Fatty Acid Metabolism -NYIT Flashcards by Maria Gasque

Structure and function of fatty acids

Hydrocarbon chain with carboxyli acid

Saturated - no double bonds
Unsaturated - double bonds

Function - energy, components of membranes, used to make hormones (steroids) etc..

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What are the commonly ingested lipids/fats?

Palmitate C16
Stearate C18
Oleate C18:1/9

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What are the essential fatty acids

Linoleate (C18:2) and linoenate (C18:3)

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What tissue perfer to use fatty acids? What tissues cant usee fatty acids?

Perferred - skeletal muscle, heart muscle and liver

Cant - RBC and Brain (Brain can use ketone bodies in time of starvations)

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Fatty acid breakdown starts with what process/enzyme? (Hint: it is the freeing of the fatty acids from the TAGs)

Lipolysis by lipase which removes the FA from the glycerol backbone giving a glycerol and 2-3 FA’s

Main site of regulation

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What blood chemicals inactivase lipase and promote storage of fatty acids as triacylglycerrides?

Insulin through protein phosphatase 1

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What blood chemicals mobilize TAGs?

Glucogon, epinephrine or cortisol

Fasting state - lipase has been activated through cAMP and PKA

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What happens to the FA and glycerols?

FA are transported in the blood using serum albumin

Glycerol is transported to the liver and fed into gluconeogenesis

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Metabolism of Long-chain fatty acids

Transported across plasma membrane by ‘fatty acid binding protein’

Activated by Fatty acyl CoA synthetase (added a CoA) - found on ER or Mito membrane - this gets transported into the mitochondria by carnitine, theres a special system called the carnitine transpot system.

Once in the mitochondria - beta-oxidation

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Fates of Acetyl-CoA

During fast -> acetyl coa can be converted into ketone bodies

Into the CAC

fatty acid synthesis

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Where is energy sacraficed in fatty acid metabolism/breakdown? Where does this happen?

Activation of fatty acid by fatty acyl coa sythetase

Uses 2 ATP

ER or mito outer membrane

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What is the rate limiting step of fatty acid breakdown?

CPT-1 the transportation of fatty acylcarnitine across the outer mito membrane, this is regulated by malonyl CoA

Cpt-2 transports across the innner mito membrane

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How do short and medium chain fatty acids get into the mito matrix?

Diffusion

Unregulated

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Beta-oxidation

4 reactions

Two carbons are removed and released as Acetyl-CoA

Enzyme are different for different lengths

Two dehydrogenases giving FADH2 and NADH

Acyl CoA dehydorgenase - step 1, used for all chain lengths (except VLCFA)

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MCAD Deficiency

Medium chain fatty acyl CoA dehydrogenase

Common inborn error of metabolism, most common error of fatty acid oxidation

Severe hypoglycemia and hypoketonemia

Impaired oxidation of 6C to 10C FA’s

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How is lipase regulated?

Insulin and glucogon/epinephrine

Insulin - inhibits

Glucogon/epinephrine - stimulates (PKA Pathway)

How is CPT-1 regulated?

Malonyl CoA

From fatty acid synthesis

Malonyl CoA is blocked by AMP-dependent protein kinase (AMPK) and PKA during times of low energy to allow beta-oxidation can occur

How are unsaturated FA’s degraded?

Natural double bonds in fats are in cis-form, the undergo oxidation they need to be in trans

This is done by isomerase

What’s special about odd numbered chain FA?

The final product of beta-oxidation is propionyl CoA which is 3 carbons and this gets converted into succinyl coa which feeds into TCA

Propionyl coa carboxylase reqiures biotin, later on B12 is also required

Very Long Chain Fatty Acids

Shortened in peroxisomes which produces H2O2 and releasing NADH - oxidase

Catalase coverts the peroxide into water and oxy

Zellweger syndrome

Absense of peroxisome and leads to accumulation of VLCFA, born blind, deaf, cant eat and die by 6mo

Alpha-oxidation

Primarily used for branched fatty acids, ex is phytnic acid

Enzyme is fatty acid alpha-hydroxylase

Defect -> refsum’s disease

Needed because beta-oxidation (straight chain links) can only be oxidized if the beta carbon has two H attached.

Omega oxidation

Detoxification of foriegn compounds and unwanted acids

Oxidation happens are the distal end or the omega carbon

Enzyme - cytochromee P450 ocygen and NADPH

Ketone bodies

Major alternate energy supply during long term starvation

Aacetoacetate and beta-hydroxy-butyrate (also acetone)

Formed in liver

Dont need protein transportation in the blood because they are small and soluble

When there’s excess Acetyl-CoA in the liver it’s converted into ketone bodies because its exceeded the oxidative ability of the liver

Ketogenesis

HMG-CoA synthase forms HMG CoA out of 3 acetyl-coa - rate limiting step HMG-CoA lyase splits it into acetyl coa and acetoacetate Acetoacetate can be reduced to beta-hydroxy-butyrate Acetone is formed from the spontaneous decarboxylation of acetoacetate (acac -> acetone and CO2)

Ketolysis

In brain, heart, muscle, kidney ... Liver acks thiophorase (adds CoA to acetoacetate)

Excessive ketone bodies

Happens in starvation and untreated type I diabetes Low insulin causes fatty acid mobilization by activation of lipase by PKA Leads to ketonemia and ketoacidosis, ketouria and fruity odor in breath due to acetone (diabetes) This happens because either there is no glucose or it cant be used so instead theres excessive lipolysis which become ketone bodies

Where are FA synthesized?

Liver Lactating mammary gland Adipose tissue

What are the sources of Acetyl-CoA?

Oxidation of pyruvate | Catabolism fatty acid, ketone bodies or some amino acids (ketogenic)

How do acetyl-coa get out of the mitochondria to undergo fatty acid synthesis?

Forms citrate, citrate is transported into the cytosol, citrate lyase splits it back into oxa and acetyl-coa

What is malic enzyme? What is it used for?

It converts malate into pyruvate Produces pyruvate for more citrate synthesis but also a small amount of NADPH for FA synthesis

What is the rate limiting step of fatty acid synthesis and it's regulation?

Acetyl coa carboxylase Requires biotin Activated by citrate Inhibited by palmitoyl coa (LCFA) and AMPK Adds CO2 to acetyl coa making malonyl coa (which goes on to inhibit CPT-1 of FAA lysis) Turned off by glucogon, on by insulin

Fatty acid synthase

Poly-functional enzyme - 7 enzymatic activies Cofactor - vit B5 derivite pantethine Starts with Acetyl-CoA and Malonyl-CoA which bind to cys residue and pantethine respectively. Malonyl CoA releases that previously added and activating CO2 followed by alternating Carbonyl C=O reduction and dehydrogenation rxns (use of NADPH) Then another malonyl coa is attached to pan-sh and repeat elongated to 16 carbons

where does elongation of a fatty acid beyond 16 carbons occur? what are the requirements?

elongation past C16 happens in the smooth endoplasmic reticulum. Requirements are malonyl CoA and NADPH

what is omega-6?

linoleic acid found in vegetable oil ``` can form: arachidonic acid thromboxane A2, which is a strong platelet aggregating component prostacyclin I2 also, decreases cholesterol ```

what is omega-3?

linolenic acid found in ocean fish and fish oil good for preventing heart attacks, precursor for thromboxase A3 -aggregating/platelet- and prostacyclin I3 - anti aggregating - agents

Triacylglycerol synthesis

TAGs is the storage molecule for fatty acids glycerol or glucose (through DHAP step of glycolysis) is phosphorylated/converted into Glycerol-3-Phosphate activated FA's, Fatty Acid CoA, are added to the glycerol by Acyltransferase forming Phosphatidic acid phosphate is removed giving DAG (diacylglycerol) another FA-CoA and acyltranferase add the final FA to DAG making TAG Either be transported to the liver in the chylomicron known as VLDL or stored in adipose

how is TAG synthesis different in the liver vs adipose?

adipose can't make TAG's using glycerol because they lack glycerol kinase