Fatty Acids, Ketones B&B Flashcards
what enzyme is responsible for degrading triacylglycerol into fatty acids?
hormone sensitive lipoprotein lipase - found on endothelial surfaces of capillaries, abundant in adipose and muscle
what are the basic steps of fatty acid synthesis (4)?
- citrate shuttle transports excess acetyl CoA from mitochondria to cytosol
- citrate converted back to acetyl CoA
- acetyl CoA converted to malonyl CoA via acetyl-CoA carboxylase - rate limiting, requires biotin
- synthesis of palmitate via fatty acid synthase - requires NADPH (from HMP shunt)
fill in the steps regarding fatty acid synthesis:
1. ______ transports excess acetyl CoA from mitochondria to cytosol
2. ____ converted back to acetyl CoA
3. acetyl CoA converted to malonyl CoA via ________ - rate limiting, requires ______
4. synthesis of ______ via fatty acid synthase - requires _____
- citrate shuttle transports excess acetyl CoA from mitochondria to cytosol
- citrate converted back to acetyl CoA
- acetyl CoA converted to malonyl CoA via acetyl-CoA carboxylase - rate limiting, requires biotin
- synthesis of palmitate via fatty acid synthase - requires NADPH (from HMP shunt)
which 2 tissues do NOT use fatty acids for energy?
- RBC - no mitochondria, anaerobic glycolysis only
- brain - glucose and ketones only
what are the basic steps of beta oxidation of fatty acids? (4)
- convert FA to fatty acyl CoA
- carnitine shuttle transports fatty acyl CoA to inner mitochondria
- beta oxidation removes 2 carbons - generates NADH, FADH2, acetyl CoA
- 3C propionyl CoA remains, converted to succinyl CoA for TCA via propionyl-CoA carboxylase - requires biotin
fill in the blanks regarding beta oxidation:
1. convert FA to fatty acyl CoA
2. ________ transports fatty acyl CoA to inner mitochondria
3. beta oxidation removes 2 carbons - generates ___, ____, _____
4. 3C _______ remains, converted to succinyl CoA for TCA via _______ - requires _______
- convert FA to fatty acyl CoA
- carnitine shuttle transports fatty acyl CoA to inner mitochondria
- beta oxidation removes 2 carbons - generates NADH, FADH2, acetyl CoA
- 3C propionyl CoA remains, converted to succinyl CoA for TCA via propionyl-CoA carboxylase - requires biotin
what is carnitine required for and what results from deficiency?
carnitine: required to shuttle fatty acyl CoA to inner mitochondria in FA beta oxidation (basically, you need this to utilize FA for energy!)
deficiency (malnutrition, liver disease, hemodialysis, etc) —> muscle weakness, cardiomyopathy, hypoketotichypoglycemia when fasting (tissues overuse glucose and ketone synthesis is low without FA breakdown)
how does MCAD (medium chain acyl-CoA dehydrogenase) deficiency present?
MCAD required for beta-oxidation of medium-chain fatty acids
MCAD deficiency: AR, severe hypoglycemia (overuse of glucose) without ketones (ketone synthesis requires acetyl CoA from beta oxidation)
gluconeogenesis shut down (lack of acetyl CoA) - fasting can be life-threatening
which organs/tissues use ketones, which does NOT?
muscle/heart mainly use ketones to spare glucose for brain, though brain can also use ketone bodies
liver cannot use ketones - forces liver to release the ketones it makes into plasma for use by other tissues
explain why there is high ketone production in diabetes
diabetes - low insulin causes higher utilization of fatty acids (not responding to glucose)
fatty acids broken down to acetyl CoA, which is diverted to ketone synthesis when in excess !
explain why there is high ketone production with heavy alcohol intake
ethanol metabolism generates a lotttt of NADH
this causes TCA cycle to be halted at the place where NADH is made (converting malate to oxaloacetate)
the step after (which cannot be reached) is the point at which acetyl CoA enters TCA - since it cannot enter stalled TCA, acetyl CoA accumulates —> diverted to ketone production
how does the citrate shuttle transport acetyl CoA out of the mitochondria?
citrate synthase combines acetyl CoA and oxaloacetate to make citrate
citrate can enter TCA (first substrate) or leave mitochondria for fatty acid synthesis - this is favored when energy is high and mitochondria citrate concentration rises
in cytoplasm, citrate is split into oxaloacetate and acetyl CoA again
what is the committed step of fatty acid synthesis?
acetyl CoA carboxylase converts acetyl CoA to malonyl CoA with input of CO2 and ATP
(analogous reaction to pyruvate carboxylase)
what are the 4 reaction phases of fatty acid synthase (FAS)?
- condensation
- reduction (using NADPH)
- dehydration
- reduction (using NADPH)
*note every cycle of fatty acid synthesis requires 2 NADPH!
how does the catabolism of very long chain fatty acids differ from that of short/medium chain fatty acids?
very long chain fatty acids are first broken down in peroxisomes, prior to beta oxidation
peroxisomes also contain enzymes necessary for alpha-oxidation of some fatty acids with methyl branches
how are long chain fatty acids transported into the mitochondria for beta oxidation?
via carnitine shuttle
- FA converted to fatty acyl-CoA via acyl CoA synthetase
- CPT-I transfers acyl group from CoA to carnitine = acylcarnitine
- acylcarnitine is transported into mitochondrial matrix in exchange for free carnitine via CACT
- CPT-II transfers acyl group from carnitine to CoA in the matrix, regenerating free carnitine
fill in the blank regarding the carnitine shuttle:
1. FA converted to fatty acyl-CoA via _____
2. _____ transfers acyl group from CoA to carnitine = acylcarnitine
3. acylcarnitine is transported into mitochondrial matrix in exchange for free carnitine via ____
4. ____ transfers acyl group from carnitine to CoA in the matrix, regenerating free carnitine
- FA converted to fatty acyl-CoA via acyl CoA synthetase
- CPT-I transfers acyl group from CoA to carnitine = acylcarnitine
- acylcarnitine is transported into mitochondrial matrix in exchange for free carnitine via CACT
- CPT-II transfers acyl group from carnitine to CoA in the matrix, regenerating free carnitine
malonyl CoA regulates fatty acid breakdown (beta oxidation) via inhibitor of _____
CPT-I: enzyme located in outer mitochondrial membrane, transfers acyl group from CoA to carnitine to form acylcarnitine and free CoA
part of the carnitine shuttle for long chain fatty acids
what are the 4 cyclic reactions of beta oxidation?
- oxidation (dehydrogenase)
- hydration (hydratase)
- oxidation (dehydrogenase)
- cleavage (thiolase)
each cycle produces 1 acetyl CoA, 1 NADH, 1 FADH
2 truths and a lie:
a. alpha oxidation initiations oxidation of branched-chain fatty acids
b. unsaturated fatty acids yield more FADH2 when they are oxidized
c. odd-numbered fatty acids are broken down by beta-oxidation to acetyl-CoA and propionyl CoA
a. alpha oxidation initiations oxidation of branched-chain fatty acids
b. unsaturated fatty acids yield LESS FADH2 when they are oxidized (already partially oxidized)
c. odd-numbered fatty acids are broken down by beta-oxidation to acetyl-CoA and propionyl CoA
what are the only fatty acids that can generate glucose?
fatty acids with an odd number of carbons
broken down to acetyl CoA and propionyl CoA, requiring biotin as cofactor
succinyl CoA is produced downstream which can enter TCA (anapleurotic reaction)
what kind of receptors are that of glucagon vs insulin?
glucagon - GPCR
insulin - tyrosine kinase
how do CPT-I vs CPT-II deficiencies differ?
CPT-I and CPT-II both enzymes in carnitine shuttle for beta oxidation
CPT-I deficiency: primarily affects liver —> high free carnitine in blood, low acylcarnitines in blood —> hepatomegaly
CPT-II deficiency: primarily affects skeletal muscle —> low free carnitine, high acylcarnitines —> rhabdomyolysis
MCADD, aka sudden infant death syndrome (SIDS)
MCAD (medium chain acyl CoA dehydrogenase) deficiency: hypoketotic hypoglycemia triggered by fasting/vomiting —> elevated medium chain acyl carnitines in serum, dicarboxylic acids due to omega oxidation in urine, hyperammonemia (via liver damage)
treat with frequent feeding + carnitine supplements, high carb/low fat diet
[recall MCAD is first step of medium chain FA beta oxidation]
