Maltese - Lipids 1 - Fatty Acids & The Beta-Oxidation Pathway

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1

List 5 functions of lipids

1. Components of cell membranes
2. Concentrated energy stores
3. Metabolic Fuel
4. Vitamins
5. Hormones
6. Intracellular Messengers

2

List 3 functions of fatty acids

1. Structural components of various membrane and storage lipids
2. Metabolic Fuel
3. Source of carbons for biosynthesis
4. Precursors for biologically important hormones

3

Describe what is meant by the term "amphipathic" lipid

Both polar and non-polar parts, eg. phospholipids

Phosphate-alcohol charged groups are hydrophilic, fatty acid side chains off the glycerol backbone are hydrophobic

4

Determine the hydrocarbon chain-length in a fatty acid, based on standard systematic and common nomenclature

CH3(CH2)nCOO- (n=0-24)

Standard Names / Common Names
eg.
n-Dodecanoate (12 C) / Laurate
n-Tetradecanoate (14 C) / Myristate
n-Hexadecanoate (16 C) / Palmitate
n-Octadecanoate (18 C) / Stearate

5

Describe the number and location of double bonds in common unsaturated fatty acids, when given standard nomenclature

Monounsaturated = 1 double bond
Polyunsaturated = 2-6 double bonds

standard nomenclature:
-anoate = no double bonds
-enoate = 1 double bond
-dienoate = 2 double bond

6

Recognize the three different ways to designate the double bond positions in an unsaturated or a polyunsaturated fatty acid

1. Delta + superscript "x" : indicates first carbon of double bond counting from carbon 1 (the carboxyl C)
2. wx : "x" is first carbon of double bond counting from omega end
3. A:B(x) : A = chain length, B = # db, x = first carbon of double bond counting from carbon 1

7

Recognize the structures (chain lengths, double bonds) of the following common fatty acids: myristic, palmitic, palmitoleic, stearic, oleic, linoleic, linolenic, and arachidonic

Myristate: 14:0
Palmitate: 16:0
Palmitoleate: 16:1(9) (w 7)
Stearate: 18:0
Oleate: 18:1(9) (w 9)
Linoleate: 18:2(9,12) (w 6, 9)
Linolenate: 18:3(9,12,15) (w 3, 6, 9) FISH OILS
Arachidonate: 20:4(5,8,11,14) (w 6, 9, 12, 15)

8

Describe the general effects of fatty acid chain length and unsaturation on melting point

longer the chain length and the more saturated (less double bonds, more H's), the higher the melting point

9

Describe fate of a fatty acid

Fatty acids travel through the blood to muscle tissue where they are activated (by Acetyl CoA Synthetase) to enter the mitochondria.

Inside the mitochondria, fatty acyl chains are metabolized by the process of beta-oxidation. Beta-oxidation occurs in a series of steps, breaking down the fatty acyl chain to form 2 carbon subunits of Acetyl-CoA.

Each time Beta-oxidation occurs, NADH and FADH2 are produced. These electron donors pass their electrons down the ETC to yield ATP (2.5 ATP/NADH molecule and 1.5 ATP/FADH2 molecule).

The Acetyl-CoA units generated are also later used in the TCA Cycle to produce more ATP.

10

Describe the effects of hydrogenation and double bond configuration (cis, trans) on the properties of unsaturated fatty acids

Hydrogenation of polyunsaturated fatty acids (making them more saturated) raises their melting temperature

Conversion from cis to trans of fatty acids makes them act more saturated (less kinks), decreasing fluidity or increasing hardening (raise melting temperature)

11

Why can't fatty acids enter the mitochondrial matrix? How is this overcome?

-they are too hydrophobic

-instead they are activateed by acyl-CoA synthetase
(requiring ATP) to go from R-C(=O)-OH (R-COOH) to R-S-CoA where R is a long hydrocarbon chain

-short fatty acyl-CoA chains can simply diffuse through the inner mitochondrial matrix membrane, but chains longer than 10 C have to use a translocase (carnitine shuttle)

Overall: Fatty Acid + ATP + HS-CoA → Acyl-S-CoA + AMP + PPi

Step 1: Fatty acid (R-COO-) + ATP → Acyl AMP + PPi

where Acyl AMP is R-COO-PO3-Ribose-Adenine

Step 2: Acyl-AMP (R-C(=O)-AMP) + Coenzyme A (HS-CoA)→Acyl-CoA (R-C(=O)-S-CoA) + AMP

12

Describe the reactions required to transport long-chain fatty acids from the cytoplasm into the mitochondrial matrix

1. Activation of free fatty acid by linkage to CoA with Acyl-AMP intermediate, catlazyed by Acyl-CoA Synthetase.

2. Transport across inner mitochondrial membrane into the matrix involving conjugation to carnitine (carnitine shuttle) with Acyl-Carnitine intermediate. Catalyzed by CPT-I/II.

3. Acyl-CoA (cytoplasm) → Acyl-Carnitine (intermembrane space) → Acyl-CoA (matrix)

13

Why does linkage to coenzyme A allow the fatty acyl chain to get into the matrix?

hydrolysis of the thioester (CoA-S-CO-R...) more thermodynamically favorable than oxygen ester (HO-CO-R) (standard free energy change is exergonic <0)

14

Describe the reactions involved in converting Fatty Acyl-CoA to Acetyl-CoA (beta-oxidation reactions)

OH→OC

1. OXIDATION: Fatty Acyl CoA oxidized by FAD (rate limiting step): the single bond between Carbons 2 & 3 (alpha and beta carbon) turns into a double bond and 2 Hs released to make FADH2 (anoate→enoate)

2. HYDRATION: H2O added such that the double bond is broken and the beta carbon (C3) gets an OH group (the alpha carbon gets another H)

3. OXIDATION: Carbonyl group is recreated on the Beta carbon (C3) and 2 H's are released to NAD+ to get NADH + H+

4. CLEAVAGE (THIOLYSIS): Cleavage occurs between the alpha & beta carbon and -S-CoA binds to the beta carbonyl carbon. The H from the CoASH added goes onto the alpha carbon to form acetyl coA.

END PRODUCTS: Acyl CoA (shortened by 2 C), Acetyl CoA, ATP, NADH, FADH2, H+

15

Recognize the names of enzymes and the reaction products for each of the above steps in beta-oxidation reactions

1. Acyl CoA Dehydrogenase:
Oxidation of Acyl-CoA by FAD to get trans-Δ2-enoyl CoA + FADH2

2. Enoyl-CoA Hydratase (Cronotase):
Hydration of trans-Δ2-enoyl CoA by H2O to get L-β-hyrdoxyacyl CoA

3. L-β-hyrdoxyacyl CoA Dehydrogenase:
Oxidation of L-β-hyrdoxyacyl CoA By NAD+ to get β-ketoacyl CoA + NADH + H+

4. β-ketothiolase (thiolase):
Cleavage of β-ketoacyl CoA by CoA-SH to get Acyl-CoA (2 carbons shorter) + Acetyl-CoA

16

Recognize the general structure of Coenzyme A and identify the major structural units

Consists of 2 parts: Pantetheine (HS-CH2-CH2-NH-C....) & 3'P-ADP (has 3 phosphate groups)

17

Describe how the carnitine shuttle works in fatty acid transport across the mitochondrial membrane

Carnitine is a zwitterionic alcohol

1.Carnitine shuttle takes Acyl-CoA and converts it to Acyl-Carnitine via CPT-I

2. Acyl-Carnitine deposited in transmembrane space of mitochondria

3.Translocose brings carnitine into transmembrane space in exchange for Acyl-Carnitine

4. Carnitine Acyl Transferase II (CPT-II) cleaves acyl group from carnitine and reattaches it to CoA in matrix

Net effect: transport Acyl-CoA from cytoplasm into matrix

18

Tabulate the amount of ATP generated from complete oxidation of a common saturated fatty acid (myristate and stearate), including the conversion of the resulting acteyl-CoA to CO2 and H2O in mitochondria

(0.5*n - 1) * 14 + 8 = total ATP where n=# carbons

1 Acetyl-CoA = 10 ATP in TCA Cycle (NADH/H=2.5 ATP, FADH2 = 1.5 ATP, 1 substrate level ATP in TCA Cycle)

Each round of Beta-oxidation produces 1 Acetyl CoA, 1 NADH + H+, 1 FADH2 = 14 ATP/round

You produce 1 Acetyl CoA per round + 1 extra at the end (eg. cut 6 times to get 7 pieces). Since activation of fatty acid (attachment to CoA-SH) requires 2 ATP, add 10-2 = 8 ATP at the end

Myristate (14 C): 6*14 + 8 = 92 ATP
Stearate (18 C): 8*14+8 = 120 ATP
Palmitate (16 C): 7*14+8 = 106 ATP
Laurate (12 C): 5*14+8 = 78 ATP

19

Write the summary equation for beta-oxidation of a given fatty acid (eg. palmitate, myristate, stearate)

1 Palmityl-CoA + 7 FAD + 7 NAD + 7 CoA-SH + 7H2O → (7 cycles) → 8 Acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+

1 Myristyl-CoA + 6 FAD + 6 NAD + 6 CoA-SH....

1 Stearate-CoA + 8 FAD + 8 NAD + 8 CoA-SH...

20

List the Beta-oxidation end products for pentadecanoic acid

15/2 = 7.5 -> 6 cycles using 6 Acetyl-CoA (12 C) and 1 Propionyl-CoA (3 Carbons)

End with:
1 Succinyl CoA + 6 NADH, 6 H+, 6 FADH2, 6 Acetyl-CoA (6*10 + 6*2.5 + 6*1.5 -2 = 82 ATP)

21

Recognize the additional reactions and accessory enzymes needed for Beta-oxidation of unsaturated and polyunsaturated fatty acids

2 Accessory Enzymes needed for B-oxidation of unsat/polyunsat fatty acids:

1. Cis-Δ3-Enoyl-CoA Isomerase
2. 2,4-Dienoyl-CoA Reductase

You need the isomerase because the cis-enoyl cannot be metabolized by enoyl-COA hydratase...need to switch to trans-Δ2-CoA

You need the 2,4-Dienoyl-CoA Reductase because ...

22

Describe the enzyme defect in MCAD

MCAD: Medium Chain Acyl-CoA Dehydrogenase Deficiency

-beta oxidation of med chains (6-12 carbons) is deficient due to DEFECT in MCAD

-cannot break down fatty acid chains --> cannot produce ATP from beta oxidation -->sudden death if untreated

-symptoms: vomiting, lethargy, coma

-can occur during periods of fasting (hypoglycemia)

23

How do they test for MCAD and what is the treatment?

Urine contains MCFA esters of glycine and carnitine

Treatment with IV glucose, high carb diet, avoid fasting

24

Explain why a patient with a genetic defect in CPT-I or CPT-II would benefit from addition of medium chain-fatty acids to the diet

CPT-I and CPT-II are required to translocate long chain fatty acids across the mitochondrial membrane, but med and short chains can just diffuse through. Therefore, the body will be able to make energy using more medium chain-fatty acids rather than less long chain just via proper diet.

25

Describe the differences between fatty acid oxidation in mitochondria versus peroxisomes

in PEROXISOMES:

-oxidation cycle ends with octanyl-CoA rather than acetyl-CoA. Octanyl coA probably gets transproted to mitochondria for complete catabolism to Acetyl-CoA though

-first step of oxidation cycle involves a different electron receptor. Acyl-CoA Dehydrogenase step in mitochondria uses FAD-->FADH2 but in peroxisomes uses O2 --> H2O2 --> H2O + .5O2

26

Effects of w3 fatty acids

-decrease blood triglycerides (high dose)
-decrease platelet adhesion
-increase nitric oxide production (blood vessel dilation)
-decrease ischemic myocardial damage and inflammation
-decrease restenosis after angioplasty (high dose)

27

long names for each step in beta-oxidation of fatty acid

Acyl-CoA → trans-Δ2-enoyl CoA** → L-β-hyrdoxyacyl CoA → β-ketoacyl CoA →Acyl-CoA (2 carbons shorter)


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