Oxidation Of Fatty Acids

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Fatty acids
General structure and carbon labeling
Fuel source: tissues that use it and tissues that do not

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Have hydrocarbon chain with carboxylate end. Alpha C is the first C next to the COOH. second is beta, last one is the omega C.

Fuel for tissues: major energy source to skeletal and cardiac muscle
-brain and RBC do NOT use fatty acids
-FA do not cross blood-brain barrier
-FA oxidation occurs in mitochondria, which RBC lack

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Triacylglycerol:
fuel source as compared with glycogen

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-more efficient energy storage than glycogen
-on weight basis: yield 2.5 times more ATP than glycogen
-has 4 times more energy yield per gram than hydrated glycogen; insoluble so it aggregates in water

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Mobilization of triacylglycerides stored in adipose tissue to result in beta-oxidation in target cells
-hormone-initiated mechanism

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-Hormone binds to receptor, Adenylyl cyclase activated and cAMP increases, PKA activated, HORMONE-SENSITIVE LIPASE phosphorylated and activated, becomes a lipid droplet

-hormone-sensitive lipase/lipid droplet hydrolyzes triacylglycerol to fatty acids:
-Perilipin (protein that coats lipid droplet) blocks FA lipase enzyme, phosphorylation allows triacyclglycerol to enter lipases and be cleaved by TRIACYLGLYCEROL LIPASE enzyme into fatty acids and glycerol

-FA released to blood and bind to ALBUMIN; FA transported to target tissues and enter cell by FA transporters

-In cells: conjugated with CoA to form fatty acyl-CoA for beta-oxidation

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Hormonal regulation of triacylglycerol metabolism
1. glugagon, epinephrine, and ACTH (adrenocoricopic hormone)
2. insulin

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1. increase cAMP, phosphorylation of FA lipase and perilipin by PKA= release of free fatty acids from adipose

2. inhibits FA lipase by promoting dephosphorylated state

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Fatty acid oxidation
Stage 1: activation of FA to Fatty acyl-CoA
-Enzyme, location of enzymes
-reaction requirements, intermediate in 2-step process, and biproducts

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Enzyme: acyl-CoA synthetases (thiokinases) in outer mito membrane and ER

Reaction: requires hydrolysis of 2 high energy bonds in ATP (ends with AMP, 2Pi, and 2 H+ as biproducts)

-**FA first bound to AMP from ATP then CoA attaches and AMP leaves

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Fatty acid oxidation
Step 2: transport of Fatty acyl-CoA to mitochondrium
-short/medium chains
-long chains

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Short and medium chain FA diffuse into mitochondria (2-12 C)

Long chains use mechanism of The carnitine shuttle to enter mito
(extraLong chains over 20C catabolized in peroxisome)

1. Carnitine Palmitoyltransferase I (CPT-I) in Outer mitochondria membrane cleaves CoA of Fatty acyl-CoA by converting carnitine to acylcarnitine.
*Malonyl CoA inhibits CPT-I in fed state to prevent fatty acid oxidation; is an intermediate of fatty acid biosynthesis, negative feedback b/c can't make and oxidize FA at same time

-Acylcarnitine moves through carnitine-acyl carnitine translocase and CPT-II (both in inner mitochondrial membrane) to add CoA to acyl group to make Acyl-CoA
-Acyl-CoA goes to beta-oxidation in the mitochondrial matrix

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Fatty acid oxidation
Stage 3: beta-oxidation of FA
-4 enzymatic rxns: know enzymes, general rxns, biproducts, and end products

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1. Acyl-CoA dehydrogenase: dehydrogenation (oxidation) of Palmitoyl-CoA (and reduction of FAD)

2. Enoyl-CoA hydratase= addition of water to new double bond formed in first step

3. Beta-hydroxyacyl-CoA dehydrogenase: oxidation of beta-hydroxyacyl-CoA to a ketone; NAD reduced to NADH

4. acyl-CoA acteyltransferase (thiolase)= thiolytic cleavage by CoA= acyl CoA and **Acetyl-CoA are formed (FADH2 and NADH also formed in overall process)

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Energy yield from beta-oxidation of fatty acids

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7 FADH2 made, 7 NADH made from palmitic acid in beta-oxidation itself
-also oxidation of each acetyl CoA in Kreb's makes about 10 ATP (8 acetyl CoA from acid)

***Total yield about 100 ATP per palmitate

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Ketogenesis
Where?
Formed from what?
When?
Exported to which organs? How?
Types of ketone bodies (3)

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Where: liver mitochondria
Formed from what: Ketone bodies formed from acetyl-CoA
When? When theres a high rate of B-oxidation in liver (starvation, aceytl CoA product available)

Exported to: heart, brain, kidney, skeletal muscle
-mitochondria of these tissues make aceytl CoA from ketone body to use in TCA cycle

Types of ketone bodies:
1. Acetoacetone
2. b-hydroxybutyrate
3. acetone
-common intermediate=HMG-CoA (also intermediate for cholesterol)

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Prolonged fasting state
Role of:
Adipose
Liver
Muscle

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Adipose: TAG to FA + Glycerol. FA go to muscle and liver to make ketone bodies. Glycerol goes to liver.

Liver: FA to acetyl CoA to ketone bodies. Ketone bodies go to muscle and brain and oxidized for energy.
-Prolonged fasting: glycerol to glucose (gluconeogenesis).
-Glycerol to Glycerol 3P by glycerol kinase; G3P to DHAP

Muscle: FA to ketone bodies (from adipose) and accepts ketone bodies from liver.

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Alt. oxidation: Omega-oxidation of fatty acids
Where? with what?
Why?
How? general mechanism, end product, biproducts

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-in ER with p450 involved

-Why? When beta-oxidation is defective, this becomes prevalent pathway for FA oxidation

How? hyroxyl group added to omega carbon, then is oxidized to a COOH
-biproducts: NADP+, 2 NADH
-end product: DICARBOXYLIC ACID formed by b-oxidation in mitochrondria***

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Carnitine Deficiencies
1. primary carnitine deficiency
2. secondary " "
A) CPT deficiency
B) carnitine translocase deficiency

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1. Primary Carnitine deficiency: defect in high affinity PM carnitine transporter in muscle, kidney, heart, and fibroblasts (NOT liver). Results in low levels of carnitine in tissues and plasma. Causes muscle cramping, severe muscle weakness, and death. Can be treated with dietary adjustments

2. Secondary carnitine deficiency: 2 types, defects in beta-oxidation pathway, accumulated acylcarnitines are secreted in urine
A) CPT deficiency: Mutation in CPT II gene; leads to muscle weakness in prolonged exercise, loss of myoglobin in urine. Servere forms: disease in infancy- hypoglycemia, hyperammoniemia,cardiac malfunction, death

B)carnitine translocase deficiency: hypoglycemic coma, hyperammoniemia, weakness, cardiomyopathy
-treated by avoiding fasting and consuming more medium chain fatty acids

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Other secondary carnitine deficiencies: inherited Acyl-CoA dehydrogenase deficiencies

*what step does it affect?
which dehydrogenases?
MCAD

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*Affects 1st rxn in beta-oxidation

Affects Short, Medium, and Very Long chain acyl-CoA dehydrogenases

MCAD: presents in first 2 yrs of life, vommiting, lethargy, coma, hypoketotic hypoglycemia and dicarboxylic aciduria
Treatment: high carb diet
-Cause of SIDS, death by hypoglycemia.

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MCAD
Cause of hypoketotic hypoglycemia

Cause of Dicarboxylic aciduria

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MCAD: Medium chain acyl-CoA dehydrogenase deficiency (secondary carnitine deficiency; affects oxidation of FA)

Hypoglycemia: no FA available for energy causes increased use of Glc, so Glc levels become low

Aciduria: accumulation of FA, degradation by omega-oxidation, and excretion in urine

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Oxidation of Very Long Chain FA
Where?
Diff from beta-oxidation: first step, end product

XALD
Zellweger syndrome
treatment

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in peroxisomes
-Difference from beta-oxidation: FADH2 made in first step and hydrogen peroxide is oxidized
-end product: octanoyl-CoA; removed as oxtanoyl-carnitine and further oxidized in mitochondria

XALD: X-linked Adrenoleukodystrophy: persoxisomes cannot hydrolyze very long chain FA

Zellweger's: cannot make peroxisomes

XALD + Zellwegers=accumulation of very long FA in blood

Treatment: Glitazones
-antidiabetics that reduce insulin resistance and decrease TAG levels, causes increase in peroxisomes

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Alt B-oxidation: Odd-Chain FA metabolism

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Propionyl-CoA formed from last cleavage rxn of b-oxidation (CoA added at carboxyl end)
-converted to Succinyl CoA
-uses vitamins biotin and cobalamin
-succinyl CoA directly enters TCA cycle

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Alt FA oxidation: Alpha-oxidation
where?
what other molecule does it involve?
important for which FA?

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in ER, mitochondria, and peroxisomes
-involves mono-oxigenases (p450) that use NADH or NADPH;
-involves a-ketoglutarate, ascorbate, and iron

-important to BRANCHED fatty acids (like PHYTANIC ACID)
-Phytanoyl CoA hydrolyzed at alpha carbon
-**end products: propionyl-CoA, aceytl CoA, and isobutyryl CoA

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CC: Refsum's Disease
(Hint: alpha-oxidation of FA)

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Lacking of peroxysomal a-hydroxylating enzyme
-leads to accumulation of phytanic acid (branched FA broken down in alpha-oxidation) in tissues
-high neurotoxicity: neuropathy, nerve deafness, ataxia, retintitis pigmentosa
-Treatment: diet restriction of dairy and meat= lowers phytanic acid and neurological syndrome regression
(Phytanic acid consumed in chlorophyll from diet- milk and animal fat)

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Alt FA oxidation: unsaturated FA

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b-oxidation in mitochondria

additional enzymes required to change double bond geometry=
**fewer NADH and ATP produced

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Insulin: regulation of lipolysis and ketogenesis in the FED state
-Enzymes it stimulates for FA synthesis
-processes it stimulates for FA synthesis

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-released by beta cells
stimulates fatty acid synthesis by increasing:
fatty acid synthase, NADPH-malic dehydrogenase, and acetyl CoA decarboxylase

Also stimulates:
-Glc uptake and breakdown to Glycerol 3P for synthesis of TAG
-phosphoprotein phosphatase to dephosphorylate/activate acetyl-CoA carboxylase
-PPP with NADPH generation

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Regulation of lipolysis and ketogenesis in FASTED state

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-glucagon and epinephrine signal FA oxidation with increased cAMP cascade
-aceytlCoA carboxylase phosphorylated/inhibited (FA synthesis enzyme)
-ketone body production in liver