ME04 - FA Synthesis and Beta Oxidation Flashcards
Where are Fatty acids synthesized?
Cytoplasm
Describe FA synthesis?
Process begins with glycolysis and ends with palmitic acid
Clinical Correlation related to the inhibition of Lipogenesis
Lipogenesis occurs in diabetes mellitus, and contributes to the development of obesity
A characteristic of starvation and of diabetes
Increased fatty acid oxidation or breakdown
The accumulation of ketone bodies
Ketoacidosis
Because gluconeogenesis is dependent on fatty acid oxidation, any impairment in the process can lead to hypoglycemia. True or False?
TRUE
Other Hyperglycemic States
Other Hyperglycemic States
Diabetis Mellitus
Non-Ketotic Hyperosmolar
Coma
Impaired Glucose Tolerance
Stress Hypoglycemia
Other Ketotic States:
Other Ketotic States:
Ketotic Hypoglycemia
Alcoholic Ketosis
Starvation Ketosis
Other Metabolic Acidotic States
Other Metabolic Acidotic States
Lactic Acidosis
Hyperchloremic Acidosis
Salicysm
Uremic Acidosis
Drug-Induced Acidosis
Where does FA Synthesis occur
Occurs in the cytosol
Enzymes involved in FA Synthesis
Acetyl CoA Carboxylase
Fatty acid Synthase Complex
What are used in FA synthesis
CoEnzyme: NADPH
Initial substrate: acetyl CoA
End-product: Palmitic acid
Acetyl CoA cannot enter the mitochondrial membrane directly, and it also cannot enter the cytosol from the mitochondria for fatty acid synthesis. True or False?
True.
FA Synthesis process
- Glucose enters liver cells and is converted via glycolysis to pyruvate
- Pyruvate enters the mitochondria
- Pyruvate is converted to Acetyl CoA by PDH and to oxaloacetate by Pyruvate carboxylase
- Acetyl CoA and OAA condense to form citrate, to cross the mitochondrial membrane
- In the cytosol, citrate is cleaved to OAA and Acetyl CoA by Citrate Lyase.
- OAA from the citrate lyase reaction is reduced in the cytosol by NADH, producing NAD+ and malate. The enzyme is malate dehydrogenase.
- Malate is then converted to pyruvate, NADPH is produced, and CO2 is released. Enzyme: Malic enzyme
What stimulates the reaction in the cytosol in which citrate is cleaved to OAA and Acetyl CoA by Citrate lyase (Citrate Lyase Reaction)
Insulin
After which the Citrate is cleaved to OAA, OAA from the citrate lyase reaction is reduced in the cytosol by NADH, producing NAD+ and malate. What enzyme is used?
Malate dehydrogenase.
When Malate is converted to pyruvate, NADPH is produced, and CO2 is released. What enzyme is used?
Malic enzyme
What is the importance of NADPH
Supplies reducing equivalents for reactions that occur in the fatty acid synthase complex (Reductive biosynthesis)
Produced by the malic enzyme and the Pentose Phosphate Pathway
Fat replacement molecule
Contains a sucrose polyester backbone with 6 to 8 fatty acid side chains, making it too bulky to be digested
Olestra
Side effects of Olestra
Side effects: flatulence, bloating diarrhea
Fatty acid synthesis controlled by activity of:
Acetyl CoA Carboxylase
FA Synthesis is activated by:
Citrate
FA Synthesis is inhibited by
Palmitoyl CoA
Hormones that over-all regulates FA Synthesis
Stimulated by insulin
Inhibited by glucagon and epinephrine
What is the initialandcontrolling step in fatty acid synthesis, and the enzyme used?
Production of malonyl CoA
Enzyme: Acetyl CoA Carboxylase
Multienzyme complex
Exists as a dimer in a head-to-tail configuration
Each monomer contains 7 enzyme activities and ACP with a 4- phosphopantetheine group (fr. Pantothenic acid)
FATTY ACID SYNTHASE
What composed the FATTY ACID SYNTHASE
- Ketoacyl Synthase
- Acetyl Transacylase
- Malonyl Transacylase
- Ketoacyl Reductase
- Enoyl Reductase
- Hydratase
- Thioesterase
ADDITION OF 2-C UNITS in FA SYNTHESIS
- Acetyl-CoA reacts with the phosphopantetheinyl (PP) residue, and then the acetyl group is transferred to the cysteinyl residue
- A malonyl group from malonyl CoA form a thioester with the PP sulfhydryl group. The enzyme is acetyl-CoA carboxylase
- Acetyl group on the FA synthase condenses with the malonyl group, forming a beta-ketoacyl group
REDUCTION OF THE BETA-KETOACYL GROUP
The beta-keto group is reduced by NADPH to a beta-hydroxyl group
Dehydration occurs, producing an enoyl group with the double bond between carbons 2 and 3
Finally, the double bond is reduced by NADPH, and a 4-C acyl group is generated
ELONGATION OF FATTY ACYL CHAIN
Acyl group is transferred to the cysteinyl sulfhydryl group, and malonyl CoA reacts with the PP group. Condensation of the acyl and malonyl groups occur with the release of CO2, followed by the 3 reactions that reduce the beta keto group
This sequence repeats until the growing chain is 16 carbons in length
The final product released by hydrolysis from the FAS complex
Palmitate (16-C, sat)
Not a simple reverse of fatty acid synthesis
OXIDATION OF FATTY ACIDS
Occurs in the mitochondria
Catalyzed by individual enzymes
Uses FAD and NAD as coenzymes
Generates ATP
Process is aerobic
Enzyme required in the activation of fatty acids to acyl CoA
Acyl CoA Synthetase
Differentiate how LCFA and SCFA are activated
In the cytosol of the cell, long chain fatty acids are activated by ATP and CoA, and Fatty acyl CoA is formed.
Short-chain FA are activated in the mitochondria
What happens to the ATP involved in the last part of Oxidation of Fatty Acids
ATP»_space; AMP + pyrophosphate (PPi) | PPi»_space; (pyrophosphatase)»_space; 2 inorganic phosphates
What is needed to transport fatty acids to the mitochondria where oxidation takes place?
Carnitine
TRANSPORT OF FATTY ACYL COA
Fatty acyl CoA from the cytosol reacts with carnitine in the outer mitochondrial membrane, forming fatty acyl-carnitine
(E: Carnitine acyltransferase I or CAT I, also called Carnitine palmitoyltransferase I or CPT I)
Fatty Acyl CoA + Carnitine»_space; (CAT I/CPT I)»_space; Fatty Acyl-Carnitine
Fatty acyl CoA passes into the inner membrane, where it re-forms Fatty Acyl-CoA, which enters the matrix (E: Carnitine acyltransferase II)
Fatty Acyl CoA»_space; (CAT II)»_space; Fatty Acyl-CoA (re-reformed)
Deficiency in plasma membrane carnitine transporter, leading to urinary wasting of carnitine
Impairs transport of fatty acids into mitochondria
PRIMARY CARNITINE DEFICIENCY
Major pathway of fatty acid oxidation
Oxidizes the beta carbon (carbon 3) of fatty acids
Aside from neurons and erythrocytes, this pathway is a major source of ATP for the cell
BETA OXIDATION - cuts the whole fatty acid into 2 carbon fragments in the form of Acetyl CoA
Principle of Beta-Oxidation
Two carbons cleaved at a time from acyl CoA starting at the carboxyl end
Chain is broken between a (C2) and b (C3) carbon
ENERGY YIELD COMPUTATION
8 ACETYL-COA (X 10 via CAC) = 80 ATP
7 FADH2 (X 1.5 via ETC) = 10.5 ATP
7 NADH (X 2.5 via ETC) = 17.5 ATP
TOTAL = 108 ATP
Minus 2 ATP (initiation) activation of palmitate to Palmitoyl CoA
108 ATP 2 ATP = 106 ATP
What hormone regulates the Fatty acid oxidation
Hormone-sensitive adipose tissue lipase (HSL)
What enzyme allosterically inhibits Carnitine Palmitoyltransferase (CPT)?
Malonyl-CoA | Malonyl CoA is formed in the regulated step of fatty acid biosynthesis
Fatty acid oxidation is inhibited when fatty acid synthesis is active. True or False?
TRUE
Fate of Excess acetyl CoA from B-oxidation
They are converted to ketone bodies.
OTHER TYPES OF FA OXIDATION
Peroxisomal B-oxidation; a-Oxidation; w-Oxidation
Type of FA Oxidation for very long chain fatty acids
Molecular O2 is used, H2O2 is formed, no ATP formed
Peroxisomal B-oxidation
Type of FA Oxidation where there is the removal of one carbon at a time from the carboxyl end of the
molecule, released as CO2
Does not generate ATP
a-Oxidation
Type of Oxidation where the Oxidation of carbon beginning farthest from the carboxyl end
(methyl carbon)
Beta oxidation follows in the mitochondria
Forms a dicarboxylic acid
w-Oxidation
Peroxisomal disorder
Results in accumulation of long chain fatty acids
Death results during the 1st yr of life
ZELLWEGER SYNDROME
The rare metabolic disorder depicted in the 1993 fil_ Lore_zos Oil
VLCFAs a__u_ulate i_ the rai _ausi_g demyelination and in the adrenal cortex causing degeneration
Psychomotor retardation and seizures
ADRENOLEUKODYSTROPHY
Formed when fatty acids are in high concentration in blood (fasting, starvation, high fat diets)
Accumulation of Acetyl CoA, which cannot condense with OAA bec. OAA is used to synthesize glucose
KETONE BODIES
Where does the synthesis of Ketone Bodies occurs
Synthesis occurs in liver mitochondria
Example of Ketone Bodies
- Acetoacetic acid moderately
- B-Hydroxybutyric acid strong acids
- Acetone
Stimulation in the formation of Ketone Bodies
When there is a high rate of Fatty Acid Oxidation in the liver
Major route of ketone bodies formation
HMG CoA PATHWAY
STEPS IN KETONE BODY SYNTHESIS
- Two molecules of acetyl CoA condense to form acetoacetyl CoA, catalyzed by thiolase
- Acetoacetyl CoA and acetyl CoA form HMG CoA catalyzed by HMG CoA synthetase
- HMG CoA is cleaved by HMG CoA Lyase to form Acetyl CoA and acetoacetate
- Acetoacetate can be reduced by 3- hydroxybutyrate dehydrogenase to 3- hydroxybutyrate (reversible)
- Acetoacetate may also be spontaneously decarboxylated to acetone (gives odor to the breath of diabetics and starvation patients)
Why does the liver cannot use ketone bodies?
The liver lacks the enzyme SUCCINYL COA- ACETOACETATE COA TRANSFERASE, so it cannot use ketone bodies
What ketone bodies are released into the bloodstream from the liver?
The ketone bodies acetoacetate and 3- hydroxybutyrate (also called beta- hydroxybutyrate)
Use of Ketone Bodies
Taken up by muscles and the kidney
During starvation, can be used by the brain because of its increased concentration in blood
Acetoacetate can enter cells directly, or it can be produced from the oxidation of 3- hydroxybutyrate by 3-hydroxybutyrate dehydrogenase. NADH is produced by this reaction.
How is acetoacetate activated?
By reacting with succinyl CoA to form acetoacetyl CoA and succinate (E: Succinyl-CoA-acetoacetate-CoA transferase)
Acetoacetate + Succinyl CoA»_space;(Succinyl-CoA-acetoacetate-CoA transferase)»_space; Acetoacetyl CoA + Succinate
ENERGY PRODUCTION IN THE KETOGENESIS
1 ACETOACETATE = 2 ACETYL COA (20 ATPs)
However, activation of acetoacetate results in the generation of one less ATP (GTP is not produced when succinyl CoA is used to activate acetoacetate)
Tus, total yield from 1 acetoacetate is 19 ATP
When 3-hydroxybutyrate is oxidized, 2.5 additional ATPs are formed because the oxidation of 3-hydroxybutyrate to acetate produces NADH
So total is either 19 ATP/21.5 ATP
Production of ketone bodies in excess of the ability of the body to use them
KETOSIS
Concentration of ketone bodies in the blood > 0.2 mmol/L
KETONEMIA
Concentration of ketone bodies in the blood >1 mg/24 hour loss of ketone bodies in the urine
KETONURIA
When does Ketosis occur?
Can occur in starvation and in uncontrolled diabetes
mellitus
The oxidative degradation of lipids.
Lipid peroxidation
Free radicals “steal” electrons from the lipids in cell membranes, resulting in cell damage.
This process proceeds by a free radical chain reaction mechanism.
Lipid Peroxidation targets what type of FA
Lipid peroxidation most often affects polyunsaturated fatty acids, because they contain multiple double bonds in between which lie methylene -CH2- groups that possess especially reactive hydrogens.
Three Steps in Lipid Peroxidation
initiation, propagation, and termination
Lipid Peroxidation
- Reactive radical abstracts atom of Hydrogen from PUFA side chain in lipoprotein
- Carbon radical reacts with oxygen.
- Resulting radical attacks adjacent FA side chain to generate a new carbon radical
- And the chain reaction continues.
When does the radical reaction stops? // Termination.
When two radicals react and produce a non-radical species.
This happens only when the concentration of radical species is high enough for there to be a high probability of collision of two radicals.
Important antioxidants
One important such antioxidant is vitamin E. Other anti-oxidants made within the body include the enzymes superoxide
dismutase, catalase, and peroxidase.
Elevation of serum TG > 1 g/dL
Pancreatitis
Excess Ethanol Consumption
Alcoholic fatty liver
Genetics, overeating, sedentary lifestyle
Obesity
TG levels over 200 mg / dL
Hyperlipidemias
HYPERLIPIDEMIAS
Pancreatitis,
Xanthomas (yellow fat papules on skin),
Lipemia retinalis (pale or milky appearance of retinal blood vessels),
Hepatomegaly
