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Biochemistry > Fatty Acid Oxidation > Flashcards

Fatty Acid Oxidation Flashcards

1
Q

FA oxidation

A
  • Take place in the mitochondria (unlike FA synth which occurs in cytoplasm)
  • Except one enzyme: Acyl CoA synthase for activation of fatty acids
  • Acetyl CoA is produced:
    1. Can enter TCA cycle for energy production
    2. synthesis of ketone bodies
  • coenzymes NAD+ and FAD are need for oxidation
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2
Q

Release of FA from TGs

A
  • FAs are released from TGs by enzyme: hormone-sensitive lipase (HSL)
    • activated by:
      1. epinephrine
      2. ACTH
      3. glucagon
    • elevated during fasting, stress, or physical exercise
    • horomone w/ receptor–>AC–>cAMP–>PKA–>HSL-P (active)
    • inhibited by: insulin
      • insulin w/ receptor–>phosphatase–>HSL (inactive)

Note: ignore arrows from HSL to DAG and MAG and glycerol. these are always present and not hormone-dependent

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3
Q

Fatty Acid Activation

A
  • FAs must be activated first before they can be oxidized.
  • occurs at outer mitochondrial membrane
  • FA + CoASH + ATP–(enzyme:fatty acyl CoA synthase aka thiokinase)–>Fatty acyl CoA + AMP + PPi
  • PPi–(pyrophosphatase)–> 2 Pi
  • to make sure rxn goes to completion and is irreversible
  • activate FA to protect endogenous enzymes from FAs detergent like behavior
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4
Q

Transport fatty acyl CoA across mitochondrial membrane

A
  • FA oxidation occus in the mitochondria but IMM is impermeable to fatty acyl CoA
  • 4-step process of transport
    1. acyl group transferred to carnitine by enzyme carnitine acyltransferase I (CAT-1) to produce acylcarnitine
      • In liver, CAT-1 inhibited by Malonyl CoA (FA synth)
    2. translocase in IMM transports acylcarnitine into matrix
    3. acyl group of acylcarnitine transferred to mitochondrial CoASH using enzyme carnitine acyltransferase II (CAT-2)
    4. the released carnitine is returned to cytosol through the translocase
  • Carnitine or CAT-1/CAT-2 deficiency can cause general muscle weakness and cramps on strenous exercise
  • Under starved conditions, FAs released from TGs inhibits ACC lowers malonyl CoA
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5
Q

Carnitine

A
  • Sources: 75% dietary, red meat, diary, nuts
  • Synthesis: from Lys and Met in liver and kidney. requirement increases during growth and pregnancy
  • Distribution: 90% in cardiac and skeletal muscle
  • transports only long chain FA (14-20C)
  • Short- and medium- chain FA do not need carnitine for transport. they can pass directly through IMM into the matrix where they are activated by acyl CoA synthase
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6
Q

Four steps of beta oxidation of FAs

A
  1. Oxidation
  2. Hydration
  3. Oxidation
  4. Thiolysis
  • In each cycle,
    • one molecule of FADH2 and one molecule of NADH + H+ are produced
    • 2C are lost from the COOH end of the acyl chain as acetyl CoA
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7
Q

Step 1 of beta oxidation: Oxidation

A
  • Two hydrogen atoms are removed from the alpha and beta carbons (C2 and C3)
  • enzyme: acyl-CoA dehydrogenase
  • the removed hydrogens are used to reduce FAD to FADH2
    • FADH2 = 1.5 ATP
  • product: trans-delta2-enoyl CoA
    • note trans double bond
  • Clinical note: medium chain acyl-CoA dehydrogenase (MCAD ) deficiency
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8
Q

Step 2 of beta oxidation: hydration

A
  • one molecule of H2O is added to reduce the double bond
  • enzyme: hydratase
  • product: ß-hydroxyacyl CoA
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9
Q

Step 3 of beta oxidation: Oxidation

A
  • ß carbon is oxidized by the loss of 2 H
  • One NADH is produced
    • one NADH = 2.5 ATP
  • enzyme: ß hydroxyacyl CoA dehydrogenase
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10
Q

Step 4 of beta oxidation: Thiolysis

A
  • bond between alpha and ß carbon is cleaved
  • enzyme: thiolase
  • one moelcule of CoASH needed
  • products: acetyl CoA and an acyl-CoA chain shortened by 2C
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11
Q

Energy Calculation from beta oxidation

A
  • the beta oxidation cycle continues until the chian is completely cleaved into acetyl CoA
  • 1 molecule Acetyl Co-A = 10 ATP
  • 1 FADH2 = 1.5 ATP
  • 1 NADH = 2.5 ATP
  • RBC cannot oxidize FAs because they don’t have mitochondria
  • Brain cannot use FAs because they cannot cross the blood brain barrier
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12
Q

Acyl CoA dehydrogenase

A
  • First enzyme of beta oxidation of FAs
  • three isoforms:
    • short chain acyl-CoA dH (2-4C)
    • medium chain acyl-CoA dH (6-12C)
    • long chain acyl-CoA dH (> 12 C)
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13
Q

MCAD deficiency

A
  • genetic defect of MCAD
  • symptoms: fasting life-threatening hypoglycemia, vomiting, lethargy, and coma, especially first 2 years of life, impaired ketogenesis
  • Gluconeogenesis also impaired because:
    • not enough ATP/GTP
    • lack of OAA b/c less acetyl CoA downregulates pyruvate carboxylase
    • high levels of fatty acyl CoA inhibits gluconeogenesis
  • Often they are diagnosed with Reye’s syndrome or SIDS instead
  • cannot switch from glucose to FA metabolism at night or during prolonged fasting
  • treatment: frequent feeding on a carbohydrate-rich diet
  • test: excessive urinary excretion of medium-chain FA
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14
Q

Ackee fruit

A
  • unripe Ackee fruit contains hypoglycin-A
  • hypoglycin-A inhibits fatty acyl-CoA dH
  • consumption can cause: vomiting and nausea
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15
Q

Fatty Liver and Cirrhosis

A
  • Ethanol metabolism requires NAD+
  • Ethanol consumption lower NAD+/NADH + H+ ratio
  • Not enough NAD+ available for fatty acid oxidation
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16
Q

Omega oxidation of fatty acids

A
  • occurs in the ER
  • omega carbon is oxidized to the corresponding alcohol
  • Four steps:
    1. Cytochrome P450 mixed fucntion oxidase; requires O2 and NADPH
    2. Alcohol dH
    3. Aldehyde dH–produces dicarboxylic acid
    4. Beta oxidation (peroxisomes)
  • product: short chain dicarboxylic acids which can enter Krebs cycle
  • Omega oxidation important for drug metabolism with alkyl chains
  • produces adipate–>excreted in blood and urine
17
Q

Oxidation of branched chain fatty acids–alpha oxidation

A
  • in peroxisomes and mitochondria
  • small portion of FAs are branched & contain methyl groups
  • ex: phytanic acid
  • B/c the ß carbon contains a methyl group, it can’t be oxidized in the first step of beta oxidation so…
  • the alpha carbon is oxidized by enzyme: alpha-hydroxylase and the first carbon COOH is removed as CO2
  • ß oxidation can now proceed.
  • propionyl CoA and acetyl CoA are released as alternating products
  • Last group: isobutyrul CoA–>succinyl CoA
18
Q

Oxidation of odd-chain FAs

A
  • products: one propionyl CoA released in addition to the acetyl CoA in beta oxidation
  • propionyl CoA–> glucose for gluconeogenesis
  • mammals cannot synthesize glucose from acetyl CoA
19
Q

Peroxisomal ß oxidation

A
  • Mitochondria cannot oxidaize very long (>22 C) FAs
  • very long FAs shortened in peroxisomes–>medium chain FAs
  • no carnitine needed for peroxisomal ß oxidation
  • FAs diffuse into peroxisomes and are converted into acyl CoA by acyl CoA synthetase
  • First reaction of peroxisomal ß oxidation:
    • Oxidation of alpha and beta carbons by acyl CoA oxidase
    • generates FADH2–>immediately used to generate H2O2
    • H2O2 hydrolyzed by a catalase
  • Subsequent steps similar to beta oxidation in mito
20
Q

Adrenoleukodystrophy (ALD)

A
  • genetic of acyl-CoA synthetase enzyme involed in peroxisomal oxidation of FAs
  • X-linked recessive disorder
  • very long-chain saturated FAs accumulate in blood
  • damage to myelin sheath
  • degeneration of adrenal glands
  • ADHD
  • Impaired vision
  • Impaired speech
  • Impaired motor speech
  • Coma & seizures
21
Q

Zellweger Disease

A
  • Absence of functional peroxisomes
  • accumulation of very long-chain fatty acids
  • Enlarged head & forehead
  • Mental retardation
  • Seizures
  • Vision impairment
  • Enlarged liver, jaundice
  • Impaired kidney functions
  • Hypotonia
22
Q

Oxidation of Unsaturated FAs

A
  • example: oleic acid
  • needs enzyme: Isomerase
    • moves the cis double bond 3 and 4 C to 2 and 3 C in a trans configuration
  • Linoleic acid (18:2 delta9,12)
    • normal beta oxidation and isomerase activity
    • double bonds moved to 2,3 trans and 4,5 cis positions
    • two bonds reduced to one 3,4 trans double bond by reductase
    • isomerase moves it to 2,3 trans
    • now beta oxidation proceeds normally
23
Q

Oxidation vs. Synthesis

A
24
Q

Regulation of Oxidation vs. Regulation of Synthesis

A

Biochemistry (5 decks)

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