Exam3Lec4FattyAcidOxidationandKetoneBodyMetabolism

Question 1

Overview of Fatty acid oxidation

Answer 1

The goal: to produce energy from fatty acids
Location: mitochondria of the liver
Metabolic conditions: fasted state
low insulin:glucagon=phosph ACC=decr malonyl CoA production=incr Beta-oxidation
6 steps 1-3 required
optional 4-6

metabolic conditions include uncontrolled type qdiabtees, prolonged disease, fasted state

Question 2

What are the conditions conducive to enhancing beta-oxidaton of fa?

Answer 2

1. prolonged fasting
2. prolong exercise
3. uncontroilled type 1 diabetes (low insulin: glucagon ratio)

Question 3

Mobilization of Fat stored in adipose tissue

breaking down triacyglycerdes (lipid stores)

Answer 3

Hormone sensitive lipase is turned on when phosphorylated.

Hormone sensitive lipase starts to breakdown TAG so we can use fat. (note that tag is how fat is stored) TAG goes to DAG, to MAG, then to Glyercol whihc is used to glycolynic (gluconeogenisis pathway)

note that each time lipase acts on TAG we release fatty acid (3 fa) to be esterfied to glycerol backbone

Question 4

Explain a general overview of activation of fa

Answer 4

Once FA are released by hormone sensitve lipase they travel to tissue that need it ( skeletal muscle and heart)

Once they get there, there is a transport system that get fre fa across plama membrane of tissue to inside tissue . One that happens, fa must be activated in cytoplasm in order for beta-oxidation to occur.

Question 5

Explain the thiokinase rxn

enzyme involved in activating free fa

acyl-CoA synthase=thiokinase

Answer 5

free fatty acid with ATP and CoA–> fatty acyl CoA , PPi and AMP

THIS REQ 2M EQUIVALENTS OF ATP
IT IS A REVERSIBLE RXN BUTIT FOLLOWS RXN GOING FROM R TO L. BUT UNDER PHYSOLOGICAL CONDITION, IT GOES TO RIGHT (REMOVING PRODUCT)

Question 6

Where does fa oxidation occur?

Answer 6

In mitochondria and peroxisomes

Question 7

Fatty acids 10 C or longer need what?

Answer 7

Carnitine to get across inner mitochindrial membrane (they get esterified to carnitine)

FA 10C or shorter don’t need carnitine, they diffuse

Question 8

What is the RLS in beta-oxidation of free fa?

Answer 8

CAT1: carnitine palmitoyl transferase 1

Question 9

What are the two functions of CAT 1?

Answer 9

translocate acycl-coA into matrix
translocate carnitine out of matrix

Question 10

How do we activate free fa for oxidation with carnitine?

Answer 10

1. under go thiokinase rxn and produce acyl-coA
2. CAT-1 in in the outermembrane an takes acyl-coa and carnintine and makes Acycl carnitine
3. Carnitine acylcarniotine TRANSLOCASE is needed to get acycl-carnitine across inner mitoc membrane
4. Once that is in the inner membrane, CAT2 esterifried acyl-coa with inner mitchondial CoA-SH ( this means that CoA is added to acyl-carnitine to get acyl-CoA) and generate free carnitine.
5. We now have acyl-coa in the inner membrane and we are ready for beta oxidation

Note that fa must be esterifies to carnitine to get across inner mitoc membrane but FA < 10) can get across

Question 11

Rxn seq in beta-oxidation

Answer 11

1st oxidation w/ acycl-CoA dehydrog yields FADH2 and has potential to give 2 ATP that will feed into complex 2 of ETC

We go through hydrolyzatioo (add water) by enoyl hydratase where we add an OH group to beta carbon.

L-3 hydroxyacyl dehydrogenase yields NADH where we have potential to give 3 ATP in the top of the ETC chain

Thiolase then clips of 2 C fragments from FA and generate acyl coa (fa shortned by 2C) which goes into TCA cycle

we get potentional for 5 ATP
BUT remember that we used 2 ATP in the beginning with the thiokinase rxn

Question 12

Explain complete beta=oxidation of unsat fatty acid

not req

Answer 12

we can undergo 3 rounds of fa like seen prev. We use enoyl-CoA hydratase to add H2O to double bond, but we cant do that here bc db is on 3,4 postion, so what do we do?
1. We** use enoyl CoA isomerase** to take double bond on 3,4 and isomerize it to 2,3 position. (move db to 2,3 position)
2. With the intermediate with db on 2,3 postion we can Now hydrotase can add H20 to 3rd carbon, BUT we noe have steric hinderance bc of db on 4,5 position.
3. What do we do? we use 2,4. dienoyl CoA reductase yo reduce the 2db in the intermediate to 1 db on 3,4 positon.
4. That is a problem once again, so we uses isomerase AGAIN to move that one db on 3,4 to 2,3 position
5.

plants, fish oil are polyunst
need to know enoyl isomerase
note that no FADH2 produces–> less energy produced

Question 13

What 2 enzymes are needed for complete oxidation of polyunsat fa?

Answer 13

enoyl isomerase
2,4 dienoyl CoA reductase

Question 14

Explain complete beta-oxidation of odd-chain fatty acids unsat fatty acids

Answer 14

You start with any odd -chain number and end up with 3 c )15, 13, 11, etc to 3c which is propionyl coA.

Propionyl CoA turns into Succinyl CoA which then feeds into TCA cycle (it is a TCA intermediate). How does this happen?

Propionayl CoA to D-methylmalonyl CoA using: propionyl CoA carbocyle + ATP + Biotin

D-methylmalonyl CoA to L-methylmalonyl CoA using: methylmalonyl CoA epimerase

L-methylmalonyl CoA to Succinyl Coa using: methylmalonyl CoA mutase + B12.

Question 15

What two enxymes are needed to comepleely beta-oxidize odd chain fa unsat

Answer 15

We need 2 enzymes with 2 cofactors.

1. propionyl CoA carboxylase +ATP +Biotin
2. methylmalonyl CoA mutase+B12

Question 16

Explain alpha oxidation

Answer 16

In alpha oxidation, ot the the alpha carbon that is undergoing oxidative process so we lose 1 C.

occurs in plants
do not need to mem steps

Question 17

Explain oxidations of phytanic acid in relation ot refsums disease

Answer 17

refsum’s diesease is a rare genetic disease:
issue: inability to alpha-oxidize
metabolic characteristics: high phytanic acids concentations (accumulation)
physical characteristics: neurological defects

phytanic acids coms from breakdown of chlorophyl in plants. So if you cannot carry out alpha oxidation , phytonic acid accumulated in CNS. So cannot eat vegetables.

note we cannot oxidize phytanic acid on beta carbon because large methyl grp

Question 18

Peroxisomal beta-oxidation of long chain fatty acids

Answer 18

Peroxisomames can only use very ling chain fa as substrate. Can beta-oxidze C24,26, etc to C18. Once C18 is generated it moves to mitchondria and continues process and vcomepltey beta oxizde to acyl coa.
Mitochondria cant handlemfa beyond 18 C.

Note that in the mitochinsia you make energy in the 1st step. In peroxisomes you dont make energy in 1st step, just hydrogen peroxide.

Question 19

Regulation of fatty acid metabolism

synthesis and oxidation

Answer 19

Malonyl CoA has 3 potential fates
1. Synthesize fat
2. Inhibits FA acids oxidation (breakdown) by ihib CAT1
3. Makes Acetyl CoA using malonyl decarboxylase

Acetyl COA turns into Malonyl using acety carboxylase

There is compartmentalization:
synthesis of FA: cytosol
oxidation of FA: mitochondria

low insulin: glucagon vs high insulin:glucagon

Question 20

MSP3 students eats a snicker bar everyday for 3-4 months and becomes very fat. What are the key reasons?

Answer 20

1. What is the ratio of insulin: gluagon: HIGH
2. If ratio of insulin to glucagon is high what is the phosphorylation state of Acetyl coa carboxylase? Dephosphorylated (activated) becasue activity state is high
3. What is malonyl Coa level? High
4. What is the rate of glycolysis synthesis? High this causes more fat

review dephps part

Question 21

Animals have genetically enhances malonyl decarboxylase activity. What is the rate of fa synthesis in the rats?

Answer 21

**Low b/c we are making more substrate (acetyl coA) rather than malonyl **

Here we have low insulin: glucgaon ration so malontyl decarb is activated

Question 22

For ketogenesis: the insulin: glucagon ratio is

Answer 22

LOW
1. not enough glucose in blood
2. not enough “quick” energy stores

we have high rate of fatty acid oxidation (breakdown) so ratio is low

Question 23

What is the location of the ketone body?

Answer 23

mitochondria of liver

beta oxidation also occurs here

Question 24

What are the products of the ketone body?

What are the ketone bodies.

Answer 24

acetoacetate, acetone, beta-hydroxybutyrate

Question 25

What is the rate limiting enzyme of ketone body synthesis?

Answer 25

HMG CoA synthetase

Question 26

What are the metabolic conditions of the ketone bodies?

Answer 26

Fasted state state–> low insulin: glucagon–> increased acetyl-coA

low insuline: glucagon–> increased gluconeogenesis –> decreased ocaloacetate –> acetate-coA within mitochondria combines with itself

Question 27

Explain ketone body synthesis

Answer 27

1. Combine two acetyl-CoAs  acetoacetyl CoA (thiolase)
2. Add a 3rd acetyl-CoA and create carboxyl group –> HMG CoA (HMG CoA synthetase )
3. Release one acetyl-CoA –>acetoacetate (HMG CoA lyase)
4. Reduce acetoacetate–> β-hydroxybutyrate (Β-hydroxybutyrate dehydrogenase)

Question 28

What is the goal of using ketone bodies?

Answer 28

to provide energy to extra-hepatic tissues.

in extrahepatic tissues low NAD:NADH ratio means that we have low energy meaning that 3-hydroxybutyrate turns into acetoacetate

in liver high nad: nadh ration means that we have high energy means that we turn acetoacetate to 3-hydroxybutyrate

Question 29

Thiophorase (ketoacyl CoA transferase) is only found where? and what does it allow for?

Answer 29

Outside the liver and allows for extrahepatic tissesu to use ketone bodies for energy

Question 30

We isolate liver cells from **fasting rat **and incubate them one w/3 fa, one in with 3-hydroxybut in another, and acetoaceacetate in the oter. Which of the follwing enzymes will show the greatest metabolism (breakdowinw) of starting product (3 fa, 3-hydrbut, acetoacetae)

Answer 30

Fatty acids for the primary reason that the liver cant use ketone bodies but it cannn use fatty acids. Liver MAKES fa. Remember that the liver does not have thiophorase.

Question 31

Explain integration of pathways in relation to gluconeogenesis

slide 6 ta finish

Answer 31

you have low insulin:glucagon ratio that means that means that thers low gluc in blood so there is high gluconeogenis occuring.

SO you have pyrivate going to OAA leaves mitcohindria to turn PEPCK going to Glucose

So there is not alot of OAA in mitochondria so low levels of OAA

Question 32

Explain integration of pathways in relation to TCA cycle

Answer 32

low insulin: glucagon–> low glycolysis–> inhibition of TCA cycle

Question 33

Explain integration of pathways in relation to beta oxidation

Answer 33

low insulin: glucagon–> low nadh:nad ration–> high acetyl coa( inhibits pyruvate, but more oaa, malate etc to feed into gluconeogenesis)