BBMB 405 1nd Edition Lecture 10 Outline of Last Lecture XIV. Chapter 22: Fatty Acid MetabolismA. The utilization of fatty acids as fuel requires three stages of processingB. Unsaturated and odd-chain fatty acids require additional steps for degradationXV. Handout (1/30)XVI. Handout (2/2)Outline of Current Lecture XIV. Chapter 22: Fatty Acid MetabolismC. Unsaturated and odd-chain fatty acids require additional steps for degradationCurrent LectureXIV. Chapter 22: Fatty Acid MetabolsimC. Unsaturated and odd-chain fatty acids require additional steps for degradation1. An isomerase and a reductase are required for the oxidation of unsaturated fatty acidsThese 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.a.b. Trans-(delta)2-Enoyl CoA: subject to hydration (H2O breaks double bond)c.d. Pathway of oxidation of C18:2e. Difference of ATP production? Don’t need to make the double bond and FADH2 soless ATP production2. Odd-chain fatty acids yield propionyl CoA in the final thiolysis stepa. Propionyl CoA is final product; 3C-CoA is there any value? Yesb. Convert to Succinyl-CoAc. First step: propionyl-CoA carboxylase; second step: racemized; third step: methylmalonyl CoA mutase dependent on Vitamin B12d. Enter TCA cycle at step of succinyl CoA and are either converted to oxaloacetate or glucose in the liver (gluconeogenesis)e. Handout (2/2) Sources of propionate/propionyl-CoAi. Digestive tract- Ruman: about 2kg/day in dairy cow, bacteria make propionate so cow has to remake glucose that it ate- Large intestine: about 5 g/day in adult human- Cecum (between small and large intestine): about 500 g/day in horseii. Cell Metabolism: (methionine, isoleucine, threonine, valine, thymine, uracil, cholesterol tail)  propionyl-CoA  L-Methylmalonyl-CoA + B12  Succinyl-CoAiii. Odd-chain fatty acidsiv. Propionate is of some significancef. Handout (2/2) Methylmalonic aciduriai. Methylmalonic gets in urine and has a negative charge, has to be countered so release Na+ to nutralizeii. Autosomal Recessive disorderiii. Cause:- Mutation in L-methylmalonyl-CoA mutase (B12-requiring enzyme)- Deficiency of Vitamin B12 in diet- Thus, propionyl-CoA  Succinyl-CoA is slow- L-Methylmalonyl-CoA isn’t converted to succinyl-CoA, but is converted to methylmalonic acid and dumped into urineiv. Symptoms:- Failure to thrive, dehydration- Skin lesions- Developmental delay- Lower glomerular filtration ratev. Treatment: if not treated result in death- Limit protein intake (no excess protein so minimize amino acids to propinyl)- Increase carnitine- Hemodialysis if necessary to remove NH3 and metabolic acidosis (liver starts function less and there is more ammonia in blood)3. Vitamin B12 contains a corrin ring and a cobalt atoma. Cobalt atom has different molecules attachedb. Handout (2/2) Vitamin B12i. Required nutrient (1-2 micrograms/day)ii. Only in animal derived foods (beef liver, oyster), not in plantsiii. Synthesized by bacteria in intestinal tract, need Co+iv. Carrier-mediated absorption with aid of R protein and intrinsic factorv. Forms:- 5-deoxyadenosylcobalamin- Methylcobalamin- Hydroxycobalamin (CN- poisoning) Active coenzyme forms- Cyanocabalamin (form in vitamin pills)vi. Pernicious anemiavii. If deficiency, often injected because of poor absorptionviii. Methionine synthesis from homocysteine: homocysteine + MeTHFA  methionine + THFAix. dNDP synthesis in bacteria: NDP + NADPH  dNDP + NADP+4. Mechanism: Methylmalonyl CoA mutase catalyzes a rearrangement to form succinyl CoA (skipped)5. Fatty acids are also oxidized in peroxisomes (normally in mitochondria)a. Handout (2/4) Peroxisomal Oxidation of fatty acidsi. Metabolic function- Chain shortening of very long chain fatty acids, prostaglandins, dicarboxylic acids, and various xenobiotic compounds- Unsaturated fatty acids used also- Major end product is C8 CoA (octanoyl-CoA)ii. Less ATP/fatty acid because FADH2 + e-  O2 via catalase rather than oxidation phosphorylationiii. Questions- Reoxidation of NADH?- Exit of acyl-CoA (usually octanoyl-CoA)- Physiological significance: degradation of very long chain fatty acidb. Handout (2/4) Peroxisomal diseasesi. X linked adrenoleukodystrophy (X-ALD)- Defective intake of fatty acids by peroxisomes (transporter missing)- Very long chain fatty acids (VLCFA) ex C24:0 accumulate in tissues and cause symptomsii. Zellweger syndrome- No peroxisomal enzymes- Accumulation of VLCFA- Death by 6 months of age- No curec. Handout (2/4) Omega and alpha oxidation of fatty acidsi. Omega- oxidation of fatty acids- Happens in endoplasmic recticulum of liver- Could lead to 4 carbons that are glucogenic- Use amount of adipate in urine to measure reaction efficiency/if working properlyii. Alpha- oxidation of fatty acids- Happens in peroxisomes- Used on branched chain fatty acids- If reaction doesn’t happen acid accumulates and causes nerve damage, that is why reaction so important6. Ketone bodies are formed from acetyl CoA when fat breakdown predominates (introduction)a. What if too much FA coming into liver, excess end up as ketone bodies (KB) and dumped into blood streamb. Fatty acid  (irreversible) Pyruvate  glucosec. Ac-CoA d. KB  --TCA cycle 2CO2e. Fatty acid oxidation is incomplete: ketone metabolismf. Anything that produce Ac-CoA is non glucogenicg. Handout (2/4) Major Fates of FA in liverh. FA  FA-CoA  TAG in VLDL (very low density and get out of liver)i. FA-CoA via beta-oxidation  Ac-CoA  KB (when lover overwhelmed) or 2CO2 via TCA cyclej. Ketone bodies: acetoacetate, Beta Hydroxybutyrate (not really ketone), ketone, possibly acetatek. Enzymes of ketogenesis: Thiolase, HMG-CoA synthase, HMG-CoA lyase, BHBA dehydrogenasel. Will continue next