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Biochemistry Final Review > Zaidi (Lipid Metabolism I/II) > Flashcards

Zaidi (Lipid Metabolism I/II) Flashcards

1
Q

Fatty Acid Synthesis and precursor/end product

A
  • occurs primarily in liver; also in adipose tissue, brain, kidneys, lactating mammary glands
  • requires coordination between cytosolic and mitochondrial reactions

Precursor: Acetyl-CoA (2 carbon molecule)
End product: Palmitic Acid (16 carbon molecule)

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2
Q

3 phases of FA Synthesis

A

Phase 1: Cytosolic entry of Acetyl-CoA
- made in mitochondria/needed in cytoplasm
Phase 2: Generation of Malonyl-CoA
- Acetyl-CoA carboxylated to Malonyl-CoA
Phase 3: Fatty Acid Chain formation
- fatty acid synthase catalyzes 7 reactions to form palmitate

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3
Q

What is the most important substrate of Fatty Acid Synthesis?

A

Malonyl-CoA –> RATE LIMITING STEP

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4
Q

Phase I: Cytosolic Entry of Acetyl-CoA

A
  • oxaloacetate + Acetyl-CoA in mitochondria = citrate (citrate synthase)
  • citrate shuttle moves citrate into cytoplasm
  • ATP citrate lyase breaks citrate into Acetyl-CoA (FA synthesis in cytosol) and Oxaloacetate (+: glucose/insulin and -: PUFA/leptin)
  • Oxaloacetate –> Malate (back into mitochondria) –> pyruvate (back into mitochondria) –> oxaloacetate
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5
Q

Phase I: Regulation of Oxaloacetate

A

1) malate into mitochondria via transporter and oxidized to OAA by malate dehydrogenase
2) cytosolic malate –> pyruvate (malic enzyme), transported into mitochondria via transporter and carboxylated to OAA by pyruvate carboxylase

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6
Q

Phase II: Synthesis of Malonyl-CoA

A
  • ACoA –acetyl CoA carboxylase –> MCoA (3 carbon)
  • acetyl CoA carboxylase = RATE LIMITING ENZYME of FA Biosynthesis pathway
  • ACC adds CO2 to ACoA; uses ATP and BIOTIN (MUST HAVE)

+ regulation: insulin, citrate
- regulation: glucagon, epinephrine, palmitate, PUFA, high AMP

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7
Q

Malonyl CoA

A
  • FA synthesis substrate
  • REGULATOR = inhibits carnitine acyltransferase (RATE LIMITING STEP IN FA DEGRADATION)
  • prevents FA synthesis and degradation from happening simultaneously
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8
Q

Phase III: Fatty Acid Chain Formation

A
  • occurs on Fatty Acid Synthase Complex (FAS)

- two carbons from malonyl CoA are added to growing fatty acyl chain in 7 reactions = palmitate (16:0)

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9
Q

Fatty Acid Synthase

A
  • large multi-enzyme complex (2 identical dimers)
  • arranged in head to tail conformation
  • 7 enzyme activities and an acyl carrier protein (ACP)
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10
Q

Stoichiometry of Palmitate Synthesis

A

IN: 1 ACoA + 7 MCoA + 14 NADPH + 14 H

OUT: Palmitate + 14 NADP + 8 CoA + 6 H2O

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11
Q

Reactions catalyzed by FAS (4)

A
  1. Condensation (Acetyl + Malony = B-ketoacyl group)
  2. Reduction (B-ketoacyl group –> B-hydroxyl group)
  3. Dehydration (B-hydroxyl group –> trans-enone group)
  4. Reduction (trans-enone group –> 4 C fatty acyl group)

Repeat 6 more times = Palmitate

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12
Q

Regulation of Fatty Acid Synthesis

A
  1. ATP citrate lyase (Phase 1)
  2. Acetyl-CoA Carboxylase (Phase 2 - RLS)
  3. Fatty Acid Synthase (Phase 3)

expression induced by low fat, high carb diet (25-100 fold more active in FED STATE)

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13
Q

Regulation of ATP Citrate Lyase

A

(+) regulation: phosphorylation, glucose/insulin

(-) regulation: PUFAs, leptin

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14
Q

Regulation of Acetly-CoA Carboxylase (Allosteric/Phosphorylation/Induction)

A

1) Allosteric
- (+) –> citrate
- (-) –> palmitate

2) Phosphorylation (-)/Dephosphorylation (+)
- (+) –> insulin
- (-) –> epinephrine, glucagon, AMP

3) Induction: high carb/low fat

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15
Q

Regulation of Fatty Acid Synthase

A

1) Allosteric –> phosphorylated sugar = inc. activity

2) Induction/Repression @ gene level
- (+) –> insulin, glucocorticoid hormones, Hi carb/Lo fat
- (-) –> high fat, starvation, high PUFA

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16
Q

Synthesis of Longer FA chain - ELONGATION

A
  • palmitate converted to longer chain FA in SMOOTH ENDOPLASMIC RETICULUM/MITOCHONDRIA
  • lengthened 2 carbons at a time, NADPH = reducing power
  • SER: Malonyl CoA = carbon donor
  • Mito: Acetyl CoA = carbon donor

BRAIN NEEDS LONGER FATTY ACID CHAINS (C18-C24)

17
Q

Desaturation

A
  • introduction of double bonds in FA, occurs in SER and uses NADH/NADPH w/oxygen
  • Acyl CoA Desaturases (4, 5, 6, 9) –> where DB is at in chain
  • FA w/DB beyond C9/C10 cannot be synthesized in humans
  • ingest precursors: Essential Fatty Acids (Omega-3/Omega-6)
18
Q

Essential Fatty Acids

A
  • humans cannot synth omega-3/6 FA; need to ingest in diet or their precursors: linoleic acid (6) and linolenic acid (3)
  • Linoleic Acid –> arachidonic acid (precursor for prostaglandins, leukotrienes, thromboxanes)
  • Linolenic Acid –> eicosapentanoic acid (EPA) and docosahexanoic acid (DHA)
19
Q

Human Desaturases cannot…

A

introduce unsaturation beyond C9 and the methyl end (omega end)

20
Q

What are FA incorporated into?

A
  • triacylglycerols (storage form of lipids)

- used to provide energy (adipose tissue)

21
Q

What is the major source of carbon for fatty acid synthesis?

A

dietary carbohydrates

22
Q

Eicosanoid Hormones

A
  • short-lived local hormones
  • stimulate inflammation, regulate blood flow to particular organs, control ion transport across membranes, modulate synaptic transmission, induce sleep

Aspirin: blocks enzyme that converts arachidonate into postaglandin

23
Q

TAGs (Triacylglycerol)

A
  • glycerol and 3 fatty acid chains

MAG (monoglycerol) - 1 FA
DAG (diacylglycerol) - 2 FA
TAG (triacylglycerol) - 3 FA

24
Q

Sources of TAGs

A

dietary TAG: processed in intestinal cells

de novo TAG: in hepatocytes/adipocytes

25
Q

Mobilization of FA from Adipocytes

A
  1. glucagon/epinephrine –> GPCR –> adenylate cyclase
  2. Adenylate cyclase activates cAMP
  3. cAMP activates Protein Kinase A
  4. PKA phosphorylates HS Lipase (DAG to MAG) and Perilipin (ATGL causes TAG to DAG)
  5. MAG Lipase (MAG to FA + glycerol)

Inhibition: Insulin Receptor (RTK): protein phosphatase (PP1) dephosphorylates/inactivates HS Lipase (hormone sensitive lipase)

26
Q

Perilipin

A
  • proteins that coat lipid droplets in adipocytes/muscle cells
  • regulate lipolysis by controlling physical access to lipid breakdown enzymes
  • overexpression of Perilipin 1 inhibits lypolysis, and knock-out has converse effect
  • target of obesity treatment
27
Q

Overview of Fatty Acid Breakdown

A

Phase I: FA activation (cytosol)
Phase II: Beta-oxidation (mitochondrial matrix)

Outer mitochondrial matrix: FA not permeable
Inner mitochondrial matrix: FACoA not permeable

28
Q

Phase I: Fatty Acid Activation

A
  • 1st rxn in FA metabolism (traps FA in cells), makes it metabolically active
  • Acyl-CoA synthetase

2 steps: FA –> Acyl adenylate –> Acyl-CoA
- PP hydrolysis makes it IRREVERSIBLE

FA in cytosol, FA-CoA in Inner Membrane Space

29
Q

Translocation to Mitochondrial Matrix

A
  • Translocase moves Acyl Carnitine (carnitine + FACoA) across inner mitochondrial membrane (not permeable to FA-CoA)
  • Carnitine acyltransferase I (RATE LIMITING ENZYME inhibited by Malonyl-CoA) adds carnitine and FACoA
  • Carnitine acyltransferase II removes carnitine from FACoA once inside mitochondrial matrix
30
Q

Phase II: Beta Oxidation Steps

A

Four steps

1) Oxidation - Acyl CoA Dehydrogenase (ACAD)
2) Hydration - Enoyl CoA Hydratase
3) Oxidation - 3-Hydroxyacyl CoA Dehydrogenase
4) Thiolysis - Acetyl CoA Acetyltransferase (B-keto thiolase)

31
Q

Steps of Beta Oxidation (4)

A
  1. ACAD oxidizes B carbon = FADH2 and trans-enoyl CoA; FADH2 enters ETC and generates 2 ATP
  2. Enoyl CoA Hydratase saturates alkene with water to for B hydroxy acyl CoA
  3. B hydroxy acyl CoA dehydrogenase oxidizes carbon to form ketoacely CoA and NADH; NADH enters ETC and generates 3 ATP
  4. Acyl CoA acyl transferase attaches sulfur of CoA to ketone formed from cleavage of acetyl CoA from fatty acyl chain which is shortened by 2C
32
Q

ATP released from Beta Oxidation of Palmitic Acid

A

FADH2 : 7 x 2 = 14 ATP
NADH : 7 x 3 = 21 ATP
ACoA : 8 x 12 = 96 ATP

Total = 131 ATP - (2 used to activate) –> NET = 129

33
Q

Links between Lipid and Carbohydrate Oxidation

A

“fat burns in the flame of carbohydrates”

  • ACoA enters TCA cycle –> combines w/Oxaloacetate to form citrate
  • low OOA (low carbs) = ACoA NOT utilized –> condenses to form Ketone Bodies
  • fasting/diabetes = OAA converted to glucose by gluconeogenesis
34
Q

Ketone Bodies

A
  • water-soluble and acidic compounds
  • acetoacetate, B-hydroxybutyrate, acetone
  • produced in LIVER ONLY
  • provide energy for peripheral tissues during fasting, and brain during starvation
35
Q

Formation of Ketone Bodies

A
  • Acetoacetate becomes D-3-Hydroxybutyrate and Acetate
  • Acetoacetate –CoA transferase–> Acetoacetyl CoA
  • Acetoacetyl CoA –Thiolase–> 2 Acetyl CoA
36
Q

Diabetic Ketoacidosis

A

Adipose Tissue: no glucose = FA acids released

Liver: no glucose = OAA lvl low, CAC slows, FA converted to ketone bodies –> blood pH drops –> coma and death

Biochemistry Final Review (8 decks)

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