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Foundations 1 > Lipid Metabolism > Flashcards

Lipid Metabolism Flashcards

1
Q

When and where does fatty acid oxidation occur?

A
  • Primarily in the mitochondrial matrix

- Between meals, during fasting, during increased energy demand

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2
Q

Compare the energy yields of glycolysis and fatty acid oxidation.

A
  • More energy per mole from FAs than glucose because they are more reduced.
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3
Q

How are long chain fatty acids transported into mitochondria?

A

Part 1: activated transport from cytosol to intermembrane space

  1. FA => fatty acyl CoA. FA activation by acyl CoA synthetase; requires two ATP equivalents + CoA
  2. Transport across outer membrane

Part 2: Translocation from intermembrane space to matrix

  1. fatty acyl CoA => fatty acylcarnitine by carnitine palmitoyl transferase I (CPTI). Requires carnitine and releases CoA
  2. transport across inner membrane by carnitine acylcar-nitrine translocase

Part 3: Conversion back to fatty acyl CoA

  1. fatty acylcarnitine => fatty acyl-CoA. Conversion by carnitine palmitoyl-transferase II; requires CoA and releases carnitine.
  2. Carnitine translocated back to intermembrane space by carnitine acylcar-nitrine translocase.
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4
Q

How are short and medium chain FAs transported from the cytosol into the mitochondria?

A
  1. Diffusion across outer membrane
  2. Transport across inner membrane by the monocarboxylate transporter
  3. Activation to fatty acyl-CoA by acyl-CoA synthetase
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5
Q

Describe the structure of a fatty acyl coA.

A
  • SCoA attached to carbonyl carbon
  • Carbons starting after carbonyl carbon numbered a, B, etc…
  • Last carbon = omega carbon
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6
Q

What are the steps of B-oxidation?

A
  1. Oxidation:
    - Oxidation by acyl CoA dehydrogenase forms double bond between a and B carbons.
    - Generates 1 FAD(H2) ~ 1.5 ATP
  2. Hydration
    - Hydroxyl group added to B carbon by enoyl coA hydratase.
    - Requires water.
  3. Oxidation
    - Hydroxyl group on B carbon oxidized to a ketone by B-hydrozy acyl CoA dehydrogenase.
    - Generates 1 NADH ~ 2.5 ATP
  4. Cleavage
    - Acetyl CoA is cleaved from the FA chain by B-keto thiolase, shortening the chain by 2 C.
    - Requires CoASH

Steps repeat in a spiral until the final cleavage where a 4 chain FA is broken into 2 x acetyl CoA

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7
Q

Where do odd chain FAs come from and how are they oxidized differently than even chain FAs?

A
  • Dietary
  1. B-oxidation:
    - until cleavage of acetyl CoA results in propionyl CoA (3C)
  2. Carboxylation:
    - Propionyl CoA carboxylated by propionyl CoA carboxylase
    - Requires 2 ATP equivalents, biotin, and CO2
  3. Epimerization
    - Stereochemical rearrangement of D-methyl malonyl CoA to L form by methyl maolonyl CoA epimerase or racemase
  4. Rearrangement
    - L-methyl malonyl CoA rearranged to form succinyl CoA by methyl malonyl CoA mutase
    - Requires B12
  • Succinyl CoA then enters the TCA cycle
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8
Q

What is the ATP yield from B oxidation of palmitate?

A

C16 = 7 cycles (2 x 7 + 2 = 16)

7 FADH2 ~ 10.5 ATP from oxidative phosphorylation
7 NADH2 ~ 17.5 ATP from oxidative phosphorylation
8 Acetyl CoA = 80 ATP from TCA cycle
-2 ATP from FA activation

106 mol ATP / mol palmitate

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9
Q

How is B-oxidation regulated?

A

By energy state!

  1. Transcriptionally:
    - Use of FAs as fuel increases transcription of FA metabolism genes
  2. Inhibition of CPTI during fatty acid synthesis
    - FA synthesis activated with high insulin
    - AMP-PK inhibited during FA synthesis; phosphorylation
    by AMP-PK necessary to activate acetyl CoA carboxylase
    - Malonyl CoA inhibits CPTI
  3. ETC: high energy/reducing power inhibits B-ox
    - high ATP/ADP ratio inhibits ETC
    - inhibited ETC increases NADH/FAD(H)2
    - high NADH/FAD(H)2 inhibit B-oxidation
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10
Q

What is the function of the peroxisome?

A

Oxidation of very long chain FAs

Reoxidation of FAD used in B-oxidation of very long chain FAs

  • FAD(H)2 oxidized by O2 forming H202
  • H202 decomposed to water + O2 by catalase

Synthesis of plasmalogens

Detox of phenols, formaldehyde, alcohols

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11
Q

How are very long chain FAs oxidized?

A

Oxidation begins in the peroxisome:

  1. Activation
    - VLCFA activated to VLCFA CoA by VLACS (very long chain acyl coA synthetase)
  2. Transport of activated VLCFA into peroxisome
  3. Oxidation of activated VLCFA CoA until chain is 4-6C
    - Step 1 = oxidation by oxidase; generates H202
    - Later steps produce NADH and Acetyl CoA
  4. Addition of carnitine to acetyl-CoA and short acyl-CoAs
  5. Diffusion from peroxisome to be taken up by mitochondria for further oxidation
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12
Q

What is a-oxidation?

A

Pathway for oxidation of branched chain FAs occurring in the peroxisomes

Occurs only at branch sites, then normal B-oxidation can occur in peroxisomes/mitochondria

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13
Q

What is omega-oxidation?

A

Alternate pathway for FA oxidation that occurs in the ER when there is a defect in B-oxidation.

  1. Oxidation of omega carbon (farthest from carbonyl)
    - addition of hydroxyl group
  2. Further oxidation to form carboxylic acid on omega carbon
    - Product = dicarboxylic acid; more soluble than normal FAs and can be released into the bloodstream
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14
Q

Where and how are ketone bodies oxidized?

A

Produced by the liver, but used (and oxidized) in peripheral tissues

  1. Oxidation
    - D-B-hydroxybutyrate oxidized by D-B-hydroxybutyrate dehydrogenase (hydroxyl to ketone)
    - Generates 1 NADH
  2. Activation
    - Acetoacetate activated by succinyl CoA:acetoacetate CoA transferase.
    - Requires succinyl CoA; generates succinate
  3. Cleavage
    - Formation of 2 acetyl CoA by thiolase
    - Requires CoASH
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15
Q

How and where is alcohol metabolized?

A

Mainly occurs in the liver:

  1. Oxidation
    - ethanol oxidized by alcohol dehydrogenase (hydroxyl to aldehyde)
    - cytosolic
    - generates 1 NADH
  2. Oxidation
    - acetyaldehyde oxidized by acetaldehyde DH to form acetate
    - mitochondrial
    - generates 1 NADH
    - inhibited by disulfiram: buildup of toxic acetaldehyde => positive punishment to stop drinking
  3. Activation
    - acetyl coA formed by activation of acetate by acetyl CoA synthetase
    - requires COSH and 2 ATO equivalents

Also occurs in ER (microsomal ethanol oxidizing system):

  1. Oxidation
    - cytochrome P450 enzyme oxidizes ethanol to acetaldehyde
    - requires NADPH + O2
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16
Q

What disorders are associated with FA oxidation?

A

impaired LCFA oxidation - carnitine related issues

hypoketotic hypoglycemia - MC fatty acyl CoA DH deficiency

dicarboxylic aciduria - when B-ox is impaired and omega oxidation is primary oxidation

Zellweger syndrome - peroxisome defect and can’t oxidize VLCFAs

17
Q

How are acetyl CoA and malonyl CoA generated for FA synthesis

A
  1. Conversion of glucose to mitochondrial acetyl CoA
    - pyruvate from glycolysis converted to OAA by pyruvate carboxylase and acetyl CoA by PDH in mitochondria
  2. Transport of mitochondrial acetyl CoA to cytosol
    - OAA and acetyl CoA condense to form citrate via citrate synthase
    - high levels of citrate => export to cytosol
    - citrate lyase breaks cytosolic citrate into OAA + acetyl CoA
    - OAA recycled to pyruvate by cytosolic malate DH and malic enzyme
    - regulation: citrate lyase and malic enzyme upregulated by demand
  3. Synthesis of malonyl CoA
    - acetyl CoA carboxylated by acetyl CoA carboxylase
    - requires ATP, CO2, and biotin
    - malonyl coA can be converted back to acetyl-CoA by MCD
18
Q

How is acetyl CoA carboxylase regulated?

A

Feedback/feedforward regulation:

  • activated by citrate
  • inhibited by palmityol CoA

Covalent modification:

  • phosphorylated enzyme = inactive
  • AMP-activated protein kinase phosphorylates - activated by low energy levels
  • Phosphatase dephosphorylates - activated by insulin
19
Q

How are the FA anabolic and catabolic pathways co-regulated?

A

CPTI is inhibited by malonyl CoA during FA synthesis to block B-oxidation

20
Q

How are FAs synthesized from acetyl CoA and malonyl CoA?

A

Catalyzed by FA synthase on the cytosolic side of the ER. Enzyme is a homodimer with 7 active sites per monomer - palmitate (C16) can be synthesized w/o substrate-enzyme release

FA synthase has an acyl carrier protein (-SH) and a condensing site (cys-SH)

  1. Acyl carrier site picks up acetyl CoA, which is then transferred to the condensing site
  2. Malonyl CoA picked up by acyl carrier site
  3. Condensation (nucleophilic attack and decarboxylation):
    - basically, malonyl CoA decarboxylated and acetyl transferred to end of malonyl coA
  4. Reduction
    - ketone reduced
    - requires 1 NADPH
  5. Dehydration
    - reduction of alcohol to alkene
  6. Reduction
    - alkene reduced to alkane
    - requires 1 NADPH
  7. Chain transferred to condensing site
  8. New acetyl CoA binds acyl carrier protein and cycle repeats
21
Q

How are FAs desaturated?

A

Primarily desaturated at C9, C6, C5 (counting from a-C); omega 3 and 6 must come from diet

  1. Oxidation by fatty acyl CoA desaturase
    - requires O2 and 2 H+
    - requires oxidation of 2 cyt b5 (Fe 2+ -> Fe 3+)
  2. Reduction of cyt b5 by cyt b5 reductase
    - Requires 1 NADH
22
Q

When and how are ketone bodies synthesized?

A

In the mitochondria of hepatocytes during fasting or carb restriction

  1. Condensation
    - 2 acetyl coA condensed by thiolase
  2. Addition of acetyl CoA to acetoacetyl CoA
    - HMG CoA synthase
  3. Removal of acetyl CoA from HMG CoA
    - HMG CoA lysase
  4. Conversion of acetoacetate into (a) D-B-hydroxybutyrate and (b) acetone
    (a) D-B-hydroxybutyrate DH; requires NADH
    (b) spontaneous decarboxylation
23
Q

How is ketone body synthesis regulated?

A

Increased when fatty acids levels are elevated during fasting, starvation, or low carb diet

High levels of NADH inhibit isocitrate DH in the TCA cycle => acetyl CoA buildup

Acetyl CoA => ketone bodies

24
Q

Which are the ketogenic amino acids and how are they used?

A

Ketogenic amino acids can be used to generate acetyl CoA and acetoacetate and are thus a fuel source during starvation (when all fat stores are depleted)

trp, thr, lys, ile, lys, leu, phe, tyr

25
Q

What are the steps of triacylglycerol synthesis?

A
  1. Generate G3P via GK or glycolysis
  2. Addition of 2 activated FA-CoAs
    - forms phosphatidic acid
  3. Dephosphorylation
    - forms diacylglycerol
  4. Addition of another activated FA-CoA => triacylglycerol
26
Q

How does triacylglycerol synthesis differ between the liver and adipose tissue?

A

The liver has glycerol kinase, which phosphorylates glycerol to form G3P.

Adipose tissue doesn’t have glycerol kinase and must get G3P from glycolysis (can only occur in a well fed state)

27
Q

How are TAGs degraded in the intestines and in adipose tissue?

A

Intestines:
1. pancreatic lipase digests triacylglycerol to monoacylglycerol + 2 unesterified FAs

Adipose tissue = lipolysis:

  1. triacylglycerol lipase (ATGL) digests TAG to diacylglycerols
  2. hormone sensitive lipase digests to monoacylglycerol
  3. hormone-sensitive and monoacylglycerol lipases digest to free FAs and glycerol
28
Q

What are the two pathways for membrane phospholipid synthesis?

A

Production of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine:

  1. dephosphorylation of phosphatidic acid to form diacylglycerol
  2. CDP added to head group with hydrolysis of CTP
  3. Head group added to diacylglycerol
    - forms glycerophospholipid
    - CMP released

Production of phosphatidylinositol, cardiolipin, phosphatidylglycerol:

  1. CDP-diacylglycerol formed from phosphatidic acid with hydrolysis of CTP
  2. Head group added with release of CMP
    - forms glycerophospholipid
29
Q

What are the steps of isoprenoid synthesis?

A
  1. acetyl CoA + acetoacetyl-CoA = HMG-CoA
  2. Reduction:
    - forms mevalonate
    - HMG CoA reductase (inhibited by statins)
    - Requires 2 NADPH
  3. Phosphorylation:
    - multiple steps requiring 3 ATP
    - generates isopentenyl–PP dimetylallyl–PP
  4. Combination to form larger isoprenoids
    - farnesyl diphosphate synthase
    - inhibited by aminobisphosphonates
30
Q

What larger products are generated from isoprenoids?

A

prenylated membrane proteins (from geranylgeranyl-PP and farnesyl-PP – inhibition of farnesyl transferase = anti-cancer)

cholesterol (from squalene) => steroid hormones, bile acids, vitamin D

heme A, dolichol, CoQ (from farnesyl-PP)

Foundations 1 (26 decks)

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