Fatty Acid Metabolism - Lecture notes 1 PDF

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Fatty Acid Metabolism Lecture...

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Fatty Acid Metabolism/Synthesis Triacylglycerols      

Avoid ‘Triglycerides’ Provide building blocks Phospholipids – Membranes Glycolipids – Signalling, embedding in membranes Hormones – Lipid based, intracellular receptors Intracellular messengers – IP3, DAG

Main TAG Store = White Adipocytes  

Low numbers of mitochondria Single nucleus

Using TAG for Energy 

Mobilisation of TAG from Adipose - Glucagon, epinephrine, cortisol - HSL → 3x FFA, 1x glycerol – in blood vessels - Exercise and fasting will stimulate these receptors

Fatty Acid Activation     

Linked to CoA prior to oxidation in cytoplasm – Coupled to ATP→AMP (2ATP equivalent) What is the enzyme? Made irreversible in vivo by rapid hydrolysis of pyrophosphate Thioester bond formed ↑by [S]

Fatty Acid Metabolism 

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Oxidation and Synthesis mirror each other - Reaction type - Reaction order Different pathways Different enzymes Compartmentalisation

Mitochondrial Shuttle       

Acyl-CoA needs to be oxidised in the mitochondrial matrix CPT-1 takes the fatty acid part off Acyl-CoA and attaches it to carnitine (carrier molecule) Carnitine diffuses through the outer mitochondrial membrane Translocase enzyme transports carnitine through the inner mitochondrial membrane CTP-2 reforms Acyl-CoA from carnitine and liberates carnitine Carnitine gets transported via an antiporter out and joins with more acyls Regulated by malanile CoA – made during fatty acid synthesis

Acyl CoA Dehydrogenase    

Oxidation reaction Reducing agent is FAD FADH2 can go into the ETC Double bond formed

Enoyl CoA hydratase   

Hydration reaction Water is added Enzyme can only produce L-isomers

L-3-hydroxyacyl CoA dehydrogenase   

Oxidation reaction Reducing agent is NAD+ Keto group is formed

β-ketothiolase        

Lysis Shorten the fatty acid by 2C Introduces another CoA The acetyl joins to the CoA CoA is replaced however is shorter by 2C Acetyl CoA then enters the Krebs cycle Has to be cut down to 2C β-ketothiolase is inhibited by acetyl CoA

Odd Chain Fatty Acids    

End up with propionate Propionate is converted to succinate (carboxylation) coupled to ATP Isomerisation x2 Vitamin B12 is required to do this

Ketone Bodies   

Oxaloacetate required for entry into TCA Fasting / diabetes - Oxaloacetate → gluconeogenesis Animals cannot produce glucose from FFA - Link reaction is irreversible

3-ketothiolase   

High energy thioester bond in acetyl CoA Essentially reversal of thiolysis in β-oxidation 2x 2C → 4C

Hydroxymethylglutaryl CoA Synthase

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Condensation reaction

Hydroxymethylglutaryl CoA Cleavage Enzyme    

Lyase reaction Irreversible Forms Acetoacetate (4C) Water soluble, acetyl transport

β-Hydroxybutyrate Dehydrogenase    

Reduction of acetoacetate Ratio of acetate:butyrate Dependent upon [NADH+H+ ] & [NAD+ ] in mitochondria Butyrate doesn’t spontaneously decarboxylate

Ketones as Fuel  

Some cells use Ketones in preference to glucose During fasting other tissues utilise ketones - Brain – blood brain barrier - 75% provided by ketones during prolonged starvation

CoA Transferase    

High energy thioester in succinyl CoA Drives group transfer CoA + acetoacetate → acetoacetyl CoA Thiolysis - Acetoacetyl CoA → 2x acetyl CoA → TCA

β - Oxidation in Peroxisomes      

Less than mitochondria – very long chain Oxidation – Hydration – Oxidation – Thiolysis No ATP formed in peroxisomes Electrons transferred to O2 Acetyl CoA can be transported to TCA cycle First Oxidation different

α – Oxidation (Peroxisomes)   

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Much less than β – oxidation First oxidation occurs at the α carbon Allows oxidation of specific fatty acids - E.g. phytanic acid - Methyl group prevents β – oxidation Refsum’s disease - Can’t metabolise phytanic acid - Derivative of chlorophyll

ω – Oxidation (Liver ER) 

From methyl end of the fatty acid

  



Used when β – oxidation is blocked Used to oxidise xenobiotics Reaction: - Hydroxylation - Oxidation - Oxidation Products enter the TCA cycle

Other Oxidations  

Arachidonic acid - Derived from linoleic acid Precursor for a range of molecules

Fatty Acid Synthesis    

Acetyl CoA is produced in the mitochondria Acetyl CoA must be in the cytoplasm Carnitine only transports long chain Fas Requires another shuttle to transport acetyl CoA from mitochondria – Uses ATP & NADH – Produces NADPH

Transport of Acetyl CoA       

Pyruvate gets converted to oxaloacetate Acetyl CoA joins with oxaloacetate to form citrate in the mitochondrial matrix Citrate gets transported into the cytoplasm ATP is used to reverse the reaction to form acetyl CoA and oxaloacetate Oxaloacetate is converted to malate Malate is converted to pyruvate Pyruvate is transported back into the mitochondrial matrix

Fatty Acid Synthesis    

Acetyl CoA is first carboxylated to form malonyl CoA Acetyl CoA Carboxylase Committed Step Coupled to ATP → ADP

Regulatory Point  

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Breakdown of fats is regulated by how much fatty acids are coming in and how much acetyl CoA is being produced AMP activated protein kinase that stops synthesis is regulated by AMP - High AMP mean low ATP - Need to increase ATP levels – triggers lipolysis Allosteric regulation - Citrate is a metabolite in the Krebs cycle - Excess metabolites = excess energy - Store energy as fat

Fatty Acid Synthase

  

Complex of several enzymes - One polypeptide chain Long chain FAs Involves a special carrier protein

Acyl Carrier Protein   

Intermediates are linked to ACP Covalent Shares structural similarities with CoA – Phosphopantetheine group

Acyl-malonyl ACP Condensing Enzyme    

Condensation reaction Increases the chain length Malonyl (3C) – acetoacetyl ACP (4C) Powered by decarboxylation of malonyl ACP

β-ketoacyl ACP Reductase    

Reduction (oxidation) Reducing agent is NADPH D isomer formed Theme: - NADH is generated in energy yielding reactions - NADPH is used in biosynthesis

3-Hydroxyacyl ACP Dehydratase   

Dehydration reaction Substrate preparation Aiming for Saturated FA

Enoyl ACP Reductase     

Reduction (oxidation) NAPH = reducing agent Inhibited by triclosan – antibacterial In the next round butyryl ACP will condense with another malonyl ACP - 4C → 6C Stops at 16C Palmitate

Other Fatty Acids  

    

Longer chain lengths Further condensations - Membrane bound SER - Add malonyl CoA – 2C increase Unsaturated Fas – desaturase A further complex of enzymes Cannot introduce double bonds beyond C9 α - Linolenic acid (linoleate) Linoleic acid (lenolenate)

Lipid Transport  

Fatty acids from adipose are transported to various tissues bound to serum albumin Triglycerides transported as: - Chylomicrons - VLDL - LDL - HDL

Chylomicrons    

Formed in the intestine Transport dietary triacylglycerols and cholesterol to muscles and fat cells Fat is removed by lipoprotein lipase Become chylo remnants and taken up by the liver by remnant receptor

Liver    

Converts excess carbohydrates into fat Package as VLDL Taken to muscle where they are converted to IDL and LDL Taken back to liver and recycled by LDL receptor

HDL 

Brings excess cholesterol from the peripheral tissues to the liver...