Faculdade de Desporto, Universidade do Porto, 1º Ciclo, 1º Ano

2011_20012

BIOQUÍMICA E BIOLOGIA CELULAR

António Ascensão, José Magalhães

Metabolism of lipids

Metabolic conversions of nutrients

Metabolic pathways overview

Molecular structure of triglycerides

Adapted from “Understanden human anatomy and physiology”, 5fh Edition, McGraw-Hill, 2004

Steps of lipid catabolism

•  Mobilization - hydrolysis of TG stored on adipocytes

•  Circulation – Plasmatic transport of free fatty acids with albumin to muscle

•  Absortion - entrance of fatty acids in muscle (FABP)

•  Activation – formation of fatty acyl-CoA in cytosol (ATP dependent)

•  Translocation – Transport of fatty acyl-CoA to mitochondria through carnitine shuttle

•  Beta-oxidation – production of NADH, FADH2 and acetyl-CoA from fatty acyl-CoA

•  Mitochondrial oxidation – Krebs cycle and electron transport chain

The example of G Protein on lipolysis …

↑ Catecolamines ↑ Glucagon

Triacylglycerols Lipase

Fatty acids transport from adipocytes to myocytes

↑ Catecolamines ↑ Glucagon

Lipid metabolism animation

http://www.wiley.com/legacy/college/boyer/0470003790/animations/fatty_acid_metabolism/

fatty_acid_metabolism.htm

Entry of fatty acids into mitochondria – the Carnitine Shuttle

(fatty acid binding proteins)

Carnitine Shuttle (3 steps process)

β - oxidation

1

2

3

Carnitine Shuttle (rate limiting step for fatty acids oxidation)

Acyl-CoA synthetase

Carnitine acyltransferase

I

Carnitine acyltransferase

II

1

2

3

Beta (β)-oxidation cycle (4 steps)

FADH2

H+ + NADH

(HADH)

1º Step

2º Step

3º Step

4º Step

(continues for new cycle)

(beginning of the process) (end of the process)

Beta (β)-oxidation cycle

Electron Transport Chain

Electron Transport Chain

2 carbon compound to Krebs cycle

Re-enters β - oxidation with 2 less carbons

( Fatty-Acyl CoA )

Steps of Beta (β) oxidation cycle (summary)

•  Reaction 1 (1st Step) –  Oxidation of fatty Acyl-CoA

–  Catalyzed by Acyl-CoA Dehydrogenase

–  Generates 1 FADH2 (ETC)

•  Reaction 2 (2nd Step)

–  Hydration

–  Catalyzed by Enoyl-CoA Hydratase

–  Forms β-Hydroxyacyl-CoA

•  Reaction 3 (3rd Step) –  Oxidation

–  Catalyzed by Hydroxyacyl-CoA Dehydrogenase

–  Generates 1 NADH (ETC)

•  Reaction 4 (4th Step)

–  Bond Cleavage between β and α carbon

–  Catalyzed by Thiolase

–  Requires CoA

–  Forms Acetyl-CoA (enters Krebs cycle)

–  Forms Fatty Acyl-CoA (2 carbons shorter (re-enters β - oxidation)

Beta (β)-oxidation

•  Breakdown of fats into

–  Acetyl coenzyme A (CoA) --> Kreb Cycle

–  FADH2 --> Oxidative Phosphorylation

–  NADH --> Oxidative Phosphorylation

•  Breaks off two carbons at a time to acetyl CoA

–  Remaining Acyl-CoA goes another round

Beta (β)-oxidation cycle … goes on …

Beta (β)-oxidation … an example

14 carbon fatty acid

6 rounds on Beta-oxidation

7 acetyl-CoA formed

CH3 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – C

SCoA

O

α β γ

Beta (β)-oxidation cycle interconnections

Lets remind Krebs cycle !

Lets remind Krebs cycle !

β - oxidation

Glycolysis

Summary of the flow of electrons and protons through the four complexes of the respiratory chain. Electrons reach CoQ via Complexes I and II. CoQH2 serves as a mobile carrier of electrons and protons. It transfers electrons to Complex III, which transfers them to another mobile connecting link, cytochrome c. Complex IV transfers electrons from reduced cytochrome c to O2. Electron flow through Complexes I, III and IV is accompanied by proton flow from the matrix to the intermembrane space. Electrons from fatty acid b-oxidation can also enter the respiratory chain though UQ.

Mitochondrial electron transport chain

Mitochondrial electron transport pathway

Beta (β)-oxidation cycle … an example !

Fatty acids oxidation … the energetic yelding !

Beta (β)-oxidation of odd-numbered fatty acids

Integration of β-oxidation with Krebs cycle !

β - oxidation

Glycolysis

Propionyl-CoA

Odd-numbered fatty acids

Even-numbered fatty acids

Ketogenesis (formation of ketone bodies)

Physiological condition

Biochemical impact

Ketogenesis

Ketone bodies

Ketosis

Fasted-state (starvation) Prolonged exercise Diabetes …

Glycogen deplection (↓ oxaloacetate - gluconeogenesis) Excess of β-oxidation (↑ acetyl-CoA)

Liver

Acetoacetate Acetone β-hydroxybutyrate

Metabolic acidosis

↑ plasma ketonic bodies

Ketogenesis (formation of ketone bodies) in liver

X

Ketogenesis (formation of ketone bodies)

Extreme ketogenesis … the case of diabetes

Mitochondrial metabolism_overview