyme that have overlapping specificities for substrates of differing chain length!- when you transfer e-'s from an alkane -> alkene --> FADH2!- when you oxidixe --> NADH!- What to know about Fatty Acid Oxidation!- FA's have to first be activated by adding coenzyme A before their oxidation, which req. 2 ATPs!- Transport of acyl-CoA into mitoch. matrix occurs as an acyl-carnitine intermediate, highly reg.!- B-oxidation occurs by successive removal of 2-carbon units from the carboxyl end of the fatty acyl-CoA chain w/concurrent oxidation of the B carbon to a carboyxl group!- For each round of B oxidation: 1 acetyl CoA + 1 NADH + 1 FADH2 are formed!- all can provide E thru the TCA and oxidative phosphorylation !- Way more E in palmitate (110 ATPs) than glucose (32 ATPs) because f.a. has more C's and is completely reduced whereas glucose has been oxidized a bit already and fewer C's!- Peroxisomal Oxidation of Fatty Acids - very long chain fa's can't be metabolized by B oxi in mitochondria, have to be oxidized in liver by peroxisomes!- transported into peroxisome by ATP-binding cassette protein!- defects in this transport protein --> adrenoleukodystrophy = accumulation of very long chain fa's in brain and adrenals --> neurodegen and adrenocorticol insufficiency!- oxidation in perox --> acetyl-CoA + octanoyl (C8) CoA --> transported to mitochondria to complete oxidation!- Use of Proteins and Amino Acids as E sources - excess ditary protein --> E utilization or storage pathways!- during periods of long fasting, proteins can be broken down for E!- To use proteins for E, proteins have to be broken down into amino aicds by:!- degradation in the proteosome, degradation in lysosomes, formation of autophagosomes --> lysosomes, hydrolysis by proteases in digestive tract!- problems w/using aa as E sources:!- Humans don't oxidize the NH3+ group of proteins, have to deal w/ammonia accumulation (via formation of urea and excretion in urine)!- specific amino-transfereases for each aa, req. PyrP= pryidoxal phosphate as a cofactor (gets the NH3+ off the aa we want to use)!- no specific pathways for oxidizing aa's exist so aa's have to be converted into metabolic intermediates that can go into glycolysis or the TCA!- in amino acid metabolism we're transferring e's to mobile carriers, just like for all other E nutrients!- Metabolism of Propionyl-CoA!- we get it from the catabolism (breaking down) of isoleucine and valine, metab of fatty acid odd # chains, and fermentation of soluble fiber!- Propionyl-CoA convereted in a 3 step metabolic process to succinyl-CoA (TCA intermediate)!- Rxn can provide substrate for driving gluconeogenesis, yielding E OR as way to replenish C atoms of the TCA (anaplerosis)!- Genetic Disorders of Amino Acid Catabolism!- Maple syrup urine disease= muts in gene for a dehydrogenase req. for breakdown ofbranched-chain aa's (which are essential)!- patients excrete branched a-keto acid and other metabolites --> odor to urine!- ketoacidosis, mental retardation, short life span!- neonatal screening: measuring leucine levels in blood!- treatment by dietary restriction difficult because abnormalities in metab of 3 essential aa's are involved!- Phenylketonuria (PKU)= autosomal recessive mut. in gene for enzyme to convert phenylalanine --> tyrosine!- phenylalanine accumulates --> coverted to other metabolites --> excreted in urine!- accum. of phenyl + metabs --> mental retardation, delayed psychomotor stuff, tremors, seizures!- treatment: diets that restrict intake of phenylalanine!- all infants in US screened for this by testing for elevated phenylalanine in blood!!S56: Energy Storage: Triglyceride Synthesis and Hepatic Steatosis Energy Storage - Humans eat more calories that req. to meet their immediate E needs!- Excess cals stored in specialized forms that can be used during times of E need!- For carbs: principle E storage form= glycogen= polymer of glucose!- For lipids: E stored in triglycerides = triacylglycerols!Triglycerides for E storage - Fatty acids have higher E content (9 kcal/g) than all other metabolic fuels!- Since hydrophobic, triglys don't assoc. w/water so they take less mass to store vs. glycogen that req. more water to store (2.7x its weight)!- Triglys have about 6x the E yield per wet weight of glycogen!- Trigly stores can greatly expand w/caloric intake - Most fatty acids in trigly are C16 or C18 unsat. or monounsat. fatty acids, composition varies on diet!Sources of Triglycerides - Dietary fatty acids: re-esterified
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