L13 - Lipid biosynthesis Flashcards
Fatty acids: what are their fates after being synthesised?
- TAG production
- Phospholipid production
Triacylglycerol synthesis
Occurs with the same pathway as triacylglycerol synthesis - uses glycerol-3-phosphate, G3P is obtained from using glycerol and dihydroxyacetone phosphate (DHAP) as well as a minor pathway in the liver and kidney.
DHAP - obtained from glycolysis
After getting G3P, the carbon chains can be built up to form triacylglycerols:
* Fatty acids are activated by esterification to form acyl-CoA by acyl-CoA synthase
* Acyl chains from acyl-CoA are transferred to the -OH group on G3P, catalysed by acyl transferase
* Once two acyl chains have been added to G3P by esterification, phosphatidic acid is produced
* Phosphatidic acid phosphatase removes the phosphate, forming 1,2 diacylglycerol
* Triacylglycerol is formed as a third acyl group is transferred to 1,2 diacylglycerol by acyl transferase
Cytosolic face of ER/mitochondria
leccy
Molecular mechanisms not well understood
Enzymes have ≥ 2 isoforms, highly hydrophobic
Several potential regulatory points:
GPAT
PAP
DGAT
Phospholipid synthesis
Occurs with the same pathway as triacylglycerol synthesis - uses glycerol-3-phosphate, G3P is obtained from using glycerol and dihydroxyacetone phosphate (DHAP) as well as a minor pathway in the liver and kidney.
DHAP - obtained from glycolysis
After getting G3P, the carbon chains can be built up to form phospholipids:
* Fatty acids are activated by esterification to form acyl-CoA by acyl-CoA synthase
* Acyl chains from acyl-CoA are transferred to the -OH group on G3P, catalysed by acyl transferase
* Once two acyl chains have been added to G3P by esterification, phosphatidic acid is produced
* Addition of a head group to this forms a completed glycerophospholipid
Cytosolic face of ER/mitochondria
leccy
Molecular mechanisms not well understood
Enzymes have ≥ 2 isoforms, highly hydrophobic
Several potential regulatory points:
GPAT
PAP
DGAT
TAG: what is it, how is it stored, where is it presented, where is it formed, what is its pathway, and how is it moved around?
Triacylglycerol
Stored in lipid droplets
Present in all cells
Form at the endoplasmic reticulum
Bud off into cytoplasm
Surface covered by proteins - perilipins, these form a ‘shell’ around the lipid droplet and allow movement?
Lipase enzymes (TAG breakdown)
Lipase regulatory proteins
Enzymes for TAG synthesis (ACS, GPAT, AGPAT, DGAT)
Places of high TAG synthesis(?)
Newborn mammals and hibernating animals - high need for energy
Thermogenin forms channels in mitochondrial membrane – no proton gradient
Oxidation of FA doesn’t produce ATP
TAG breakdown > FA oxidation > HEAT
Brown vs white adipose tissue
White - typical fat storer, contains many lipid droplets
Brown - brown bc of high mitochondria presence, generates heat - babies, hibernating animals etc
TAG synthesis: when is it used and how is it regulated?
TAG synthesis is a ‘storage’ reaction
Maximum rate when organism has plentiful supply of nutrients
Regulated by hormones
Insulin: stimulates TAG synthesis
Glucagon: inhibits TAG synthesis
GPAT
Glycerol phosphate acyl transferase (GPAT)
Lowest specific activity of pathway
Inhibited by phosphorylation – PKA (glucagon, adrenaline) and AMPK (energy status)
- Glucagon /adrenaline
- Low energy status (Low ATP:AMP)
↑ FA oxidation
decreased FA synthesis
decreased glycogen synthesis
decreased TAG synthesis
Co-ordinated regulation of anabolic and catabolic pathways – fatty acids channelled away from storage to oxidation - probs delere sounds pointless
PAP
Phosphatidic acid phosphatase
Moves between ER membrane and cytosol
Association with ER membrane stimulated by fatty acids
Feed-forward activation by substrates
Cholesterol
Component of biological membranes - fluidity
Precursor for steroid hormones
Associated with cardiovascular disease
Efficiently absorbed from diet
Synthesised by all animal cells (liver)
Cholesterol biosynthesis
Acetyl-CoA - HMG-CoA - mevalonate - cholesterol
HMG-CoA reductase
- Covalent modification – inhibited by phosphorylation
- Transcription – inhibited by cholesterol (SREBP-2)
- Degradation – stimulated by cholesterol
- Translation – inhibited by cholesterol
Rate of cholesterol synthesis is responsive to level of cellular cholesterol, hormones and ATP
HMG-CoA reductase phosphorylation: what type of regulation is it, what are the mechanisms behind it, and ??
Short term
- Insulin - protein phosphatase activation
- Glucagon/epinephrine - PKA activation
HMG-CoA reductase proteolysis: what type of regulation is it, what are the mechanisms behind it, and ??
Coarse control?
