Regulation and other lipid synthesis Flashcards
How is lipid synthesis regulated generally?
Controlled by the release of fatty acids from adipose tissue through lipolysis, during starvation
Lipolysis is controlled by phosphorylation of hormone-sensitive lipase (cAMP-dependent phosphorylation activates this lipase)
Glucagon, adrenalin and noradrenalin = increased phosphorylation and lipolysis
Insulin = reduced phosphorylation and lipolysis:
(uses G proteins)
What is a major control point for regulation of fatty acid metabolism?
Acetyl CoA carboxylase
Phosphorylation of acetyl CoA carboxylase is controlled by the insulin:glucagon ratio The product (malonyl CoA) inhibits fatty acid oxidation through inhibition of carnitine-facilitated transport of fatty acids = reduced oxidation
Summarise the aim of regulation when feeding and starving?
Feeding = promote synthesis and storage of fatty acids Starving = promotion of lipolysis and fatty acid oxidation
What other lipids can be synthesised?
Triacylglycerols
Phospholipids
Glycolipids
Sphingolipids
How can triacylglycerols be sythesised?
From fatty acyl-CoA esters and either glycerol-3-phosphate or DHAP
Either reactant leads to lysophosphatic acid which is converted into phosphatidic acid
From here either phospholipids can form or diacylglycerols
Diacylglycerols can then be converted into: monoacylglycerols, triacylglycerols and phospholipids
What is important for triacylglycerol biosynthesis?
Glyceroneogenesis
It is necessary during starvation
How are glycerophospholipids formed?
Diacylglycerol and phosphatidic acid (precursors of triacylglycerol)
How are phospholipids synthesised?
ATP phosphorylates the OH group of choline or ethanolamine
Transferred onto CMP
Yeilding either phosphatidylethanolamine or phosphatidylcholine
You can replace the ethanolamine head with serine = phosphaditylserine, using a tranferase
How is phosphatidylinositol and phosphatidylglycerol synthesised?
Phosphatidic acid attacks the P in CTP
And then either:
Can then attack inositol = phosphatidylinositol (+CMP)
OR
Can attack of glycerol-3-phosphate on CDP (=CMP) and then hydrolysis of the phosphoryl group = phosphatidylglycerol
How is cardiolipin produced?
The condensation of two molecules of phosphatidylglycerol = elminination of 1 glycerol molcule
It is a key component of mitochondrial membranes – interacts with/stabilises respiratory complexes
Barth syndrome caused by a mutation that leads to cardiolipin deficiency – causes dilated cardiomyopathy in infants
What are sphingolipids produced from? General facts?
Sphingolipids consist of a sphingoid base (e.g. sphingosine) linked via an amide bond to a long chain fatty acid
These are key components of lipid rafts in mammalian membranes
Sphingomyelin is a vital component of myelin in nervous tissue
What are ceramides produced from?
It is synthesised from serine and palmitoyl CoA 1. Decarboxylation 2. reduction using NADPH 3. transfer of an acyl group 4. FAD oxidation reaction = Ceramide
A number of lipids derived from ceramide have carbohydrate units to the head group e.g. Gangliosides
What are some lysosomal storage diseases?
As a result from lack of lysosomal enzymes responsible for ganglioside degradation
Tay Sachs disease results when ganglioside GM2 accumulates in lysosomes due to absence of enzyme hexosaminidase A, leads to:
Pale colouration of retina caused by accumulated GM2
Fovea shows up as red spot
It is a rare autosomal recessive condition: common with Ashkenazi Jews (interbreeding)
What other sphingolipids are important?
Sphingomyelin is a nonglycosylated lipid
Important structural lipid in nerve cell membranes
What are prostaglandins?
They are synthesised from C20 fatty acids
Dietary PUFAs are converted to longer fatty acids which are incorporated into membrane phospholipids:
Linoleic acid - arachidonic acid
Linolenic acid - eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
Synthesis depends on availability of omega 3/6 fatty acids
What are some functions of prostaglandins?
They vary in a tissue specific manner
several of them trigger pain, fever, or inflammation
How are prostaglandins synthesised?
Formation of a cyclopentane ring, by prostaglandin H2 synthase
(The heme containing enzyme is made up of cyclooxygenase (COX) and peroxidase)
COX adds 2O2 to arachidonate
Peroxidase converts the OOH to OH
Forms PGH2 which can be converted into thromboxanes and prostacyclin’s
Explain the isoforms of COX?
3 known isoforms COX-1, COX-2 and COX-3
COX-1: expressed and is needed for tissue and organ homeostasis
COX-2: only expressed in a limited number of tissues in response to inflammatory stimuli - inducible (much more specific)
COX-3: expressed mainly in the central nervous system
What are NSAIDs?
Nonsteroidal anti-inflammatory drugs
Aspirin, Ibuprofen and Paracetamol (they inhibit the COX enzymes at the active site)
Aspirin irreversibly inhibits COX-1 &COX-2 by acetylation
Ibuprofen reversibly inhibits COX-1 & COX-2
Paracetamol (acetaminophen) inhibits COX-3 in the CNS – it reduces pain & fever, but is NOT anti-inflammatory
What needs to be considered with NSAIDs?
Side effects e.g. gastric bleeding - due to preferential inhibition of COX-1
Therefore drugs were developed to preferentially bind to target COX-2
COX-2 needs to be targeted for anti-inflammatory purposes
What are some specific inhibitors of COX-2?
Vioxx and Celebrex
These are too big to fit into the active site of COX-1 and therefore don’t affect it
Vioxx was withdrawn due to increased risk of heart attacks and stroke
What is the risk of inhibiting COX-2?
There is an imbalance of eicosanoid synthesis
Inhibition of COX-2 activity decreases PGI2 leading to constriction of blood vessels
Unaffected COX-1 activity leads to continued TXA2 synthesis, increasing blood clotting
Together changes lead to increased risk of heart attacks & strokes
