bmsc 230 module 8 fatty acid degradation

How much energy does glycogen stores provide?

About 24 hours worth of fuel in the form of glucose

What is the major storage form of fuel in our bodies?

Fatty acids stored as triacylglycerol in adipose tissues

What is the degradation of fatty acids called?

B-oxidation

Why does b-oxidation generate more ATP than the oxidation of glucose?

Because fatty acids are far more reduced, and thus possess more electrons to donate to the ETC

What does fatty acid degradation rely on?

The availability of oxygen

Why is glucose a more versatile energy source?

Because it can be metabolized under aerobic or anaerobic conditions, whereas fatty acids always require oxygen

What is the basic nature of B-oxidation?

It is a repetitive process whereby long-chain fatty acids are sequentially degraded to acetyl CoA, depending on the length of the fatty acid

What happens to acetyl CoA produced from B-oxidation?

It can directly enter the citric acid cycle, since B-oxidation occurs in the mitochondrial matrix.

What is produced during each cycle of B-oxidation?

Both NADH and FADH2, which can send electrons to the ETC

What is the first stage of fatty acid degradation?

mobilization of fatty acids from triacylglycerol in adipose tissue

What is the second stage of fatty acid degradation?

Then the fatty acids arrive at a cell, they are imported to the cytosol - so the transport of fatty acids from the cytosol into the mitochondrial matrix where B-oxidation occurs

What his the third stage of fatty acid breakdown?

The actual reactions of B-oxidation

What is the basic structure of a fatty acid?

A long, hydrocarbon chain with a carboxylic acid group at the end

What are commonly occurring lengths of fatty acids?

From 12-20 carbons in length

What is the nature of hydrocarbon chains?

They are very non polar, can be fully reduced, or have some double bonds

What orientation do most double bonds in fatty acids have?

Most are cis

What do cis double bonds mean?

That the substituents on each side of the double bond are on the same side - this induces a kink in the chain

How are the carbons in fatty acids numbered?

The carboxyl terminal carbon is usually assigned to carbon 1

What are other names for carbon 2 and 3 in a fatty acid chain?

The alpha and beta carbons, respectively

How is the position of the double bond denoted in the systematic name of a fatty acid?

With a ∆ sign followed a number indicating the position of the first carbon that is part of the double bond

What does each part of 18:1(∆9) mean?

That there are 18 carbons, 1 double bond with the first participant in the double located at carbon 9

What is the methyl carbon end?

The Omega carbon

How are omega-3 fatty acids notated differently?

They are counted from the methyl carbon end (The omega carbon)

What are omega3 fatty acids?

Where the double bond is between carbons 3 and 4

How are fatty acids stored?

As triacylglycerol, a neutral lipid, in adipose tissue.

Why is adipose tissue very important and necessary in our bodies?

Because it stores an important fuel, and because it secretes small biomolecules called adipokines, which control overall body metabolism and appetite

What type of adipose tissue is of most concern?

Visceral adipose, which accumulates in the abdomen around heart, liver and intestine in obese individuals

What is the structure of a triacylglycerol?

A glycerol backbone to which three fatty acids are attached via an ester bond

What must happen before fatty acids can be used by other organs in the body as fuel?

They have to be cleaved off of triacylglycerol (or mobilized) by an enzyme called lipase, and then released into the blood

What happens once a fatty acid is released into the blood?

It must be linked to Coenzyme A, and then undergo B-oxidation to release acetyl CoA.

What type of reaction occurs to remove fatty acids from glycerol?

Lipases catalyze a hydrolysis reaction - three water molecules are used to cleave off the fatty acid residues

What are the three different lipase involved in triacylglycerol breakdown?

One which acts on triacylglycerol, one which works on diacylglycerol, and one that works on monoacylglycerol

What are the enzymes that cleave off the first two fatty acids?

adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HS-lipase)

What regulates the activity of ATGL and HS-lipase?

Hormones that signal a need for more fuel (epinephrine and glucagon)

How do epinephrine and glucagon signal cells to breakdown triacylglycerols

They bind to their respective receptors and activate the cAMP signalling system

What is the action of the cAMP cascade?

It activates kinase A, which either or indirectly activates ATGL and HSL

Why is the control system for triacylglycerol breakdown important?

It ensures that triacylglycerol is only degraded when the body is low on energy

How are fatty acids transported in the blood?

They are transported while bound to the blood protein albumin, as they are insoluable in water.

Where do fatty acids go once they enter the blood?

To many tissues, where they are used as fuel

What happens to glycerol once it enters the blood?

It is taken up by the liver, where it is converted to dihydroxyacetone phosphate

What are the potential fates of dihydroxyacetone phosphate?

It can be directed towards glycolysis and gluconeogensis

What is the most probable fate of dihydroxyacetone phosphate?

It is usually directed towards gluconeogenesis.

How do fatty acids enter cells?

They diffuse across the membrane with help from special proteins. There are fatty acid binding proteins which help shuttle them around

How are fatty acids activated?

By reacting with coenzyme A, which occurs on the outer mitochondrial membrane.

What is required to bind a fatty acid with Coenzyme A?

The input of ATP, broken down to AMP and PP

Why is dihydroxyacetone phosphate usually directed towards gluconeogenesis instead of glycolysis?

Because the signal that initiates the breakdown of triacylglycerols are usually in response to a hormone signalling a need for more fuel the response of the liver to the same hormones and the need for fuel leads to glycogen breakdown and gluconeogenesis to provide more glucose for other tissues to use.

What happens after fatty acids are activated?

At the surface of the inner mitochondrial membrane, on the cytoplasmic side, the acyl group of Acyl CoA gets transferred to carnetine, forming acyl carnintinge

What is the enzyme that transfers the acyl group from Acyl CoA to carintine?

Carnitine acyltransferase I

How does acetyl carnitine enter the mitochondrial membrane?

A specific translocase can move it

What happens once acyl carnitine reaches the inside of the mitochondria?

The reaction is reversed via carnitine acyltransferase II, which reconstitutes acyl CoA and releases free carnitine

What happens to the free carnitine inside the cell?

It is shuttled back out to the cytol so so it can be re-esterified to another fatty acid to assist in bringing it into the mitochondria

Why has carnitine become a popular supplement?

Because it helps the body metabolize fat, it is thought that increasing carnitine availability will increase fat burning, resulting in better performance and weight loss

Why do clinical trials show little positive effects of carnitine supplementation?

Because we an make all that we need

When might a carnitine supplement be wanted?

If your body is not manufacturing sufficient doses of carnitine

What is the third stage of fatty acid breakdown?

The degradation of Fatty Acyl CoA to Acetyl Coa

What happens to fatty acyl CoA when it reaches the mitochondrial matrix?

It undergoes B-oxidation

What does the term B-oxidation mean?

It is derived from the fact that it is the B-carbon (third from the carboxyl end) which becomes oxidized in each successive round

How many reactions are in B-oxidation?

Four

What is the first step in B-oxidation?

Oxidation where FADH2 is produced

What is the second step in B-oxidation?

A hydration step where H2O is added

What is the third reaction in B-oxidation?

A second oxidation step where NADH is produced

What is the fourth step in B-oxidation?

A thiolysis step, where CoA is used to cleave off an acetyl CoA unit and leave behind an acyl CoA that is two carbons shorter than what was started with at the beginning

What happens after one round of B-oxidation?

It continues on and on until it is completely degraded to acetyl CoA

What bond changes in the first oxidation reaction in B-oxidation?

The bond between the alpha and beta carbons becomes oxidized to a double bond, with the electrons used to reduce FAD to FADH2 - FADH2 can then donate its electrons to the electron transport chain to produce ATP

What type of double bond is formed in the first oxidation reaction in B-oxidation?

A trans bond

On which carbons does the hydration reaction occur in B-oxidation?

Water is added across the double bond, putting an -OH on the B-carbon and an H on the A-carbon

What is the product of the hydration reaction in B-oxidation?

3-hydroxyacyl CoA, since the hydroxyl is on the number 3 (B) carbon

What is the enzyme in step 3 of B-oxidation?

B-hydroxyacyl CoA dehydrogenase

What happens in detail in the 3rd reaction of B-oxidation

3-hydroxyacyl CoA is oxidized to form 3-ketoacyl CoA and NAD+ becomes reduced - the B-carbon is now fully oxidized, having started out as CH2 and now is a C=O

What is the fate of NADH from the third step of B-oxidation ?

It can donate electrons to the ETC

What is the enzyme in the final reaction of B-oxidation?

Thiolase or 3-ketoacyl thiolase

What is taking place in the thiolysis reaction ?

A two-carbon unit is cleaved off the end of the 3-ketoacyl CoA, which is an acetyl CoA unit. This cleavage is achieved using free CoA, with the -SH group attacking the bond between the alpha and beta carbon - this gives the second product, acyl CoA, which is two carbons shorter than what was started with.

When is B-oxidation complete?

When the acyl CoA is degraded to a four carbon unit, the final round of B-oxidation releases two acetyl CoA and completes B-oxidation

What is palmitate?

A common, 16-carbon fatty acid with no double bonds

How many rounds of B-oxodiation does palmitate require?

7

How much NADH and FADH2 does each cycle of B-oxidation release?

1 FADH2 and 1 NADH

How many ATP does an NADH generate?

2.5

How many ATP does FADH generate?

1.5

How many ATP does an acetyl COA produce?

10

How many ATP does the degeneration of palmitate make?

108

How many h high energy bonds are required to activate the fatty acid to get it into the mitochondria?

2

What is the net ATP from a 16-carbon fatty acid?

106

What are fatty acids with double bonds called?

Unsaturated fatty acids

What is palmitoleate?

A 16-carbon fatty acid with a double bond between C9 and C10.

What happens after pamitoleoyl CoA undergoes 3 rounds of Beta oxidation?

It is not able to be a substrate for the first enzyme in B-oxidation, because of the double bond between C3 and C4 - so a new reaction occurs

How is cis-∆3-enoyl CoA able to enter another cycle of B-oxidation?

Cis-∆3-enoyl CoA isomerase converts the cis double bond to a trans double bond, which results in a normal intermediate of B-oxidation, so it can continue

What happens if a fatty acid has more than one double bond or if the position doesn't fall in line nicely ?

A reductase is used after the first reaction in b-oxidation - it reduces the double bond using NADPH as a reducing agent.

ex. trans-∆3-enoyl CoA is converted to trans-∆2-enoyl CoA, which can continue on in B-oxidation

What does complete oxidation of unsaturated fatty acids sometimes require?

An isomerase, or an isomerase and a reductase

What happens when a fatty acid enters B-oxidation with an odd-number of carbons?

Rather than ending up with two acetyl CoA, you get one acetyl CoA and a 3-carbon acyl CoA called propionyl CoA

What happens to propionyl CoA?

it is carboxylated at carbon 3, generating a four carbon molecules called D-methylmalonyl CoA, which undergoes intramolecular rearrangement to the L-isomer

What catalyzes the intramolecular rearrangement of propionyl CoA?

Methylmalonyl CoA mutase - a vitamin B12 containing enzyme

What is the final product of the mutase reaction of proprionyl CoA?

Succinyl CoA, which can enter the citric acid cycle

What is a small portion of the acetyl CoA produced in the liver used for?

To synthesize ketone bodies

What are ketone bodies?

An important and useful fuel molecule since they are water soluble and can be used a fuel by the brain when fatty acids can not.

What tissue uses ketone bodies preferentially over glucose?

Heart and kidney

When does ketone body production increase?

Under starvation conditions and in uncontrolled diabetes when fatty acid oxidation rates are high

What are the three different ketone bodies produced from acetyl CoA?

acetoacetate, B-hydroxybutyrate, and acetone

Where is the biosynthetic pathway for ketone bodies?

In the mitochondrial m atrix

What is the basic pathway of ketone body creation?

Two acetyl CoA molecules are used to make acetoacetate, which is then converted to 3-hydroxybutyrate or acetone (through spontaneous decarboxylation)

How are ketone bodies degraded?

3-hydroxybutyrate and acetoacetate are metabolized to acetyl CoA, which can enter the citric acid cycle.