Catalyzes conversion: citrate —> Acetyl-CoA - Requires ATP - Forms oxaloacetate Inhibited by: PUFA, leptin Stimulated by: Glucose, Insulin

Fatty Acid Metabolism Flashcards by Rusheil Patel

FA synthesis location

PRIMARILY liver.

Also, in adipose tissue, brain, kidneys, lactating mammary glands

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How citrate gets from mitochondria to cytosol?

Citrate transporter

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Citrate Lyase

Catalyzes conversion:
citrate —> Acetyl-CoA

Requires ATP
Forms oxaloacetate

Inhibited by: PUFA, leptin
Stimulated by: Glucose, Insulin

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Acetyl-CoA Carboxylase (ACC)

Catalyzes conversion:
Acetyl-CoA —> Malonyl-CoA

Requires ATP, CO2 and Biotin as a CO-FACTOR
RATE-LIMITING ENZYME in FA synthesis

Allosterically regulated:
Stimulated by - Citrate (+)
Inhibited by - Long chain fatty acids I.e. palmitate (-)

ACC dimeric form = inactive, polymeric form = active

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What does Malonyl-CoA inhibit?

Carnitine-Acyltransferase

Enzyme in FA degradation
Rate limiting step in the degradation

Prevents FA synthesis and degradation from occurring simultaneously

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Malonyl-CoA

Substrate for Fatty Acid Synthase Complex (last phase of FA synthesis)

Requires 7 Malonyl-CoA molecules.

Malonyl-CoA is a 3C molecule, FA Synthase adds on 2 carbons from Malonyl-CoA to a growing fatty acid each time.

1 Acetyl-CoA (2C) + 7 Malonyl-CoA (2C each = 14C) —> 16C Palmitate

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Fatty Acid Synthase

Multi-enzyme complex with 2 identical diners (260 kDa each)
- arranged in head to tail conformation

Each dimmer contains 7 enzyme activities plus an Acyl Carrier Protein (ACP)

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Order of reactions catalyzed by Fatty Acid Synthase (FAS)

Condensation
Reduction
Dehydration
Reduction
(Then repeat steps 2-4 x6)

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What is the source of NADPH in FA synthesis?

Malic enzyme: 1

PPP: 2-12

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Leptin

Hormone secreted by adipose tissue. “Fat-Brain axis”

Communicates with the brain (hypothalamus) to reduce food intake when the body is fed/full. Regulates body weight

Leptin K/O mice = obese
-If mice are given leptin —> weight reduced

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Where is palmitate converted to longer-chain FA?

Smooth Endoplasmic Reticulum or Mitochondria
-Brain requires longer chain FA (C18-24)

SER uses Malonyl-CoA as carbon donor
Mitochondria uses Acetyl-CoA as carbon donor

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Acyl CoA Desaturase

Introduces double bonds in FA’s.
-Occurs in the SER and uses NADPH

Cannot synthesize double-bond beyond C9-10 in humans (i.e. omega-3), must be obtained from diet.

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Desaturase regulation

Insulin increases expression

PUFA suppress expression

Dietary cholesterol induces expression of delta9-Desaturase and suppresses all others

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Fatty acid lengths regarding mitochondrial entry

Can diffuse into mitochondria:

Short chain FA (SCFA)
Medium chain FA (MCFA)

Need to be actively transported in:

- Long chain FA (LCFA)
- Very long chain FA (VLCFA) —>oxidized in peroxisomes to LCFA —> Carnitine shuttle

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Fatty Acyl CoA Synthetase

In cytoplasm, adds a CoA to fatty acid —> Fatty Acyl CoA, so it can pass through the Outer Mitochondrial Membrane

Requires ATP
thioester bond formed between FA and Acyl CoA

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Carnitine Palmitoyltransferase I (CPT-I)

Located in intermembrane space
-Catalyzes FA-CoA —> FA-Carnitine

RATE LIMITING ENZYME for FA degradation

Inhibited by Malonyl-CoA

Carnitine-Acylcarnitine Translocase (CACT)

Transports FA-Carnitine into mitochondrial matrix.

-Antiporter: FA-Carnitine (in) Carnitine (out)

CPT-II

Located on inner mitochondrial membrane
-Catalyzes FA-Carnitine —> (back to) FA-CoA

FA-CoA now in the matrix —> Ready of beta-oxidation

Order of steps of B-oxidation

Oxidation
Hydration
Oxidation
Thiolysis

(Opposite of

Acyl CoA dehydrogenase (ACAD)

First enzyme in FA degradation
-Oxidizes FA via FAD+ —>FADH2 (to CoQ in ETC = 1.5 ATP)

Four types of ACADs:
Short Chain Acyl CoA Dehydrogenase (SCAD)
Medium chain ————————-—- (MCAD) 
Long Chain ——— ————————(LCAD)
Very Long Chain —————————(VLCAD)

Enol CoA Hydratase

Step 2 in FA degradation: Hydration - adds water to the alkene forming beta-hydroxy Acyl CoA

Beta-hydroxyl Acyl CoA dehydrogenase

Step 3 of FA degradation - oxidizes the beta carbon to form double bond.

-NADH produced (2.5 ATP in ETC)

Acyl CoA acyltransferase (beta ketothiolase)

Last enzyme in FA degradation

Attaches sulfur of a new CoA to ketone formed after cleavage of Acetyl-CoA from Fatty Acyl chain —-shortened by 2 carbons

Acetyl-CoA = 12 ATP

ATP generated from beta-oxidation of palmitic acid

129 ATP

Propionyl CoA Carboxylase

First enzyme in degradation of Odd #C FA chain once FA is degraded down until Propionyl-CoA remains. Carboxylates Propionyl-CoA —> Methylmalonyl-CoA -Requires ATP

Methylmalonyl CoA Mutase

2nd enzyme used in odd #C FA degradation. Catalyzes Methylmalonyl CoA —> Succinyl-CoA Succinyl-CoA enters TCA cycle

Reductase and Isomerase

Enzymes used in degradation of UNsaturated FA. Reductase: reduces double bond Isomerase: moves disruptive bond

Peroxisomes

Degrade VLCFAs greater than 20C. Beta-oxidizes but FADH produced but electron energy transferred to O2 to make H2O2 instead of TCA. First step catalyzed by Acyl-CoA oxidase When FA < 20 —> Sent to mitochondria for further beta-oxidation

MCAD Deficiency

Disorder of FA beta-oxidation that impairs breakdown of MCFAs. - Autosomal recessive - Leads to secondary Carnitine deficiency = excessive excretion of MCA carnitines in urine - C8 FA accumulate in liver - poisonous and interferes with urea cycle - elevated ammonia - Patient requires glucose as energy source - Hypoglycemia/sudden death without timely intervention

Three ketone bodies

1. Acetoacetate - 23 ATP 2. Beta-hydroxybutyrate - 26 ATP 3. Acetone

Ketone body properties and purpose

Water-soluble, acidic compounds Provide energy for peripheral tissues during fasting/starvation

Where are ketone bodies produced?

Liver only - Mitochondrial matrix of hepatocytes

Where/when ketone bodies are used?

Brain: Starvation when glucose is completely depleted Muscle: During fasting Kidneys: During fasting

Pathological ketoacidosis

Occurs when glucagon/insulin ratio is high - Favoring FA breakdown Increased Acetyl-CoA and hepatic mitochondria —> increased ketone bodies Acetoacetate and b-hydroxybutyrate are strong acids —> lower blood pH causing acidosis. Increased concentration found in urine

Diabetic Ketoacidosis

Diabetics cannot take up glucose from the blood. Adipose tissue releases FA to be beta-oxidized in the liver for energy Ketone bodies form —> blood pH drops —> coma/death