BCMB 3100- Case 10

lipids

- rich in carbon and hydrogen (little oxygen)

- not soluble in water

1. fatty acids

2. triacylglycerols

3. membrane lipids (phospholipds, cholesterol)

fatty acids

- simplest lipids

- long chain hydrocarbons with carboxylate group at one end

- most prominent fuel (yield more ATP than glucose)

- excess storage leads to problems (fatty liver, LDL)

carboxyl group

COOH

triacylglycerols

- triester made of one glycerol and 3 fatty acids

- can be mix of saturated and unsaturated

- ester linkage

membrane lipids

- diester contains one glycerol and 2 fatty acids (nonpolar tails) and one phosphate-amino alcohol (polar head)

steroid

- four fused ring structures (3 cyclohexane and 1 cyclopentane)

saturated fatty acid

- C-C is single bonded

- more hydrogen atoms a fatty acid has the more "saturated" it is and the higher its melting temperature will be

unsaturated fatty acid

- has C=C double bond

- causes a bend in the carbon chain and prevents the chains from coming near each other and interacting strongly

1. cis- monosaturated (one C=C)

2. trans- monosaturated (one C=C)

3. omega-3 fatty acid- polysaturated (>one C=C)

phospholipids

- amphipathic

- major component of cell membranes

- consist of a 3-carbon glycerol linked to a negatively charged phosphate group and two fatty acids

amphipathic

Amphipathic molecules have a nonpolar region (hydrophobic) and a polar region (hydrophilic)

adipocytes

- cells that primarily compose adipose tissue, specialized in storing energy as fat

- gram of nearly anhydrous fat stores more than six times as much energy as a gram of hydrated glycogen

glycerol

three-carbon alcohol with a hydroxyl group attached to each carbon

ester linkage

formed between the glycerol molecule and the fatty acids in a fat

naturally occurring fatty acids

1. even number of C atoms

2. all cis (no trans)

trans fat

- A type of unsaturated fats that are uncommon in nature

- Created in an industrial process that adds hydrogen to liquid vegetable oils to make them more solid (longer shelf life)

- raises LDL and lowers HDL

- increased risk of coronary heart disease

- Increases triglycerides in the bloodstream and promoting systemic inflammation

- Alzheimer's risk may be 75% higher

trans fat structure

Has a trans formation around double bond

emulsion

- a mixture of lipid droplets and water

- enhanced with bile salts (make the triacylglycerols more readily digested)

chylomicron formation

- Free fatty acids and monoacylglycerols are absorbed by intestinal epithelial cells

- Triacylglycerols are resynthesized and packaged with other lipids and proteins to form chylomicrons

- released into lymph system

peptide hormones as regulatory signals

1. insulin

2. glucagon

fatty acid processing stages

1. lipolysis/mobilization

2. activation

3. b-oxidation

lipolysis

- Triacylglycerols are degraded to fatty acids and glycerol

- lipase

1. glycerol (LIVER)--> glycolysis or gluconeogenesis

2. fatty acids (OTHER TISSUES) --> fatty acid oxidation

activation

- Fatty acids must be activated and transported into mitochondria for degradation

- acyl CoA synthetase

1. activated in cytoplasm (2 ATP --> AMP + 2Pi)

2. translocation into inner membrane space

Fatty acid translocation

- Fatty acid oxidation takes place in mitochondrial matrix

- Transport across inner membrane requires fatty acids be linked to carnitine

- Activated fatty acids cross inner mitochondrial membrane through Acyl carnitine Translocase

b-oxidation

Fatty acids are broken down in a step-by-step fashion into acetyl CoA, FADH2, and NADH which is then processed in the citric acid

b-oxidation process

1. Fatty acids are linked to Co A --> Acyl CoA

2. Acyl CoA is translocated to the mitochondrial ma

3. Fatty acids are degraded by repetition of a 4-reaction (oxidation, hydration, oxidation, and thiolysis)

- each round gets rid of 1C except for last round takes 4

fatty acid degradation steps

1. fatty acid + CoA + ATP --> acyl CoA + AMP + PPi

2. carnitine + acyl CoA --> acyl carnitine + CoA

3. b-oxidation (oxidation, hydration, oxidation, and thiolysis)

why more energy released from a fat molecule than from a glucose molecule

- fats require more oxidation to become CO2 and H2O than carbohydrates

- the carbons in fats are more reduced

- carbohydrates are already partly oxidized

highest energy form of a single carbon

methane

lowest energy form of a single carbon

CO2

Degradation of Unsaturated Fatty Acids Requires Additional Steps

- cis-Δ3-Enoyl CoA isomerase allows the β oxidation of fatty acids with a single double bond to continue

- no Acyl CoA dehydrogenase reaction

- less FADH2 produced

double bonds and ATP produced

- most ATP- least # of double bonds

- least ATP- most # of double bonds

Excess of Ketone-Body Production

- can result from an imbalance in the metabolism of carbohydrates and fatty acids in people without diabetes

- excess can be dangerous

ketone bodies and diabetes

1. oxaloacetate level drops due to no glucose stored in liver

2. CAC slows

3. free fatty acids are released

4. ketone bodies form

5. pH drops

6. coma/death

ketogenesis location

liver mitochondria

types of ketone bodies

1. acetoacetate

2. D-3-hydroxybutyrate (β-hydroxybutyrate)

3. acetone

ketone bodies benefits

- water soluble

- easily transportable form of acetyl units

- heart muscle and the renal cortex of the kidney may use acetoacetate in preference to glucose

acetone

produced by the slow, spontaneous decarboxylation of acetoacetate

molecule released from the final round of b-oxidation of Odd-Chain Fatty Acids

Propionyl CoA in final thiolysis step

Propionyl CoA

- Produced during the oxidation of odd-chain fatty acids and some amino acids

- converted into the citric acid cycle intermediate succinyl CoA

- allows for replenishment of oxaloacetate and high energy electrons for the electron transport chain

Acetyl CoA starting points

- all in matrix of mitochondria

1. pyruvate

2. fatty acids

3. ketone bodies

acetyl CoA fates

1. citric acid cycle- matrix of mitochondria

2. ketone bodies- matrix of mitochondria

3. fatty acid synthesis- cytoplasm

stages of fatty acid synthesis

1. Acetyl CoA transported from mitochondria to cytoplasm (converted to citrate then back)

2. Acetyl CoA is activated to produce Malonyl CoA (requires ATP and biotin)

3. Condensation, reduction, dehydration, and reduction

Acetyl CoA transported from mitochondria to cytoplasm

- acetyl CoA + oxaloacetate --> citrate via Citrate synthase

- Transporter --> Citrate Carries across membrane

- acetyl CoA and oxaloacetate broken down via ATP citrate lyase

- NADH --> NADPH

Acetyl CoA is activated to produce Malonyl CoA

- carboxylation step

- Acetyl-CoA carboxylase 1(regulatory enzyme in fatty acid metabolism)

- committed step

Condensation, reduction, dehydration, and reduction

- fatty acid synthase

- Fatty acid is synthesized (two carbon atoms at a time)

NADPH

- reducing power required by fatty acid synthesis

pentose phosphate pathway

- important source of NADPH (biosynthetic reducing power)

- catalyzes the interconversion of the three- and six-carbon intermediates of glycolysis with five-carbon carbohydrates

- interconversions enable the synthesis of pentose sugars required for DNA and RNA synthesis as well as the metabolism of five-carbon sugars consumed in the diet

regulation of fatty acid synthesis

- Acetyl CoA Carboxylase- regulated by cellular conditions (AMPK)

- carboxylase is inactivated when the energy charge is low

- fats not synthesized when energy is required

- glucagon- inhibits

- insulin- stimulates

AMPK

- AMP-activated protein kinase

- activated by AMP and inhibited by ATP

active carboxylase

- protein phosphatase 2A

- H2O --> Pi

- activated by insulin (dephosphorylates Acetyl CoA carboxylase)

- absence of citrate

inactive carboxylase

- AMP-activated protein kinase

- ATP --> ADP

- activated by glucagon (phosphorylates Acetyl CoA carboxylase)

- partly activated by citrate

citrate

- allosterically activates Acetyl-CoA Carboxylase

- concentration is high when there is adequate acetyl-CoA entering citric acid Cycle

- Excess acetyl-CoA is then converted via malonyl-CoA to fatty acids for storage

Synthesis of lipids

- Triacylglycerol synthesized in liver (Triacylglycerol synthase catalyzes triacylglycerol formation on the ER membrane)

- Fatty acids are synthesized in the cytoplasm

- Phosphatidate (phospholipid) is produced in the cytoplasm.

cholesterol function

1. structural component of cell membrane

2. precursor of synthesis of other steroids

3. essential ingredient in lipoproteins

4. fatty acids are transported to liver as cholesterol for oxidation

ethanol metabolism and NADH

- produces NADH --> low NAD+ levels

- hypoglycemia

- prevents lactate conversion --> pyruvate

- lactate builds up --> lactic acidosis

- inhibits fatty acid oxidation --> low ATP

- Triacylglycerols accumulate in the liver à Fatty liver

ethanol metabolism

1. ethanol --> acetylaldehyde via alcohol dehydrogenase

2. acetylaldehyde --> acetate via aldehyde dehydrogenase

ketone bodies in ethanol metabolism

- acetate can be converted into Acetyl CoA

- TCA cycle is blocked due to high NADH --> ketone bodies

- increase severe acid condition (in addition to lactic acidosis)

- Processing of acetate in liver becomes inefficient so acetaldehyde builds up even more

acetylaldehyde

- toxic product of ethanol metabolism

1. covalently binds to a variety of proteins (alters function)

2. decreases the polymerization of microtubules thereby impairing protein secretion (swells liver cells)

3. impairs some enzyme activities (favors lipid peroxidation)

4. mitochondrial functions are altered (particularly after chronic ethanol consumption which sensitizes the mitochondria to the toxic affects)

high Km for ALDH

- least efficient form of the enzyme for detoxifying acetaldehyde

- alcohol side effects

low Km for ALDH

most efficient form of the enzyme for detoxifying acetaldehyde

ALDH

Aldehyde dehydrogenase

ADH

alcohol dehydrogenase

molecule glycerol os converted into so that it can enter glucose metabolism

glyceraldehyde 3-phosphate

chemical reaction for activation of fatty acids

fatty acid + CoA + ATP --> fatty-acyl-CoA + AMP + PPi

equivalents of ATP used in fatty acid activation

2

- one for ATP --> ADP

- one for ADP --> AMP

beta-oxidation of acyl-CoA

acyl-CoA + FAD +NAD+ + H2O + CoA --> acyl- CoA + FADH2 + NADH + acetyl-CoA + H+

ATP per acetyl CoA, NADH, and FADH2

- acetyl CoA = 10 ATP

- NADH = 2.5 ATP

- FADH2 = 1.5 ATP

ketogenesis location

mitochondria of liver cells

ketone bodies as fuel

- fatty acid synthesis.

- occurs when glucose is scarce and a low energy charge.

- begins with D-3-hydroxybutyrate oxidized to acetoacetate

- acetoacetate --> acetoacetyl CoA to form 2 acetyl CoA molecules

- acetyl CoA molecules are then able to enter the citric acid cycle for ATP production and the NADH is used in the electron transport chain in ATP synthesis

lack of carbohydrates affect on ability to use fats

- lead to the formation of ketone bodies due to energy being created through fatty acid synthesis

- fruity breath from acetone

reaction catalyzed by Acetyl CoA carboxylase

Acetyl CoA + HCO3- + ATP --> malonyl CoA + ADP + Pi

insulin and acetyl CoA carboxylase

- signals that glucose should be stored by liver cells and lower amount of glucose in blood

- dephosphorylates acetyl CoA carboxylase to convert Acetyl CoA + HCO3- + ATP --> malonyl CoA + ADP + Pi

- more acetyl CoA is required from pyruvate (from glucose in glycolysis)

- Glycolysis is initiated when glucose levels are high which is similar to insulin which is also signaled when glucose levels are high

NADH and glycolysis

inhibits

NADH and gluconeogenesis

- inhibits

- this is because the high levels of NADH means that there are low levels of NAD+ which is an intermediate in the lactate --> pyruvate conversion

- causes an accumulation of lactate and less pyruvate which is a starting material for gluconeogenesis

- With less pyruvate gluconeogenesis would also be inhibited

NADH and TCA

inhibits

NADH and fatty acid oxidation

inhibits

NADH and fatty acid synthesis

activates

heavy drinking and fatty liver disease

- consumption of a lot of ethanol which produces NADH

- NADH can cause the citric acid cycle (ATP generating pathway) to be inhibited due to the high energy charge which would result in accumulation of acetyl CoA

- high NADH will also cause fatty acid synthesis which is an ATP utilizing pathway due to the high energy charge.

- Accumulation of acetyl CoA along with fatty acid synthesis results in triacylglycerol to accumulate in the liver resulting in fatty liver disease

acetylaldehyde damage of liver

- accumulation of acetyl CoA and ketone bodies due to the inhibition of citric acid cycle by NADH

- Acetaldehyde is supposed to be converted to acetate but the ketone bodies will lower the pH and cause acidic conditions causing inability to process acetate by liver

- causes significant damage of the liver such as impairing protein secretion, impairing enzyme activities, and altering mitochondrial functions.