Lipids Flashcards
8 classes of fatty acids
- fatty acyls: long chain with carboxyllic acid
- glycerol lipids: -OH on glycerol reacts with -COOH to form eater bond
- glycerolphospholipids: crucial membrane component
- sterol lipids: ringed structure such as cholesterol
- sphingolipids: contains hydroxyl and amine group
- saccharplipids: lipids attached to one or more carbohydrate residues, very hydrophilic
- prenol lipids: ie. vitamin A
- polyketides: found in bacteria and eukaryotes (doxycycline is an example)
Lipid biochemical reactivity
- forms ester bonds by recating carboyllic acid group to alcohol groups
- it is a proton donor
- can form thioester bonds with -SH groups
Serum albumin
- most abundant protein in the serum
- carrier protein for fatty acids in the blood, including thyroid hormones, immunosuppressor drugs etc
Fatty acid uptake in cells
- lipoprotein lipase expressed on cell membranes is an esterase and cleaves fatty acid from carrier protein
- carboxyllic acid group is hydrophilic and allows entry via CD36 channel
Other roles of lipids: signalling, gene regulation and protein trafficking
1) signalling: pancreatic cell insulin secretion. FFA Binds to GPR40 receptor and causes downstream signalling, causing formation of DAG and inositol which is coupled with Ca2+ and insulin release
2) gene transcription: Arachidonic acid promotes heterodimers of TFs PPAR and RXR to form which promotes transcription of genes involved in lipid metabolism
3) protein trafficking/targeting: acylation of proteins can change functions and cause anchoring into cell membrane. Thioester bonds can form between cysteine -SH and -COOH group of acyl chain
Lipolysis stimulated by adrenaline
1) adrenaline binds to GPCR
2) alpha subunit of G protein activates cAMP kinase which converts ATP-> cAMP.
3) cAMP activates PKA which phopshorylates hormone sensitive lipase which breaks down diglycerides to monoglycerides
4) monoglycerides broken down firther by monoglyceride lipase to glycerol and FFA
5) FFA then need to be further oxidised by beta-oxidation
Lipolysis: beta oxidation
1) if long chain (12-20C) then FFA in cytosol need to be activated (if only 8-10 C then can enter mitochondrial directly for beta-oxidation) so they can enter the mitochondria, this is done by addition of CoA via acyl-CoA synthetase in energy-dependent process
2) then via carnitine transferase enter the mitochondira via a translocase which involves the removal of carnitine and passage of acyl-CoA
3) 4-step beta-oxidation process:
- dehydrogenation via acyl-CoA dehydrogenase= FADH2
- hydration (+H2O) via enoyl-CoA hydratase
- dehydrogenation= NADH
- addition of CoASH by acyl-CoA transferase to yield fatty acid CoA and acetyl CoA which is available for the TCA cycle
The last 3 reactions are localised to the mitochondrial trifunctional protein (MTP) therefore very efficient
Exceptions for beta oxidation
- shorter chains (8-10 C) can go straight into mitochondria for beta-oxidation without prior activation by CoA
- if very long (>22C) need to be oxidised in peroxisomes first, which produces heat as FADH forms H2O2 with O2 (peroxisomes are often found close to mitochondria)
- unsaturated fatty acids tend to have cis double bonds and need to be isomerised to trans
Role of insulin
- signalling inhibits HSL (lipolysis)
- increases glucose transport into cells
- citrate from TCA cycle is used for lipogenesis
Lipogenesis steps (liver and adipose tissue)
1) citrate transported out of mitochondria via CTP1. Converted to oxaloacetate by ATP citrate lyase in energy dependent process
2) acetyl coA carboxylase then converts to malonyl CoA with addition of CO2 and acetyl CoA, using energy and biotin as cofactor
3) remaining steps take place on FA synthetase. ACP tethers malonyl CoA and incoming acetyl CoA as the condense. Acetoacetyl ACP then reduces by NADH on distal carobyl ro form hydroxyl. H2O then removed leaving double bone. NADH reduces double bone. Then process repeated adding 2C at a time
Regulation of acetylCoA carboylase
- feedforward mechanism: enzyme activated by citrate
- weakly inhibited by FA (products of pathway)
- activated by insulin which activates phosphatase (removed phosphorylation on inactive enzyme)
- inhibited by action of adrenaline which activates PKA via cAMP (phosphorylates and deactivates enzyme)
Functions of cholesterol
- OH group on A ring allows formation of ester bonds
- steroid hormones: progesterone
- membrane fluidity
- bile acids: cholic acid
- covalent addition for signalling proteins i.e hedgehog
Cholesterol synthesis (in liver)
1) 3 acetyl CoA
2) HMG- CoA
3) Mevalonate (via HMG reductase which is the rate limiting step, and inhibited by statins)
4) isopentyl pyrophosphate (which is important for signalling proteins)
5) squalene
6) cholesterol
Important to remember there are lots of branch points here! Could form dolichol (for glycoproteins) and ubiquinone (for e transport chain)
Could be via Bloch (last intermediate: desmosterol) or Kandutsch Russel (last intermediate: 7-dehydrocholesterol) and can interchange via DHCR24
LDL delivery of cholesterol to cells
- delivered in cholesteryl ester form
- cholesteryl ester bound to LDL, and binds to cells via LDL receptor
- complex endocytosed and fused with lysosome
- lysosomal acid lipase then breaks down complex Into amino acids (the receptor) and free cholesterol
The structure of lipoproteins for lipid transport
- hydrophobic core of cholesterol esters and TAG
- phospholipid membrane with phosphate hydrophilic head groups for emulsification in aqueous solution
- apo protein integral for binding and targeting cell membranes
