Fatty Acid Metabolism -NYIT Flashcards
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..
What are the commonly ingested lipids/fats?
Palmitate C16
Stearate C18
Oleate C18:1/9
What are the essential fatty acids
Linoleate (C18:2) and linoenate (C18:3)
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)
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
What blood chemicals inactivase lipase and promote storage of fatty acids as triacylglycerrides?
Insulin through protein phosphatase 1
What blood chemicals mobilize TAGs?
Glucogon, epinephrine or cortisol
Fasting state - lipase has been activated through cAMP and PKA
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
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
Fates of Acetyl-CoA
During fast -> acetyl coa can be converted into ketone bodies
Into the CAC
fatty acid synthesis
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
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
How do short and medium chain fatty acids get into the mito matrix?
Diffusion
Unregulated
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)
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
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
