Mobilization of fatty acids:

Fatty acid oxidation in animals first requires the mobilization of fat from adipose tissue:

epinephrine (glucagon) ----> bind to a receptor ----> stimulates adenylate cyclase ---->

cAMP activates a protein kinase ----> phosphorylates lipase to lipase-P (active) ---->

lipase-P hydrolyzes triacyl glycerol to diacylglycerol (DAG)

Other enzymes hydrolyze the diacylglycerols to release the remaining fatty acids.

The first step in the reaction sequence is the attachment of the fatty acid to CoA:

This reaction is driven to completion by hydrolysis of pyrophosphate PPi --> 2 Pi (the enzyme is a pyrophosphatase).

catalyzed by fatty acyl CoA: carnitine fatty acid transferase I

Acyl carnitine is translocated across the mitochondrion membrane (in exchange for free carnitine passing out of mito)

A second transferase (II) transfers acyl group to CoASH (enzyme on the inner surface of mito).

Beta oxidation:

Compare the reactions of beta oxidation with those of the TCA cycle (succinate ----> fumarate ----> malate ----> OAA).

a. oxidation (cofactor is FAD ---> FADH2)

b. hydration (addition of H2O)

c. oxidation (NAD+ ----> NADH + H+)

d. thiolysis (cleavage by CoA-SH)

Summary reaction:

Palmitoyl-CoA (C-16) + 7 FAD + 7 NAD+ + 7 CoA-SH + 7 H2O --> 8 Acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+

In the electron transport chain, each FADH2 produces 2 ATP, and each NADH yields 3 ATP. Based on these values, each palmitate yields 130 ATPs, both here and in the TCA cycle, whereas one glucose yields only 38 ATPs.

Oxidation of unsaturated fatty acids:

Most naturally occurring double bonds in lipids are cis, but enoyl-CoA hydratase is specific for trans bonds only!

Monounsaturated fatty acids are metabolized as follows:

Oleic acid (which is 18:1 D9) undergoes three oxidation cycles, then cis double bond "is in the way". The enzyme enoyl-CoA isomerase moves the double bond from the 3-4 position (cis) to the 2-3 position (as a trans double bond). Fatty acid oxidation can then proceed.

Polyunsaturated fatty acids are metabolized as follows:

proceeds until arrives at trans - D2, cis - D4

2,4-dienoyl-CoA reductase converts this combination of double bonds to a single

cis - D3, which can the be isomerized as above.

Regulation of fatty acid oxidation:

controlled by availability of fatty acids ---> not to worry -- their presence is controlled!!

covered earlier: glucagon or epinephrine (hormones) ---> stimulate triacylglycerol lipase

2. levels of malonyl-CoA (will see later) controls transport of fatty acids from the cytosol to mito.

malonyl-CoA inhibits the enzyme carnitine acyltransferase I

(converts fatty acids into a form that can pass through the mito membrane)

Ketogenesis:

In order to metabolize the acetate obtained from fats, cells need oxaloacetate, which can condenses with acetate to form citrate. This is why individuals on a diet need some carbohydrate in order to burn their stored fats.

The three ketone bodies provide the brain with about 75% of its energy during starvation. As a person gets well along into starvation the hunger mechanism fails to operate normally. Does the brain function differently when glucose is not available in adequate amounts? Possibly.

No gluconeogenesis from fats in mammals:

Mammals have significant stores of energy in the form of fats, however, the fatty acids contained in these fats can not be converted to glucose.

Acetyl-CoA + CO2 --x--> pyruvate ----> oxaloacetate ----> gluconeogenesis

When the diet is deficient in carbohydrate and protein, the body must maintain its oxaloacetate levels by breaking down its own proteins (usually muscle tissue) to free the glucogenic amino acids they contain.