Fatty Acid Catabolism ch. 17.1 and 17.3

Question 1

How do lipids yield E? Store E?

Answer 1

Through b-oxidation of FA (long chains) OR ketone bodies to get regenerated as Acetyl coA. Both = ATP!

Adipose tissues store FA as Triglycerides

Question 2

How does b-oxidation of saturated FA occur?

Answer 2

B-oxidation: occurs at carboxyl end.
B-oxidation pathway is FA b-oxidized to– acetyl CoA –TCA– ETC chain
4-step enzyme-catalyzed process of oxidation:
Palmitoyl is a 16 C FA.
1- ACYL-CoA DEHYDROGENASE (along w/ FADH2) will affect C2 (alpha) and C3 (beta). It will take out H to make a double bond between C2-C3.
2- ENOYL-CoA HYDRATASE will used H2O (in the form of OH) to take out double bond and put OH on C3.
3- B-HYDOXYACYL-CoA-DEHYDROGENASE (along w/ NADH) will reduce C3 with NADH so that 2 H are removed and forms a double bond.
4- ACYL-CoA ACETYLTRANSFERASE/thiolase will use CoA-Sh to cleave between C2 and C3. This yields a 14C long FA (16C with 2C less, because of acetyl CoA produced) and acetyl CoA ‘produced’.
5- Repeat. Until the whole palmitoyl FA is all oxidized.

For a 16C FA, b-oxidation only occurs 7 times to cleave 8 acetyl-CoA. Generated 7 FADH2 and 7 NADH (NOT 8). Will yield ATP ultimately.

Question 3

Why are FA good E source?

Answer 3

FA are highly reduced compounds (more H than OH)

Since C molecules in FA chains are at reduced state it yields more than 2 fold E than CHO and prots.

Since no oxygen is used to catabolize the FA chain, more ATP is produced.

TG are relatively inert– no risk of undesirable reactions

Question 4

How is osmolarity and lipids linked?

Answer 4

Lipids are insoluble in H2O, which does NOT increase osmolarity (measures osmotic pressure of a solution and det. how well the solvent will diffuse across a semipermeable membrane (osmosis))

Question 5

How does lipid metabolism occur from mouth to adipose tissues?

Answer 5

1- in s.i., EMULSIFICATION of fats into MICELLES
2- INTESTINAL LIPASES yield DIACYLGLYCEROLS, MONOACYLGLYCEROLS, FREE FA and GLYCEROLS 
3- mucosal epithelium absorbs these broken down molecules
4- restructurate broken molecules into CHYLOMICRONS
5-Chylomicrons are thrown out of intestinal syst., IN BLOOD SYST. 
6-Chylomicrons release TG in blood. 
LIPOPROTEIN LIPASES (in capillaries) cleave and help abs. of the FA into the cells.
7- Cells can use FA (oxidized) or store it (REESTERIFICATION = put back FA on glycerols= TG).

Question 6

What are lipoprotein lipases ?

Answer 6

In capillaries, LIPOPROTEIN LIPASES exist and CLEAVE and ABSORB the TG–FA into the cells.
These are activated by APO(C)-II

Question 7

What ate apolipoproteins?

Answer 7

Apolipoproteins are LIPID-BINDING PROTS in the
blood, responsible for the MVT of triacylglycerols,
phospholipids, cholesterol, and cholesteryl esters be-
tween organs.

Question 8

What are chylomicrons made up?

Answer 8

Chylomicrons have apolipoprots, TG, cholesterols, cholesteryl esters, phospholipids. Really big molecule, but low density of cholesterol.

Question 9

How do lipids get removed from adipose tissue to blood?

Answer 9

Neutral lipids (TG) are stored in adipose tissue in the form of a lipid droplet surrounded with a phospholipid monolayer. This monolayer has PERILIPINS (restricts access to stored TG, when unwanted).

1- When adipocytes release FA, they receive a signal:
GLUCAGON goes to GPCR receptor, activates ADENYLYL CYCLASE, produces cAMP (exctracellular message), activates PKA and phosphorylates perilipins and hormone-sentitive lipase (multiplying hydrolysis effect of TG).
2- The phosphorylated perilipins cause HORMONE-SENSITIVE LIPASE to move from cytosol to the lipid droplet, where it can hydrolyze TG to free FAs and glycerol.
3- The fatty acids thus released by HSL (free
fatty acids, FFA) pass from the adipocyte into the
blood, where they bind to the blood protein SERUM ALBUMIN.
4-Bound to this soluble protein, the (now soluble) insoluble FAs are carried to the tissues. The FAs dissociate from albumin and are moved by PLASMA MEMBRANE TRANSPORTERS into cells to serve as fuel.

Question 10

Perilipin is normally associated to CGI. How is this relevant for lipid mobilization from adipose tissue to bood?

Answer 10

Perilipins are normally associated to CGI.

• When perilipin is phosphorylated by PKA, CGI58 dissociates and binds to ADIPOSE TG LIPASE, which specifically attacks TG to make diacylglycerol.
• PKA also interacts with hormone sensitive lipase, by phosphorylating it. HSL attacks diacylglycerols made by ATGL, to take out 2nd FA and make a monoacylglycerol.
• MGL (monoacylglycerols lipase) attacks monoacylglycerols, to release last FA into bloodstream.

Question 11

Serum albumin can bind to know many NEFA (non-esterified FA, which are free FA attached to this prot.)?

Answer 11

10 NEFA

Question 12

How does insulin and glucagon affect FA metabolism?

Answer 12

Insulin = no more glucagon = store FA
Glucagon = no more insulin = release FA

Question 13

How does glycerol get broken down to yield E? (5% of total TG E)

Answer 13

Glycerol in this whole process lipid mobilization is left out. So, we get Glycerol phosphorylated by GLYCEROL KINASE, then oxidized by G-3-P DEHYDROGENASE, then isomerized by TRIOSE PHOSPHATE ISOMERASE which yields molecule of D-G-3-P to go down glycolysis and get oxidized.

Question 14

How does FA get activated and transported into the mitochondria occur?

Answer 14

1- FA needs to be activated to move through membrane of mit. The enzyme that activates FA is FATTY ACYL-CoA SYNTHETASE; It uses ATP and attaches Adenosine MONOphosphate (2 phosphate gr are released) to the first C of FA. NOTE: This is not phosphorylation
2- Fatty-acyl-CoA attaches a CoA to monophosphate-adenosine-FA and it releasse monoposhate adenosine from this molecule.
FA are now activated by CoA and can be transported to the mitochondria.

Mitochondria has 2 membranes: outer membrane has CARNITINE ACYLTRANSFERASE 1
1: CA1 removes the CoA and replaces it with carnitine; FA is inactivated.
2: Acyl-carnitine can transport the compound across the membrane, through another transporter on inner layer; has CARNITINE ACYLTRANSFERASE II, which removes carnitine and put back CoA onto molecule of FA.
FA is thus activated in the MATRIX.

Question 15

Fatty acyl-CoA transferase can also be used for…?

Answer 15

Fatty acyl CoA can also be used to synthesize longer membrane lipids. ???

Question 16

Where are all the enzymes for b-oxidation, in the cell?

Answer 16

Stuck in the mitochondria.

Question 17

How does unsaturated FA get b-oxidated?

Answer 17

b-oxidization of the whole FA chain until they find a double bond on unsaturated FA.
1-Use C3-C2-ENOYL-CoA-ISOMERASE to transfer the CIS-double bond from C4-C3 to TRANS-double bond on C3-C2 (enzymes in the b-oxidation chains love trans FA to act upon them).
2- b-oxidation occurs with trans bond.

If we get a polyunsat. FA chain;
do step 1, followed by step 2.
3- use 2,4-DIENOYL-CoA REDUCTASE + NADH to put H+ on a double bond (C4-C5) to make it a single bond. The double bond between C2-C3 will be moved to C3-C4.
4- ENOYL-CoA ISOMERASE (not C3-C2 isomerase, since no cis bond) will act upon this C3-C4 double bond and make it a C2-C3 double bond (already in trans form)
5- b-oxidation can occur, since on right Cs.

Question 18

How does b-oxidation of ODD numbered FA occur?

Answer 18

b-oxidation of odd numbered FA will end with a 3-C that can no longer be oxidized. How can we further oxidize it, completely?

1- This 3-C compound is called PROPIONYL-CoA and uses PROPIONYL-COA CARBOXYLASE (along with Biotin) to add a C to the FA chain on the C2 of the 3C compound (gives a T shaped compound).
2-METHYLMALONYL-CoA EPIMERASE transfers the CoA from C1 to the C2, and C2’s COO- to C1.
3- METHYLMALONYL-CoA MUTASE (along with Coenzyme B12) will then transfer CoA to the C3, and C3 will transfer one of it’s H to C2. This final compound is SUCCINYL-CoA.
4-TCA cycle… oxidation… E… WOUP WOUP!

Question 19

What are the 2 possible organelles in which b-oxidation can occur?
What is the difference between the 2?

Answer 19

Mitochondria vs Peroxisome.

As b-oxidation occurs in the mitochondria, the FA chain reduces FA to FADH2 (which will go to ETC to yield ATP and H2O).
The b-oxidation continues and reduces NAD+ to NADH (which will go to ETC to yield ATP and H2O) until final compound is acetyl-CoA.
Acetyl-CoA goes to the TCA cycle.

As b-oxidation occurs in the peroxisome, the FA FAD—FADH2 (and another process makes it yield H2O2… Immediately, a catalase breaks it down into H2O and O2.).
As b-oxidation continues, it reduces NAD+–NADH, which will get exported out of peroxisome to get reoxidized elsewhere. In the peroxisome, the final compound of b-oxidation is acetyl-CoA, which get exported from the peroxisome to be used elsewhere.

Mitochondria and peroxisome b-oxidation can be used simultaneously AND these organelles are in our body (eukaryotic cells). Peroxisome is NOT A COMMON method to use to b-oxidize.

Question 20

What is the difference between procaryotic (Grahm +) b-oxidation and eukaryotic mitochondrial b-oxidation systems?

Answer 20

Procaryotic GRAHM+: short-chain specific system. The FA substrate goes through 4 distinct enzymes that do not seem bound to a membrane.
GRAHM- : 3 distinc enz. with functions of 4 enz.

Eukaryotic: very-long-chain specific system. The FA substrate goes through 3 enzymes that are bound to the inner mitochondrial membrane. Enzyme 2 in eukaryotic contains the functions of Enz 2 and Enz 3 of procaryotes.

These enzymes are regulated by TF and AMPKinase.

Question 21

What are the 4 types of enzymes of b-oxidation in both mitochondria and procaryotes?
What regulates them? (2)

Answer 21

Enz1: acyl-CoA dehydrogenase (ADH)
Enz2: enoyl-CoA hydratase
Enz3: L-B-hydroxyacyl-CoA dehydrogenase
Enz4: thiolase

These enzymes are regulated by TF and AMPKinase.

Question 22

How does omega oxidation occur and in which organelle does it happen?

Answer 22

The b-oxidation of FA in the ER:
Oxidizes medium FA chains..
This pathway is generally not the major route for ox-
idative catabolism of FA: ALTERNATIVE PATHWAY TO B-OXIDATION:
1- oxidation of the Carbon most distant from the b-carbon—the OMEGA carbon- with a MIXED FUNCTION OXIDASE (along with NADPH–NADP+) add an OH gr to that omega carbon.
2- ALCOHOL DEHYDRGENASE (along with NAD+–NADH) will remove 2 H+ from this carbon end and make a double bond.
3- ALDEHYDE DEHYDROGENASE (along with NAD+–NADH) will add an OH but take 2 H+ out, so it will yield a O-.
4- Now, the 2 ends of the FA have carboxylic gr (COO-) and so b-oxidation can happen. It yields SUCCINATE and ADIPATE (adipic acid) molecules.

Question 23

How is b-oxidation tightly regulated? (5)

Answer 23

• Fatty acyl-CoA synthesized in the cyt. can b-oxidize OR synthesize TG.
• Carnitive shuttle is the POINT OF COMMITMENT of the B-oxidation; the moment the FA are in the mitochondria, it is b-oxidized.
• Malonyl-CoA (first intermediate of the FA synthesis) INHIBITS carnitine acetyltransferase I. – when we want to synthesize FA, so it blocks catabolism of FA.
• Low ATP levels (low ATP/AMP ratio) means too few E is in the cell. –This low level stimulates AMPK to INHIBIT acetyl-CoA carboxylase (which synthesizes malonyl-CoA enzyme) so, it ACTIVATES the carnitine shuttle.
• High NADH/NAD+ ratio INHIBITS the Acetyl-CoA dehydrogenase (first enz. of the b-oxidation– anabolism is favored).

Question 24

What is the difference between Gluconeogenesis, Glycolysis, Glycogenolysis, Glycogenesis?

Answer 24

Pyruvate- Glucose.
G-6-P – pyruvate.
Glycogen– G-6-P.
G-6-P– glycogen.

Question 25

Why is omega oxidation not favored?

Answer 25

Not very efficient since we have to ADD another COOH from other compound to our FA chain.

Question 26

Where do short FA get oxidized? Medium? Long?

Answer 26

In liver and in Kidney: FA of 10 or 12 Carbons (short/medium chain)
Mitochondria: long!

Question 27

What are the 3 ketone bodies? What are ketone bodies?

Answer 27

ketogenesis:

• Water soluble E molecules (easily transported to tissues
• Produced in liver from Acetyl-CoA
• ACETONE is exhaled– it is not maintained in high concentrations.
• ACETOACETATE and d-BETA-HYDROXYBUTYRATE are transported to other tissues easily and converted back to acetyl-CoA. Then, it can enter TCA cycle to make ATP.

Question 28

When does ketogenesis make) happen in the body? Where?

Answer 28

-Occurs during starvation or diabetes (or during sleep, minor ketogenesis is stopped)

• Occurs in MITOCHONDRIA (all the enzymes of ketogenesis are present in the mit. (THIOLASE, HG-CoA SYNTHETASE, HMG-CoA Lyase, ACETOACETATE DECARBOXYLASE, D-BETA-HYDROXYBUTYRATE DEHYDROGENASE, but:
  
  • HMG CoA synthase is also present in the cytoplasm,
  • while HMG CoA lyase is only present in the mitochondria)

Question 29

How is ketones used as E (broken down pathway)?

Answer 29

D-BETA-HYDROXYBUTYRATE DEHYDROGENASE, b-ACETOACYL TRANSFERASE, THIOLASE. These enzymes yield Acetyl-CoA, which can go to the TCA cycle.

Question 30

Ketone bodies are produced in the liver but cannot be broken down there, why?

Answer 30

b-ketoacyl-coA transferase is NOT present in the liver, which means that the ketone bodies produced in the liver cannot be converted back to Acetyl-CoA. Ketone bodies need to go elsewhere to get converted back to Acetyl-CoA.