MBC - Cell Metabolism 2 Flashcards
Where is Acetyl CoA Made?
Mitochondria
What molecules can contribute to Acetyl CoA
Fatty acids
Pyruvate
Amino acids
Why is the mitochondria where the bulk of cellular ATP is made?
Both polysaccharides and lipids can be broken down, and their constituents synthesise fatty acids in the mitochondria.
What are the three main sources from which we derive fats?
- Diet
- De novo synthesis in the liver
- Adipose tissue
What do we use to transport dietary fats
chylomicrons - transport diaglycerides in blood
What do we use to breakdown dietary fats
Lingual, Pancreatic and gastric lipases
What are the 2 fates of fatty acids synthesised in the liver?
- B-oxidation in the muscle, heart or liver
2. Storage in adipose tissue
How do we transport fatty acids going to the adipose or liver/muscle/heart (endogenous fats)
Very low density lipoproteins
What happens when we require fat in the adipose tissue
Fatty acids are mobilised - transported via albumin as and when we require them.
Where are bile salts generated
Liver
Where are bile salts stored
gallbladder
Where are bile salts released
Intestine via bile duct
What do bile salts do
Emulsify dietary fats
What does emulsification do
Allows the absorption of fats and fat soluble vitamins
Which vitamins are fat soluble
A D E K
What do we call a lack in bile salts
Steatorrhoea (fatty stool)
What is the other name for orlistat
Tetrahydrolipstatin
How do we derive orlistat
Chemically derived from lipstatin, a product of streptomyces toxytricini
Is orlistat effective in reducing fat absorption
Yes - reduces it by up to 30%
Does orlistat treat obesity
Yes - for up to 2 years
What are the side effects of orlistat
Abdominal pains
Urgent need to defecate
Increased flatus
Steatorrhoea
Where are chylomicrons made
Intestine
What do chylomicrons transport
Dietary fats (as diaglycerides)
Where are VLDLs made
Liver
What do VLDLs transport
Endogenous fats
Where are IDLs (Intermediate density) made
VLDLs
What do IDLs do
LDL precursor
Where are LDLs made
IDLs
What do LDLs transport
Cholesterol
Where are HDLs made
Liver
What do HDLs do
Reverse cholesterol transport
How are triglycerides incorporated into chylomicrons?
Dietary products are absorbed into enterocytes of the small intestine lining, and are resynthesised to triglycerides before incorporation to chylomicrons
How do chylomicrons enter the blood stream?
They travel in the lymphatic system (lacteal) to the thoracic duct where they enter the left subclavian vein
What do chylomicrons need before binding to LPL and where do they get it from
They need apoproteins from HDLs
Where is LPL found?
On the membrane of the capillary endothelial cells of tissues all around the body.
What happens after chylomicrons bind to LPL
Triglycerides are broken down to fatty acids which undergo B-oxidation, and glycerol which is transported to the liver for gluconeogenesis
What are lipoproteins made of
Phospholipid monolayer, with cholesterol and apoproteins. Inside of the lipoprotein, we have cholesterol esters and triglycerides
What is the need for lipoproteins
They solve the problem of transporting hydrophobic triglycerides in an aqueous environment.
How is a cholesterol ester synthesised
Cholesterol reacts with lecithin via LCAT (lecithin cholesterol acyltransferase) to form cholesterol ester and lysophosphatydilcholine
What is another name for lecithin
Phosphatydilcholine
Outline the lifecycle of a VLDL
- VLDL is synthesised by liver
- VLDL released fatty acids and cholesterol to adipose tissue or skeletal muscle/heart/liver, and glycerol which is likely to be taken back to the liver for gluconeogenesis.
- We are left with a lipid - depleted remnant
How does a lipid depleted remnant become an IDL
It donates apoproteins to HDLs, forming an IDL
How does an IDL become an LDL
It receives cholesterol esters from HDLs to become an LDL
What are the 2 fates of an LDL
It is either taken up via macrophages (bad) or taken up by the liver where the whole process starts again with the synthesis of VLDLs
How much cholesterol do LDLs transport
LDLs transport cholesterol from the liver to peripheral tissues, more than 40% of their total weight consists of cholesterol esters.
Outline roughly the process of B-oxidation
This is the metabolism of fats, occurring in the mitochondria to give us our end product of Acetyl CoA to enter the TCA cycle and subsequent oxidative phosphorylation
What is the first step of B-oxidation
Fatty acid + ATP + HS-CoA —-> Acyl CoA + AMP +PPi
What is AMP
Adenosine monophosphate - this is generated as two phosphoanhydride bonds must be broken to provide energy for this reaction.
Where does the generation of the Acyl CoA species occur?
On the outer mitochondria membrane
How do we get Acyl CoA into the mitochondrial matrix?
Via the carnitine shuttle
Outline the carnitine shuttle
Acyl CoA is converted to CoA by carnitine acyltransferase I, whilst carnitine is converted to acyl carnitine. Acyl Carnitine is then transported into the matrix from the outer membrane via translocase.
In the matrix, Acyl carnitine is converted back to carnitine and Acyl is added to CoA to re-form Acyl CoA via carnitine acyltransferase II. Carnitine is then transported back to the outer membrane via translocase.
How do people get a primary carnitine deficiency?
Autosomal recessvie disorder
Explain what happens in a primary carnitine deficiency
Gene encoding for carnitine transporter (SLC22A5) is affected - results in less carnitine uptake by cells - restricts B-oxidation
What are the symptoms of carnitine deficiency and when do they arise?
Infancy or early childhood. Encephalopathies Cardiomyopathies Muscle weakness Hypoglycaemia
Can we treat carnitine deficiency?
Carnitor (levocarnitine) can be used as a supplement
What happens after Acyl CoA is transported into the martrix of the mitochondria?
Acyl CoA then undergoes a series of oxidation, hydration, oxidation and thiolysis reactions collectively known as Beta oxidation.
What is the product from one cycle of B-oxidation?
We end up with an acyl-CoA which is 2C shorter than the original, and an acetyl-CoA molecule.
What happens with the leftover acyl-CoA?
It will undergo B-oxidation until it is depleted. Therefore, if we have an acyl-CoA that has 4C, it will undergo one last B-oxidation to produce 2 Acetyl-CoA molecules
Palmitoyl-CoA has 16C, how many B-oxidation reactions does it undergo, and how many acetyl CoA are formed?
It will go through B-oxidation 7 times, but will produce 8 acetyl CoA as the last cycle will produce 2 acetyl CoA instead of only 1.
What is the full equation for the B-oxidation of palmitoyl CoA?
palmitoyl CoA + 7 FAD + 7 NAD+ + 7 H2O + 7 CoA —-> 8 acetyl CoA + 7 FADH2 + 7 NADH.
(We also get the reduction of 1 NAD+ and 1 FAD with each cycle of B-oxidation)
Why must fat metabolism be balanced with carbohydrate metabolism
Acetyl CoA from B-oxidation can only enter TCA if oxaloacetate is present (derived from pyruvate), therefore we need a balance from carbohydrate metabolism.
When might fat breakdown predominate
Fasting
What happens as a result of fasting
formation of ketone bodies
What are the 3 ketone bodies
Acetone
D3-hydroxybutyrate
Acetoacetate.
Typically, how efficient is B-oxidation
Around 40%
How many enzymes are involved in lipogenesis (fatty acid biosynthesis)?
2
What enzymes are involved in fatty acid biosynthesis?
- Fatty acid synthase
2. Acetyl CoA carboxylase
What is the general outline of fatty acid biosynthesis?
Sequential decarboxylative condensation reactions involving 2 molecules: Acetyl CoA and malonyl CoA
What does the fatty acyl undergo after each round of elongation?
reduction and hydration by the sequential action of ketoreductase, dehyrdatase and enol reductase.
What links to the growing fatty acyl chain?
Acyl Carrier Protein (ACP)
Where does lipogenesis occur?
Cytoplasm
What would be the overall equation for the biosynthesis of palmitate?
Acetyl CoA + 7 Malonyl CoA + 14 NADPH +14 H+ ——–> Palmitate (C16) + 7 CO2+ 6 H2O + 8 CoA-SH + 14 NADP+
What happens if the fatty acyl chain needs to be elongated past 16 carbons?
Occurs separately in the mitochondria and endoplasmic reticulum
What is required for fatty acid desaturation?
Fatty Acyl-CoA Desaturase enzymes
What enzyme is used for the desaturation of stearate to oleic acid, and palmitate to palmitoleic acid?
Delta-9 desaturase.
This is because it creates a double bond 9 carbons away from the terminal carboxyl group
In what part of the body does lipogenesis mainly occur?
Liver, adipose tissue, lactating breast.
What has been observed with cancer patients and lipogenesis, and how does this play a role in finding treatment?
The reactivation of fatty acid synthesis has been observed in cancerous cells, therefore we are looking for ways to target the FASN gene which codes for fatty acid synthase to reduce tumours.
What has been shown to inhibit FASN?
Cerulenin which is an anti fungal antibiotics, has been seen to rescue the growth of ovarian tumours.
What enzymes are involved in the first step of B oxidation with the Acyl CoA
Dehydrogenases - which bind to fatty acid chains, and reduces a FAD to FADH2 in the process
What enzyme binds to fatty acids with a carbon chain of less than 6 carbons
Short chain acyl Co enzyme A dehydrogenase
What enzyme binds to fatty acids with a carbon chain of 6-12 carbons
Medium chain acyl Co enzyme A Dehydrogenase
What enzyme binds to fatty acids with a carbon chain of 13-21 carbons
Long chain 3-hydroxyacyl Co enzyme A dehydrogenase
What enzyme binds to fatty acids with a carbon chain of 22 carbons or more
Very long chain acyl Co enzyme A dehydrogenase
What is MCADD
medium chain acyl Co enzyme A dehydrogenase deficiency
How many people does MCADD affect, and who?
Affects 1 in 10,000 live births in the UK every year, primarily affecting caucasians
Is MCADD serious?
Yes - if undiagnosed can be fatal (detected in heel prick tests) - accounts for 1% of sudden infant death syndrome (SIDS).
What can be done for MCADD patients?
Make sure that they don’t go without food for 10-12 hours - high carbohydrate diet.
Also, if they have an illness where they lose their appetite or are vomiting lots, IV glucose may be needed to prevent the body trying to metabolise fatty acids.
