Fatty acid Synthesis Flashcards
Is fatty acid synthesis the reverse of beta oxidation?
No
Where does fatty acid synthesis take place?
Takes place in our liver cells and in lactating mammary glands
In which part of the cell does fatty acid synthesis occur?
In the cytosol
How is citrate shuttled out of the inner mitochondrial membrane?
Via the pyruvate malate cycle
Why is the pyruvate malate cycle important?
- It shuttles out our citrate
2. Helps generate NADPH for the pentose phosphate cycle
Name the 3 carbon intermediate that is important or fast acid synthesis to occur
Malonyl CoA
How is malonyl CoA formation require?
Acetyl CoA in an irreversible reaction
Name the rate determining step for fatty acid synthesis
The formation of malonyl CoA
How is malonyl CoA formed?
Acetyl CoA reacts with Acetyl CoA carboxylase (biotin) and citrate to form malonyl CoA
State the 2 equators involved in the production of malonyl CoA
- Biotin-enzyme + ATP + HCO3 -> CO2-Biotin-enzyme + ADP+ Pi
2. CO2-Biotin-enzyme + acetyle CoA -> malonyl CoA + Biotin-enzyme
Name a step which inhibits or activates fatty acid synthesis
The formation of malonyl CoA
How is the formation of malonyl CoA regulated?
By regulating the enzyme acetyl CoA carboxylase
When do we want a lot of malonyl CoA to be produced?
When we have a low AMP:ATP ratio (ie when we don’t have a lot of energy)
How is Acetyl CoA
carboxylase inactivated?
When there’s a high AMP:ATP ratio up regulates kinase phosphorylating our Acetyl CoA
carboxylase inactivating it
How is Acetyl CoA
carboxylase activated?
Increased insulin and decreased glucagon up regulates Phosphatase which removes a phosphate group from Acetyl CoA
carboxylase activating it
What does the fatty enzyme synthase complex do?
It catalyses different enzymatic activities to synthesis and elongate fatty acids
Describe the central part of the fatty acid synthesis complex
It is a domain where the molecule 4’ phosphopentetheine covalently bonds to the enzyme
What is 4’ phosphopentetheine ?
It is a derivative of the vitamin pantothenic acid and it is also a component of CoA
What does 4’ phosphopentetheine do?
It carries acetyl and act units on the terminal thiol group during fatty acid synthesis
Name all the steps of fatty acid synthesis
- Transfer from acetyl CoA to the SH group of the Acyl Carrier Protein
- Transfer of a 2 carbon fragment on our ACP onto a cystine residue on the enzyme
- Addition of the malonate unit from malonyl CoA onto a vacant ACP
- Acetyl attack the malonyl group
- Reduction of acetoacetyl-S-ACP
- Dehydration of beta-hydroxybutyryl-ACP to introduce a double bond
- Reduction of crotonyl-S-ACP
How is acetyl CoA transferred onto the acyl carrier protein (ACP)?
Via the enzyme Acetyl CoA-ACP transacylase
this forms Acetyl-S-CAP + CoA
What does Acetyl CoA-ACP transacylase do?
It transfers acetyl CoA transferred onto the acyl carrier protein (ACP)
What happens to Acetyl-S-CAP once it has formed?
It combines with an enzyme-sulpha hydrate too form Acetyl-S-Enzyme + ACP-SH
(no enzyme required)
What is malonate added to and how
Malonyl CoA is reacted with ACP-SH via the enzyme Malonyl CoA-ACP-transacylase
to form Malonyl-S-ACP + CoA
What does Malonyl CoA-ACP-transacylase do?
Reacts Malonyl CoA and ACP-SH together to form malonyl-S-ACP +CoA
What happens to Malonyl-S-ACP once it has formed?
It is attacked by acetyl groups
What happens to malonyl S ACP once it is attacked by acetyl groups?
It loses a CO2
Why is malonyl-S-ACP losing CO2 an important step?
It is a key step in providing the reaction with energy as the decarboxylation drives the reaction
How does the malonyl-S-ACP lose a CO2?
It undergoes an acetyl attack and is reacted with the enzyme B-Ketoacyl-ACP synthase to form acetoacetyl-S-ACP
What does B-Ketoacyl-ACP synthase do?
It aids in the conversions of malonyl-S-ACP into acetoacetyl-S-ACP
What happens to acetoacetyl-S-ACP once it has formed?
It Is reduced by NADPH to for beta-hydroxybutyryl-ACP by the enzyme b-Ketoacyl-ACP reductase
What does the enzyme b-Ketoacyl-ACP reductase do?
It aids in the reduction of acetoacetyl-S-ACP into beta-hydroxybutyryl-ACP
What happens to beta-hydroxybutyryl-ACP once it as formed?
It is dehydrated by b-hydroxyacyl-ACP
dehydratase to form crotonyl-S-ACP
What does b-hydroxyacyl-ACP
dehydratase do?
It dehydrates beta-hydroxybutyryl-ACP to form crotonyl-S-ACP
What happens to crotonyl-S-ACP once it has formed?
It is reduced by NADP and Enoyl-ACP reductase do form butyryl-S-ACP + NADP+
What doesEnoyl-ACP reductase do?
It reduces crotonyl-S-ACP to form butyryl-S-ACP
At the end of the 7 steps of fatty acid synthesis what is produced?
A 4 carbon compound is produced which has 3 terminal carbons fully saturated
After the 7 steps of fatty acid synthesis what happens?
These 7 steps are repeated in the sequence 5 times beginning with the transfer of the newly formed 4 carbon species from the ACP to the peripheral cysteine side group
After the sequence of fatty acid produce has been repeated 6 times what is the end result?
The cycle is repeated until a fully saturate 16 carbon long fatty acid chain forms
What happens when a fatty acid with 16 carbons is synthesised?
The synthetic process is terminated as a fully saturated molecule of palmitate is formed
State the overall reaction for palmitate synthesis
8Acetyl CoA + 14NADPH + 14H+ +7ATP
->
Palmitate + 14NADP+ +8CoA +7ADP +H2O
Name the principal product of fatty acid synthesis?
palmitate
What happens to palmitate once it has formed?
It can be lengthened to form stearate
How long is stearate?
It can be 18 carbons in length or longer
How are fatty acids longer than 18 carbons made?
They are made by further sequential additions of acetyl groups (This requires a different set of enzymes)
Where are the enzymes that produce larger fatty acids found?
They are found on the endoplasmic reticulum and in the mitochondria
Describe the enzyme pathway in the endoplasmic reticulum
All enzymes are discreet and are sutuated on the surface of the smooth endoplasmic reticulum
There is no acyl carrier protein all intermediates are bound to CoA
What is the mitochondrial pathway of fatty aid synthesis important for?
Important for the lengthening of short fatty acid chains
What is not needed in the mitochondrial pathway ?
The intermediate malonyl CoA is not needed
Intermediates are directly added to acetyl CoA
What occurs at the smooth endoplasmic reticulum
The addition of double bonds to unsaturated fatty acids
What is the desaturation of fatty acids?
It is the addition of a double bond to unsaturated fatty acids
It is a series of electron carriers consisting of 3 enzymes
Name the 3 enzymes involved in the desaturation of fatty acids
- NADH-Cytochrome b5 reductase
- cytochrome b5
- Fatty acid desaturase
What does NADH-Cytochrome b5 reductase do?
It reduces FAD into FADH2
What does cytochrome b5 do?
It reduces Fe3+ INTO Fe2+
What does fatty acid desaturase do?
It reduces Fe3+ INTO Fe2+
What do NADH Cytochrome b5 reductase, cytochrome b5 and Fatty acid desaturase do?
Over all they pass 2 pairs of electrons down a series of redox reactions to ultimately produce a double bond at the carbon 2,5,6 or 9 position in fatty acids
How many different desaturase enzymes do we have and what do they do?
Mammilian systems have 4 different desaturase enzymes that produce double bonds at the carbon 2,5,6 or 9 positions
How can fatty acids be different?
They can vary in their degree of saturation
How can we define the configuration of double bonds in fatty acids?
Can be defined as cis and trans
IF you describe a fatty acid as cis what does that mean?
Means the ethyl groups are on the same side of the double bonds
IF you describe a fatty acid as trans what does that mean?
Means the methyl groups are on the opposite side of the double bonds
How do we indicate where the double bond is?
By using a triangle followed by a number
Why are unsaturated fatty acids important?
As they are an important precursor to intracellular messages
and phospholipids
On which carbons can mammals form double bonds on in fatty acid chains?
Carbons: 4,5,6, and 9
Where do we get particular polyunsaturated fatty acids that we can’t synthesise?
We get them from our diet
Name some essential fatty acids
- Alpha-linolenic acid
- Linoleic acid
- Gamma linoleum acid
- Arachidonic acid
State: a. how Many carbons b. How many double bonds c. Position of double bonds in Alpha-linolenic acid
a. 18 carbons
b. 3 double bonds
c. cis carbons on: 9,12,15
State: a. how Many carbons b. How many double bonds c. Position of double bonds in linolenic acid
a. 18 carbons
b. 2 double bonds
c. cis carbons on 9,12
State: a. how Many carbons b. How many double bonds c. Position of double bonds in gamma-linolenic acid
a. 18 carbons
b. 3 double bonds
c. cis carbons on: 6,9,12
State: a. how Many carbons b. How many double bonds c. Position of double bonds in Arachidonic acid
a. 20 carbons
b. 4 double bonds
c. cis carbons on: 5,8,11,14
What can Arachidonic acid be synthesised from
Can be synthesis from linoleic acid through a series of desaturation and elongation reaction
If you can’t synthesis Arachidonic acid from linoleic acid where do you need to get Arachidonic acid from?
Need to get it from meat as it is not present in plants
Why is Arachidonic acid important?
It is an important precursor of several classes of signalling molecules
How can arachidonate be released?
In response to hormonal or other stimuli phospholipase A2 attacks membrane phospholipids releasing arachidonate
What do derivatives of arachidonate do?
They are potent biological signalling molecules that at as short range messengers which affect the tissues near the cells that produce them
What can arachidonate be converted to and where?
Enzymes of the smooth ER can convert arachidonate into prostaglandins forming an intermediate precursor Prostaglandin H2
What can inhibit Prostaglandin synthase and how?
Aspirin by blocking channel to the active site
What does aspirin do to cox?
It irreversibly inactivates the cyclooxygenase activity of COX by acetylene a serine and blocking the active site
This prevents the formation of prostaglandins and thromboxanes
How many COX enzymes are there?
2
What does cyclooxygenase-2 (COX-2) do?
It is an enzyme that syntheses prostaglandins
What are prostaglandins?
They are molecules that promote inflammation, pain and fever
What are NSAIDs?
Non steroidal anti-inflammatory drugs
How do NSAIDs work?
They work by blocking cyclooxyrgenase-2 (COS-2) thus preventing the synthesis of prostaglandins
What are the disadvantages of NSAIDs?
They also inhibit COX-1 this can lead to side effects such as ulcerations and kidney damage
How are fatty acids stored?
As components of triacylglycerols
What are monoacylglycerols
1 molecule of fatty acid esterified to a molecule of glycerol
What are diacylglycerols
2 molecules of fatty acids esterified to a molecule of glycerol
What are triacylglycerols
3 molecules of fatty acids esterified to a molecule of glycerol
How are fatty acids esterifed to glycerols?
They are esterfied by their carboxyl groups leading to the formation of neutral fats
Can triacylglycerols form micelles?
Not on their own they need to coalesce within adipocytes to
Form oily droplets that are anhydrous
Why are triacylglycerols important?
As they are a major energy source
In a triacylglycerols are all the fatty acids attached to glycerol the same?
No they can be different
What mist happen to fatty acids before they can turn into triacylglycerols ?
They must first be activated
Name the initial acceptor of fatty acids during the synthesis of TAGs?
Glycerol-3- phosphate
How can glycerol-3 phosphate be produced?
- By the liver
2. By adipose tissue
How is glycerol-3-phosphate produced by the liver?
Glycerol reacts with glycerol kinase to form glycerol-3- phosphate
This reaction requires ATP
What does glycerol kinase do?
It aids in the conversion of glycerol of glycerol-3-phophate
How is glycerol-3- phosphate produced by adipose tissue?
- Glucose is converted into dihydropxyacetone (DHAP)
2. DHAP is then reduced by NADH and glycerol 3 dehydrogenase to form glycerol 3 phosphate
What does glycerol-3- dehydrogenase do?
It aids in the conversion of DHAP into glycerol 3 phosphate
How are TAGs synthesised by glycerol 3 phosphate?
- Glycerol 3 phosphate reacts with fatty acyl-COA and acyltransferase to form Phosphatidate, 2 CoAs
- Phosphatidate then reacts with phosphatase to form diacylglycerol
- diacylglycerol recat. with fatty acyl-COA and acyltransferase to form the glycerol backbone
What does acyltransferase do when it is rented with glycerol-3-phophate ?
It aids in the conversion of glycerol-3-phophate into Phosphatidate
What does phosphatase do?
Aids in the reaction of Phosphatidate into diacylglycerol
What does acyltransferase do when it is rented with diacylglycerol
Aids in the reaction of diacylglycerol into a glycerol backbone
