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Biochemistry > Fatty Acid Biosynthesis > Flashcards

Fatty Acid Biosynthesis Flashcards

1
Q

Functions of Lipids

A
  1. metabolic energy storage (triglycerides)
  2. components of biological membranes (phospholipids and glycolipids)
  3. cholesterol used in steroid hormones and bile acid biosynthesis
  4. Fat soluble vitamins (A, D, E, and K)
  5. Arachidonic acid (C20 FA) used in biosynthesis of prostaglandins and other bioactive compounds
  6. Phosphoinositides as precursors of second messengers molecules
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2
Q

Refsum’s Disease

A
  1. accumulation of phytanic acid in CNS. Phytanic acid is a branched fatty acid
  2. neurological defect
  3. specific enzymes are required for its degradation
  4. deficiency of such enzymes results in Refsum’s disease
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3
Q

FA biosynthesis

A
  1. occurs primarily in the liver, adipose tissue, CNS and lactating mammary glands
  2. needs acetyl CoA (as carbon source) and NADPH (as reducing power)
  3. FA biosynth enzymes are located in the cytoplasm
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4
Q

Acetyl CoA transport

A
  • Glucose undergoes glycolysis and TCA cycle in the cytoplasm
  • excess glucose–>fatty acid
  • any acetyl CoA not oxidized by TCA cylce exits the mitochondira and is used for the synthesis of fatty acid (palmitate) and triglyceride
  • Acetyl CoA must be converted to citrate to exit the mitochondria and enter the cytoplasm for FA biosynthesis
  • isocitrate–(isocitrate dH)–>alpha KG; ATP inhibits isocitrate dH so the citrate level increases
  • citrate enters the cytoplasm and is converted back to acetyl CoA and OAA using citrate lyase.
    • acetyl CoA is used in FA biosynthesis
    • OAA in cytoplasm–(malate dH; NADH–>NAD+)–>malate–(malic enzyme; NADP+–>NADHP)–>pyruvate; pyruvate is transported back into the mitochondria
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5
Q

NADPH for FA biosynthesis

A
  • Comes from two sources:
    1. Pentose phosphate pathway
    2. recycling of OAA from cytoplasm to mitochondria
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6
Q

Synthesis of Malonyl CoA from acetyl CoA

A
  • acetyl CoA–(acetyl CoA carboxylase ACC)–>malonyl CoA; acetyl CoA carboxylase requires biotin
  • irreversible, rate-determining rxn; two-step process:
    1. ACC biotin is carboxylated; bicarbonate is source of CO2; ATP-dependent
    2. CO2 is transferred to acetyl CoA generating malonyl CoA.
  • Malonyl can be decarboxylated to regenerate acetyl CoA by enzyme malonyl CoA decarboxylase (MCD)
  • the activities of ACC and MCD are reciprocally regulated
    • cellular level of malonyl CoA is dependent on ACC and MCD
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7
Q

Acetyl CoA Carboxylase isoforms

A
  1. ACC1
    • cytosol; lipogenic tissues such as live, adipose, and lactating mammary gland
    • ACC1-generated malonyl CoA is utilized exclusively for synthesis of FAs.
  2. ACC2
    • mitochondrial membrane; oxidative tissues such as liver, skeletal muscle, and heart
    • ACC-2 associated with carnitine/palmitoyl-transferase 1 (CPT1)
    • ACC-2 generated malonyl CoA inihibits CPT1, preventing the entry of FAs into the mitochondria for ß oxidation and energy production
  • ACC1 maintains regulation of FA synthesis; ACC2 regulates FA oxidation
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8
Q

ACC Allosteric Regulation

A
  • Short-term
  • ACC protomeric form=inactive; ACC polymeric form=active
  1. Both ACC regulated by diet and hormones such as insulin, glucagon, epinephrine and growth hormones.
  2. Citrate (precursor to acetyl CoA) activates ACC through a feed-forward loop by promoting polymerization
  3. Palmitoyl CoA (final product of fatty acid biosynth. and other short- and long- chain fatty acyl CoAs) inhibit ACC polymerization, reducing its activity.
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9
Q

ACC regulation by covalent modification

A
  • Short term
  • regulated by phosphorylation/dephosphorylation through hormone activities
  • ACC-Phos=inactive; ACC=active
  • carb rich diet–> increased insulin–>glycolysis–(+ enzyme Phosphatase)–>ACC active–>increased malonyl CoA–>FA synth
  • starvation, diabetes (low insulin and high glucagon/insulin ratio), and elevated epinephrine–(+ enzyme PKA)–>
    • glycolysis inhibited, stimulate FA mobilization, phosphorylated ACC (inactive).
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10
Q

ACC regulation by AMPK

A
  • Short term
  • AMP-activated protein kinase (AMPK) activated by high AMP/ATP ratio
    during exercise
    hormones and cellular stressors that deplete ATP
    • AMPK phosphorylates and inhibits ACC
      during situations of increased energy demand–>AMPK activated–>increased oxidation of FA and decreased FA synth
    • AMPK also phoshporylates MCD, activating it–>decreased malonyl CoA–>increased FA oxidation
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11
Q

ACC Regulation Long-term regulation

A
  • ACC1 and ACC2 genes expression regulated by diet and hormones
  • Fat-free diet–>activates synthesis of ACC1 and ACC2 enzymes–>FA biosynth.
  • Starvation or diabetes–>represses expression of ACC enzymes-->repressed FA synth and increased oxidation of FA
  • insulin upregulates ACC1 promoter
  • glucagon downregulates ACC1 promoter
  • ACC isoforms are targets for developing drugs to regulate obesity, diabetes, cancer, and cardiovascular problems
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12
Q

FA synthase complex

A
  • large, multifunctional dimer
  • seven different enzymes and an acyl carrier protein (ACP); two of these (14 enzymes) form one FA synthase
  • ACP and ketoacyl synthase provide thiol (-SH) groups for attachment of a malonyl and an acetyl group, repectively
  • Two chains are synthesized simultaneously
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13
Q

FA biosynthesis

Rxn 1

A

Condensation

  1. malonyl group transferred to ACP of one monomer; acetyl group transferred ketoacyl sythase (KS) of the other monomer
  2. acetyl and malonyl groups are condensed to produce one molecule of acetocetyl-ACP (4C); one carbon lost as CO2
  3. Enzyme: ß ketoacyl-ACP synthase (KS); condensing enzyme
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14
Q

FA biosynthesis Rxn 2

A

Reduction

  • Acetoacetyl-ACP (4C) is reduced to ß-hydroxybutyryl-ACP. One NADPH used
  • Enzyme: ß-ketoacyl-ACP reductase (KR)
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15
Q

FA biosynthesis Rxn 3

A

Dehydration

  • ß-hydroxybutyryl-ACP is dehydrated to crotonyl-ACP.
  • One molecule of H2O is lost
  • Enzyme: ß-hydroxyacyl-ACP dehydratase (DH)
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16
Q

FA biosynthesis Rxn 4

A

Reduction

  • Crotonyl-ACP is reduced to butyryl-ACP.
  • A second molecule of NADPH is used
  • enzyme: Enoyl-ACP reductase (ER)
17
Q

FA biosynthesis Elongation

A
  • At the end of the first round of synthesis, butyryl-ACP (4C) is produced.
  • next round, butyryl-ACP condenses with another molecule of malonyl-ACP, thus lengthening the chain by 2C
  • The process of malonyl-ACP condensation continues until a 16C long palmitoyl-ACP is formed
  • At this point, synthesis stops and the palmitic acid (16:0) is released from the FA synthase.
  • Overall rxn for palmitic acid:

8 Acetyl-CoA + 14 NADPH + 14 H+ + 7 ATP–>Palmitic acid (16 C) + 8 CoA + 14 NADP+ +7 ADP + 7 Pi + H2O

*Note: 7 of the 8 acetyl-CoA are converted to malonyl-CoA before they are used for FA biosynthesis

18
Q

Carbon labeling in FA biosynth and elongation

A
19
Q

FA synthase Regulation

A
  • Transcriptionally regulated:
    1. In liver:
      • FAS synthase expression stimulated by insulin
      • insulin effect mediated by transcription factors USFs (upstream stimulatory factors) and SREBP-1 (sterol response element binding proteins)
      • PUFA (poly-unsaturated fatty acids) diminish the transcriptiof FAS gene.
    2. In fat cells:
      • Leptin inhibits expression of FAS
      • Leptin regulates food intake and fat metabolism
      • Leptin is produced by fat cells inresponse to excess body fat–diminished FA synthesis
20
Q

Elongation of FA

A
  • Palmitate (16:0) can be elongated to give longer-chain FAs through elongases
  1. In ER:
    • Malonyl-CoA serves as the 2C donor
  2. In mitochondria:
    • Preexisting short- and medium-chain FAs are elongated in the mitochondria
    • Acetyl-CoA serves as the 2C donor
21
Q

Desaturation of FA

A
  • FA can be desaturated to yield unsaturated FA
  • enzymes: desaturases

Saturated FA + O2 + NADH + H+ —(enzyme: Desaturase)–>Mono-unsaturated FA + NAD+ + H2O

  • This reaction can be repeated to produce polyunsaturated FAs
  • Mammals only have four desaturases: 9-, 6-, 5-, and 4- fatty acyl-CoA desaturases
  • Mammals can’t add double bonds beyond C9.
  • Linoleic acid (18:2 delta9,12) and Linolenic acid (18:3 delta9,12,15) are considered essential in diet
  • these are precursors for arachidonic acid (EPA and DHA)
22
Q

Synthesis of Triacylglycerols (triglycerides) Location

A
  • FA must be activated first by the addition of CoA; requires 1 ATP
  • Synthesized in liver (primarily) and adipose tissue from fatty acyl-CoA and glycerol 3-phosphate
  • In liver, Gly3P is produced by phosphorylation of glycerol by glycerol kinase, or by reduction of DHAP by Gly3P dH
    • TGs are packaged to form very low density lipoproteins (VLDL)
    • VLDL delivers newly synthesized TGs to the peripheral tissues
  • In adipose tissue, no glycerol kinase
    • Gly3P produced from reduction of DHAP by Gly3P dH.
    • therefore, adipose tissue only synthesize and store FAs in the fed state when the glucose supply is plentiful
    • TGs are stored in cytosol until needed for energy production
23
Q

Synthesis of Triglycerides (TGs)

A
24
Q

Subcellular location of biochemical processes related to lipid metabolism

A

Biochemistry (5 decks)

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