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Fat mobilization in adipocytes. b R. Note: insulin inhibits TAG mobilization. PKA. PKA. P. Hormone-sensitive lipase. Hormone-sensitive lipase. glycerol. MAG. DAG. TAG. FFA. FFA. FFA. See Fig 16.7 Horton. Fatty acid oxidation. Activation Transport into mitochondria

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slide1

Fat mobilization in adipocytes

bR

Note: insulin inhibits TAG

mobilization

PKA

PKA

P

Hormone-sensitive

lipase

Hormone-sensitive

lipase

glycerol

MAG

DAG

TAG

FFA

FFA

FFA

See Fig 16.7 Horton

slide2

Fatty acid oxidation

  • Activation
  • Transport into mitochondria
  • b oxidation cycle
  • Acyl CoA synthetase (thiokinase)
  • acylcarnitine transferase/acylcarnitine translocase
  • acyl CoA dehydrogenase
  • enoyl CoA hydratase
  • L-3-hydroxy CoA dehydrogenase
  • Thiolase
slide3

R-COO- + CoA-SH + ATP R-C- S-CoA + AMP + PPi

O

Acyl CoA synthetase

Note: 4 different enzymes specific for FA of differing chain

length.

location: outer membrane of mitochondria, ER membranes

slide4

Transport of fatty acyl CoA into mitochondria

Carnitine

Malonyl CoA

Carnitine

acyltransferase I

Fatty AcylCoA + carnitine acylcarnitine + CoA

translocase

Mito matrix

Fatty AcylCoA + carnitine acylcarnitine + CoA

Carnitine

acyltransferase II

slide6

Net yield of ATP

C16 FA + CoA + ATP C16 acyl CoA + AMP + PP1

C16 acyl CoA + 7 NAD + 7 FAD 8 AcCoA + 7 NADH + 7 FADH2

8 AcCoA 24 NADH + 8 FADH2 + 8 GTP + 16 CO2

31 NADH 77.5 ATP

15 FADH2 22.5 ATP

8 GTP 8 ATP

108 ATP

- 2 ATP

Net = 106 ATP

slide7

b-oxidation of unsaturated fatty acids

  • 2,4 dieonyl-CoA reductase: converts cis to trans double bond
  • Enoyl-CoAisomerase: converts diene to single double bond
slide8

3 rounds of b-oxidation

3 Ac-CoA

CO-S-CoA

H

C

C

C

C

C

C

C

C

C

C

C

3

16

18

14

8

12

10

Enoyl-CoA isomerase

1round of b-oxidation

Ac-CoA

C10 cis-D4

CO-S-CoA

H

C

C

C

C

C

C

C

C

C

3

12

6

8

4

2

b-oxidation of unsaturated fatty acids

e.g. Linoleic acid: C18 cis,cis-D9,12

CO-S-CoA

C

C

H

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

3

16

2

18

14

8

4

12

6

10

C12 cis,cis-D3,6

g

b

a

C12 trans,cis-D2,6

g

b

a

CO-S-CoA

H

C

C

C

C

C

C

C

C

C

C

C

3

10

12

8

2

6

4

slide9

C10 cis-D4

CO-S-CoA

H

C

C

C

C

C

C

C

C

C

3

12

6

8

4

2

Acyl-CoA dehydrogenase

C10 trans,cis-D2,4

CO-S-CoA

H

C

C

C

C

C

C

C

C

C

3

12

6

8

4

2

2,4 dieonyl-CoA reductase

NADP

C10 trans-D3

CO-S-CoA

H

C

C

C

C

C

C

C

C

C

3

12

6

8

4

2

Enoyl-CoA isomerase

C10 cis-D2

CO-S-CoA

H

C

C

C

C

C

C

C

C

C

3

12

6

8

4

2

continued b-oxidation

slide10

b-oxidation of odd numbered fatty acids

  • Requires:
  • Propionyl CoA carboxylase (biotin)
  • - adds CO2
  • methyl malony CoA racemase
  • - converts D isomer of methyl malonyl CoA to L isomer
  • methyl malonyl CoA mutase (adenosylcobalamin)
    • - rearranges MMCoA to yield succinyl CoA
slide11

Oxidation of odd-numbered fatty acids

O

CH3-CH2-C-S-CoA

CH3

O

-OOC-CH C-S-CoA

O

-OOC-CH C-S-CoA

CH3

-OOC-CH2

O

CH2

C-S-CoA

Proprionyl CoA

CO2

Biotin, ATP

D-methylmalonyl CoA

racemase

L-methylmalonyl CoA

adenosylcobalamin

mutase

succinyl CoA

slide12

Cobalamin B12

methylcobalamin

R = CH3

- transfer of methyl groups

adenosylcobalamin

R = 5’-deoxyadenosinyl

- intramolecular rearrangements

See fig 7.24 Horton

slide13

Fatty acid biosynthesis

  • Where: cytoplasm
  • liver, fat cells
  • When: good energy charge, insulin
  • Process:
  • Transfer of AcCoA from mito to cyto
  • Acetyl CoA carboxylase
  • Fatty acid synthase
slide14

Citrate lyase

Citrate + ATP + + CoA OAA + AcCoA + ADP + Pi

NADH

Citrate lyase

NADPH

AcCoA

malate

OAA

Pyruvate

citrate

cyto

Antiport with pyr or Pi

mito

OAA

H+

citrate

Pyruvate

AcCoA

  • Transfer of AcCoA from mito to cyto
slide15

Question:

Incubation of tissue using the above pathway with only one of succinate-2,3-14C or succinate-1,4-14C

will result in the production of radiolabeled fatty acid. Identify which substrate will yield 14C-fatty acids.

slide16

CH2

C - SCoA

-OOC

O

Acetyl-CoA carboxylase 1 (ACC 1)

biotin

AcCoA + CO2 + ATP malonyl CoA + ADP + Pi

  • Regulation:
  • Hormonal control
  • - AMP kinase
  • - inhibited by PKA mediated phosphorylation
  • - enhanced by insulin
  • Allosteric regulation
  • - citrate activates phospho form
  • - inhibited by palmitoyl CoA
  • glucagon (liver)
  • adrenalin (adipocytes)
  • Nutritional status
slide17

Regulation of FA metabolism by phosphorylation

Adrenalin

Glucagon

activates

inhibits

cAMP

ACT

PKA

FA

synthesis

Malonyl CoA

TAG lipase

(inactive)

ACC(active)

AMP-

activated

kinase

phosphatase

PP2A

TAG lipase-PO4

(active)

ACC-PO4(inactive)

Note: insulin activates ACC by stimulating the dephosphorylation reaction

slide18

+ ACP-SH

i.

C – S-ACP

C - SCoA

CH2

CH2

-OOC-

-OOC-

CH3

C - SCoA

CH3

C – SACP + CoASH

ii.

+ S-Synthase

O

O

O

O

O

O

CH3

C - ACP

CH3

C – S-Synthase + ACP-SH

iii.

ACP-SH

CoASH

Steps in FA biosynthesis

1. Loading: transfer to ACP and ketoacyl-ACPsynthase

slide19

HS-Synthase

CO2

O

O

CH3

C –

CH2

C – S-ACP

O

O

2. Condensation:

+

CH3

C – S-Synthase

CH2

CH2

C – S-ACP

C – S-ACP

-OOC-

slide20

3. reduction

H

H

CH2

CH3

C

CH3

C –

OH

OH

C – S-ACP

C – S-ACP

C – S-ACP

C – S-ACP

C – S-ACP

C – S-ACP

NADP

NADPH

4. dehydration

O

O

O

O

O

O

O

H

H

CH3

CH3

C

C

CH2

CH2

CH

CH

CH3

C –

H2O

5. reduction

CH3

CH2

CH

NADP

NADPH

slide21

C – S-ACP

C

C – S-ACP

C-SACP

O

O

O

O

CH3

CH2

CH2

C – S-synthase

O

CH3

CH2

CH2

Subsequent rounds of synthesis

- transfer of growing FA to S-Synthase

- addition of 2 carbon units from malonyl-S-ACP

Synthase-SH

ACP-SH

-OOC-

CH2

CO2 + Synthase-SH

CH

CH3

CH2

CH2

slide22

Chain elongation

  • introduction of double bonds
    • linoleic and linolenic acids
    • synthesis of arachidonic acid – an important precursor of
      • several biologically active molecules