lipids overview
hydrophobic organic molecules
insoluble- found compartmentalised or transported in association with protein
heterogenous group= extracted by non polar solvents
lipid structure
show greater structural variation than other bio macromolecules
- not polymeric
- can aggregate
lipid function
bilayer
energy stores
inter and intra-cellular signalling
some fat-soluble vits have a regulatory/ co-enzyme functions
what are fatty acids
carboxylic acids with long chain hydrocarbon side groups
can exist ‘free’ but usually esterified- triacylglycerols
predominantly C16 and C18
role of fatty acids
substantial amounts of ‘free’ fatty acids found in plasma
- transported on serum albumin from origin to point of consumption
oxidised by tissues (liver and muscle) for energy
form components of membrane lipids
can be linked to intra-cellular proteins to enhance membrane association
mono/ di/ tricylglycerols
1/2/3 fatty acids esterified to a glycerol backbone
triacylglycerols esterified to glycerol (via carboxyl groups- resulting in loss of charge)
fats/ oils of plants and animals are largely triacylglycerols
most abundant lipid class
adipocytes
specialised in animals for synthesis and storage of TAGs
in white adipose issues, TAGs coalesce to form oily droplets (body’s major energy reserve)
little is stored in liver- most exported to form VLDL
nascent VLDL secreted directly into blood- where they mature and function to deliver lipids to peripheral tissues
lipid lipolysis
mobilisation of stored fat in adipocytes occurs during times of metabolic need
- requires the hydrolytic release of fatty acids and glycerol from TAG
initiated by hormone sensitive lipase
- removes the fatty acid from C-1 and/ or C-3
hormone sensitive lipase activated
- glucagon/ epinephrine binds to the cells
high [insulin] or [glucose] HSL is dephosphorylated and inactivates
glycerol released are transported via he blood to the liver
- can then be phosphorylated, used to form TAG in liver
- can be converted to DHAP
B- oxidation
series of enzyme catalysed reactions progressively degrading fatty acids by removing 2C units + involves the oxidation of the B carbon atom to the carboxyl group
after LCFAs enter cell- converted in the cytosol to its CoA derivative (‘priming’)
- catalyse by long- chain fatty ‘acyl-CoA synthetases’ (thiokinases)
- found in the mitochondrial outer membrane
acyl-CoA synthetases may differ in chain length
reaction driven by exergonic hydrolysis of pyrophosphate (by pyrophosphatase)
activated in the cytosol- oxidation occurs in mitochondrial matrix
carnitine shuttle
rate-limiting transport process
fatty acid transfers its acyl part on to carnitine
acylcarnitine is transported into matrix in exchange for for free carnitine going in the opposite direction- by ‘carnitine-acylcarnitine translocase’
carnitine palmitoyltransferase II (inner mitochondrial membrane enzyme0
- catalyses transfer of acyl group from carnitine to CoA in matrix
- regenerates free carnitine
malonyl CoA inhibits CPT-I- this means during fatty acid synthesis, the palmitate cannot be transferred for degradation
carnitine deficiencies
carnitine may be obtained from diet
- can be synthesised from lysine and methionine by liver and kidneys
deficiency= tissues have decreased ability to use LCFA as metabolic fuel
1. liver disease
2. malnutrition
3. patients with increased carnitine requirements- pregnancy or burns victims
4. haemodialysis
entry of fatty acids into mitochondria
short and medium length chains
- <12 carbons can cross without carnitine shuttle
human milk filled with medium chain fatty acids
oxidation not dependent of CPT-I
- it is not subject to malonyl CoA inhibition
B oxidation reactions
fatty acyl- CoA occurs in a 4 reaction sequence- each step catalysed by enzymes with specific chain length requirements
1- formation of a trans-a, B double bond
- via heydrogenation by Flavoenzyme, Acyl- CoA deyhdrogenase
2) hydration of the double bond
- enoyl- CoA hyratase (EH)
- forms 3-L-hydroxyacyl- CoA
3) NAD+ dependent dehydrogenation of the b- hyroxacyl- CoA
4) Ca-Cb cleavage in a thiolysis reaction with CoA to form acetyl-CoA and a new acyl-CoA
reactions repeated for sat FAs of even carbon chains (n/2)-1 times
each cycle= acetyl group + 1 NADH + 1FADH2
Acetyl CoA
+ve allosteric effector of pyruvate carboxylase
links fatty acid oxidation and gluconeogenesis
acyl-CoA dehydrogenase
linked to ETC
mitochondria contain 4 acyl-CoA dehydrogenases
- different specificities for chain length
the FADH2 is reoxidised by the mitochondrial ETC
- electron-transfer flavoprotein (ETF) transfers an electron pair ffrom FADH to ETF ubiquinone oxioreductase
- reduces coenzyme Q (CoQ)
reduction of O2 to H2O by the ETC= 1.5 ATP per electron pair transferred
MCAD deficiency
in mitochondria:
- medium- chain fatty acyl- CoA dehydrogenase (MCAD) deficiency
- autosomal recessive disorder
- decreased ability to oxidise fatty acids with 6-10C- accumulate in urine
- severe hypoglycemia due to increased glucose reliance
cause 10% of sudden infant death syndrome
- an imbalance between glucose and fatty acid oxidation
long-chain enoyl-CoA’s
product of acyl-CoA dehydroenases are 2-enoyl- CoAs
depending on chain length- their processing is continued by 3 systems
1) short chain, medium chain or long chain 2-enoyl-CoA hydratases (EHs)
2) hyroxyacyl-CoA dehydrogenases (HADs)
3) 3-ketoacyl-CoA thiolases (KTs)
long chain versions- contain on a4b4 heterooctameric trifunctional protein
multi-enzyme complex advantage- the ability to channel intermediates towards final product
fatty acid oxidation- output
highly exergonic
each round of B- oxidation produces 1 NADH, 1 FADH2 and 1 acetyl-CoA
subtract 2 ATP equivalents required for fatty acyl-CoA formation
ketone bodies
acetyl-CoA that does not enter the TCA cycle can be converted into ketone bodies by ‘ketogenesis’
important energy sources in heart and skeletal muscle
produced when [acetyl-CoA] exceeds oxidative capacity
- used in proportion to [blood] by extrahepatic tissues- can spare glucose use
used in proportion to [blood] by extrahepatic tissues
- can spare glucose use
compounds known as ketone bodies
acetoacetate
3-hydroxybutyrate/ b- hydroxybutyrate
acetone (non metabolised side product)
fatty acid biosynthesis
rittenberg and bloch showed the C-2 units that are combined derive from acetic acid
later shwon that acetyl-CoA and bicarbonate are required
malonyl-CoA (C-3) unit is an intermediate
ATP + NADPH also required- occurs in liver and mammary cytosol
permits both thermodynamic favorability + independent regulation under similar physiological conditions
synthesis reactions
transfer of acetate units from mitochondrial acetyl CoA to the cytosol
acetyl CoA produced via the oxidative carboxylation of pyruvate by pyruvate dehydrogenase
acetyl CoA in TCA cycle
if ATP demand is low
meaning the citric acid and oxidative phosphorylation is minimal, then mitochondrial acetyl-CoA may be stored as fat
tricarboxylate transport system
coA portion of acetyl coA cannot cross the inner mito membrane
- only acetyl portion enters the cytosol
OAA reduced to malate by malate dehydrogenas
malate is oxidatively decarboxylated to pyruvate by malic enzyme, then returned
citrate translocation from mitochondrion to cytosol ocurs when mito citrate is high
TCA cycle (isocitrate dehydrogenase) is inhibited by high ATP
