Metabolism pathways - Biochem Semester 2
How does blood glucose levels vary through the day
After eating there will be high levels of blood glucose and then if not eat for a while then there will be lower levels of blood glucose
Can use glycogen to maintain a stable blood glucose whgen we arent eating like when sleeping as glycogen is a short term emergency store of glucose
What is the structure of glycogen
It is the animal version of starch as it is a branched polymer of glucose by glycosidic bond that are between the C1 and C4 of glucose and there are branches when glucose bonded by C1 and C6
The main chain is an alpha 1,4 C chain and is alpha due to oxygen below the chain
It will form a helical structure and there will be 12-14 glucose per chain and branching every 8-12
It will be stored in the liver as glycogen granuoles and can tgere be converted to glucose during blood glucose homeostasis
What is glycogenolysis
This is the breakdown of glycogen to glucose
What is the 1st step of glycogenolysis
This is where the glycogen has a glucose 1 phosphate removed from the chain
This is done by phosphorlysis which is the breaking of the glycosidic bond by adding a phosphate ion to make the glucose 1 phosphate, it is done via phosphorylsis so that there is no ATP wasted
What is the phosphorylase active site
There is a deep cleft active site called pyridoxal phosphate where there are 3 isozymers of it all having a slighlty different function due to being in the muscle, liver or brain respectivley
How is phosphorlysis a progressivce enzyme
Due to being a processive enzyme it wont let go of the glycoegn once on glycosidic bond has been broken but will keep going along the chain
This means due to the enzyme procession and branched glycogen structure then there will rapid glucose mobilisation
What can phosphorylase not do
It cant break the alpha 1-4 or 1-6 bonds due to being hindered by the branch that will prevent it getting further down the chain and so prevent 4 glucose molecules being remopved from the branch point
This can lead to dextrin molecules being formed from glycogen being digested as far as it can be
Why is a debranching enzyme needed
This is too prevent the dextrin formation and it will tranfer 3 glucose molecules from the branch on the glycogen to a different place so that it can then be accessed by the phosphorylase
Then also need alpha 1-6 glucosidase to then hydrolyse the final single glucose of the branch chain so that then glycogen is 1 long straight chain so then whoel chain can be turned to glucose 1 phosphate
How is glucose 1 phosphate turned to glucose 6 phosphate
This is done by the enzyme phospoglucomutase
The 1 step will be to enter the active site and tnr serine will add a phosphate to C6 to leave a 2 phosphate intermediate molecule
The enzyme will then be restored due to the phosphate from C1 will go back to the serine so step can happen again
This then make glucose 6 phosphate that can then enter glycolysis to produce glucose
What are the entrances to glycolysis
In the muscles there is glycohen to go to glycolysis to then make ATP for muscle contraction
In the liver the glycogen to gluconeogensis to create new glucose from glucose 6 phosphate to then increase the blood glucose
How is glucose 6 phosphate turned to glucose
In the liver cells there is the enzyme glucose 6 phosphatas ethat cut off the phosphate from the molecule to make glucose
There are 3 glucose + 3 Pi per cycle in the enzyme and then tbhe glucose released to the blood via transportters in the liver membrane
There are 3 transporters: 1 to bring in glucose 6 Phosphate to the liver, 1 for the removal of the Pi from the liver and 1 for the removal of the glucose to the blood
What happens when blood glucose is too high
After a meal there will be high blood glucose and so the gluvose is converted to glucose 6 phosphate that then go to glucose 1 phosphate to then go the glycogen
What is Mcardle disease
This is where the production of glycogen is prevented yet there is still glycogen in the liver
This is due to the phosphate concentration in the cell is higher than the glucose 6 phosphate so will always go glucose 6 phosphate to glucose 1 phosphate
What actually happens during glycogenesis
Glucose is converted to glucose 6 phosphate by the enzyme reversed of phosphoglucomutase
The glucose 6 phosphate then converted to UDP- glucose due to the UTP has 2 phosphate ions released by the enzyme UDP glucose pyrophosphorylase
There is then glucose activation where the glucose 1 phosphate + UTP --> UDP glucose
UDP glucose is then attached to the glycogen by glycogen synthase and will be added to current chaain by alpha 1-4 bond and then the UDP will be released
How is glycogen initiation done
Glycogenin is where build the initial 8 unit primer that is the extended by glycogen synthase
Branching enzyme - Bind to chains that are 11+ long and cut off heptamer of glucose units to then reattach via alpahg 1-6 bond by glycosyltranferase
There is a reattachment site 4 units from any previous branch point
What are fats
These group all the hydrophobic molecules and any fat soluble molecules and they are rich in triglyerides
They are solid at room temp and if its an oil will be liquid at room temp, this is due to contain different type of triglycerides
What is the structure of a fat
There are 3 fatty acid tail that ar then ester linked to a glycerol backbone
The fatty acid tails can be saturated or unsaturated and the more double bonds then the lower melting point so more likely to be an oil than fat
Cis hydrocarbons have a kink in the chain due to where the chain on the same side of C=C and trans have no kink due to long chain on opposite side of C=C
How are fatty acid converted
Elongases are used to increase the lenght of by 2 carbons and desaturases are used add carbon bonds to the hydrocarbon chain
Humans dont have the essential desaturases to add a C=C lower than omega 9
Omega 3 + 9 fats have to come from the siyte and so the human essential fats as cant be made by conversion
They can be elongated and then have to be further desaturated after that
Why do we need to convert fatty acids
There is not a need to alter for energy purposes but more to allow the phospholipid membrane to carry out its function as the fatty acid length will vary membrane thickness as well as level of saturation for the levels of membrane fluidity
Some FA need to be altered so they can be a precursor to signalling molecules
How are fatty acids digested
The majority of lipids in food come in the form of the triglycerides
They are digested by lipases in the pancreas that break the ester bond of the 1+3 fatty acid to the glycerol so then leave a monoglyceride and 2 free fatty acids chains
What happens to digested triglycerides
They are then re-esterified back to triglyceries in the gut mucosa
For this to happen there has to be they have to be activated by using co enzyme A before then being attached to glycerol
The CoA is a temporary way to provide energy to activate the FA that can then bind to the glycerol in the gut
How is the CoA atached to the fatty acid
This is done by the enzyeme acyl CoA synthetase and will remove a water molecule to do this as well as turn ATP to ADP
What are Lipoproteins
This is a mixture of lipid and proteins where there is a phospholipid and cholesterol outer layer and then triglyceride core
There are also A,B,C,D,E apolipoproteins present as well
The transport of them from the gut to the adipose tissue uses cholomicrons
How are fatty acids uptaken
Endothelial cells haev lipoprotein lipase that diegst lipids in the lipoproteins
All 3 of the fatty acids will be cut from the glycerol and then will diffuse into the adipose tissue to then be used in the cells and tissue
How can there be triglyceride formation in the adipose tissuse
This will start with 1x glycerol 3 phosphate and then 3 activated Fatty acids that have been absorbed by the adipose tissue
The Glycerol 3 phosphate will come from DHAP during glycolysis
This is done with the enzyme G3P Dehydrogenase and needs the oxidation of NADH to NAD+
Then the activated fatty acids tails are the added 1 by 1 to the Glycerol 3 phosphate
This is done by the enzyme G3P acyltransgerase so then produce Lysophosphatidic acid + the coenzyme A
The next fatty acid is then added by 1acyl G3P acyltranferase to then produce the Phosphatidic acid + the coenzyme A
Then the Phosphatidic acid is dephosphorlated to then produce Diacylglycerol by the enzyme phosphatidic acid phosphatase
Then the final fatty acid is then added diacylglycerol tranferase to make the triglyceride
How are fatty acids dense energy stores
This is due to when glucose is converted to glycoegn there is also the prodution of 2x water molecules
When fatty acids are turned to triglycerides then there is no water created
This means denser energy store due to no space taken up by water that you cant get energy from
How are fatty acids stored
They are stored as triglycerides in adipose tissue that are able to swell up to store more energy as fatty acids and each lipid droplet is surrounded by a shell of perilipin to prevent them being released
How do you release a fatty acid energy when in adipose tissue
To gain access to the fatty acid need to phosphorylate the perilipin coating to allow enzyme to get to the triglyceride in the lipid droplet
The triglyceride can then bind to enzyme to cut off 1 fatty acid tail to form diglyceride than then bind to another enzyme to release next fatty acid tail to form monoglyceride that then bind to last enzyme to form glycerol + 3 fatty acids by 3 different lipases for each step
How to release fatty acids into blood
This can be done due to bidn to HSA as it is insoluble to move in the blood on its own
The HSA will move the fatty acid from high conc in the adipose tissue to lower concentration areas in other body areas and they can then enter cells that have low concentration and go to the mitochondria outer membrane where they become activated
How does the fatty acid become activated when on outer membrane of mitochondria
This is a 2 step reaction:
1st step = Fatty acid + ATP --> Acly Adenylate + Phosphate group
2nd step = Acyl Adenylate + HS coenzyme A --> Acyl CoA + AMP
The conversion of AMP to the uselful ADP needs another ATP so there is an overall net loss of 2 ATP per reaction
How can the activate fatty acid enter the mitochondria
Acyl CoA is produced as it is able to pass through the outer membrane via a channel
The CoA is then replaced by Carnitinine in order to then cross the inner membrane into the matrix by Carnitine AcylTransferase 1
Acyl-Carnitine is then transported across the bilayer by translocase antiporter to then bind to the acyl-carnitine tranferase 2 to then remove the carnitine and replace it withy CoA to remake the Acyl-CoA from the start
Once in the matrix this can then feed acyl CoA to Acetyl CoA to start TCA cycle
What is Beta oxidation
This is the taking of fatty acids and feeding them into the TCA cycle
The fatty acids are catabolised in 2C units due to acetly being a 2C compound
The first cleavge will be next to the beta Carbon to then release acetly CoA to TCA cycle
The CoA then put back onto the new cleaved chain for the process to happen again
How to break to Beta Carbon bond in Beta oxidation Step 1 + 2
S1 - There is the oxidation of Alpha and Beta Carbons as FADH2 is produced from FAD, this is to produce a C=C between alpha and Beta Carbon
S2 - Add water to the double bond in an addition reaction to break double bond and add Oxygen to Beta Carbon by hydratase enzyme
What are Step 3+4 for beta oxidation
S3- There is another oxidation reaction to remove the hydrogen from the Beta carbon as NAD become NADH to then go to ETC
S4- There is thyolysis to then break a bond with a thiol group with the enzyme thiolase, to then lead to production of acyl CoA at the end to then start the process again
Each cycle of beta oxidation produces 1 acetyl CoA + 1 NADH and 1 FADH2
How does Beta oxidation happen with a polyunsaturated fatty acid
There will need to be a isomerase to then convert cis double bond to a trans double bond ans change position of the C=C bond to then make the product made from 1st step of Beta oxidation reaction
When are Ketone bodies made
This is when the conditions of prolonged starvation and so high level of triglyceride hydrolysis and so more fatty acids and so can get excess FA that cant be stored so liver turn them to Ketone bodies
What are Ketone bodies
They are smaller fragments of Fatty acids and are more soluble and easier to transport around the body especially to the heart
They need very little conversion to get to the TCA cycle as they are similar to acetly CoA
What is Ketogenesis
There are 3 acetly CoA that are joined together due to the excess of them and this is done by reversing the final step of Beta oxidation
This product can then be broken down to acetone that cant be use for energy and is lost by sweating
The other products acetoacetate and Beta Hydroxybutyrate can be used for energy in the body
How is energy collected from the products of Ketogenesis
Convert the Beta Hydroxybutyrate to acetoaceatate
This can then be converted to Acetoacetly CoA by: Succinyl CoA will go to succinate as well as use the enzyme B Ketoacyl transferase
Acetoacetly CoA can then be fed to the TCA cycle to then get energy
Acetone cant be converted to Acetoacetate so has no energy purposes
What is fatty acid anabolism
This is the reverse of fatty acid catabolism but there are different enzymes and co-enzymes used
NAD and FAD are used for breaking things down and then NADH is for building things up
What is the start process of fatty acid anabolism
The start point is with acetly CoA and it will end with palmitic acid and the process used is almost a reverse of Beta oxidation so can be called Beta reduction
What is used to grow the fatty acid chain in anabolism
There is no joining of acetyl CoA together to grow the fatty acid chain byut instead there is the use of malonyl A
How is Malonyl A produced
Malonly A is produced due to:
Acetyl CoA + ATP + HCO3- --> Malonyl CoA + ADP + Pi + H+
The acetly CoA is carboxylated due to the carboxyl ion that donate carbon to make a 3 Carbon compound
The enzyme Acetly CoA Carboxylase is used for this but is inhibited by palmitic acid, glucagon and adrenaline but is stimulated by citrate and insulin and is an irreversible reaction
How is the fatty acid chain extended
This is done by Fatty acid Synthase and the chain will grow 2 Carbon at a time
This is due to there being a 3C malonly CoA added to an acetyl CoA to make a 4 Carbon fatty acid chain + 1CO2 molecule released to then drive the reaction to create the bond between the 2 carbon compounds
Why is acetly CoA exported to the Cytoplasm
The fatty acid synthase + acetly CoA carboxylase are both located in the cytoplasm but the acetly CoA is made and stored in the matrix of the mitochondria
How is acetly CoA exported to the cytoplasm
It will react to form oxaloacetate citrate as part of the TCA cycle due to there being a citrate transporter in mitochondria membrane
Then in the cytoplams the citrate is broken down to the acetly CoA and oxaloacetate that can then be reduced to malate by NADH oxidation
What does Malate do in the cytoplasm
It can be converted to Pyruvate due to NADP+ reduction to then form NADPH and the decarboxylation of Co2
Pyruvte is then fed into the link reaction to then re-enter the mitochondria
What is fatty acid Synthase
It is a collection of 6 different enzymes that have joined to form 1 multidomain enzyme that has 6 active sites, this is due to their genes have become joined together over evolutionary time
There is an acly carrier protein and an extendable arm to transfer products between the different active sites
The very bottom domain are used for bond making between acetly CoA and Malonyl CoA and the top domains are for modyfying their functions
What is step 1 of the fatty acid anabolsim pathway
The making of C=C bond between the acetly CoA and Malonly CoA, in the first 2 active sites of the enzyme
There are sulphide groups where a group can be attached and then remove it after the process
There is an acetyl added to the KS enzyme via ACP arm anbd MAT enzyme and then the malonly group tranferred onto ACP arm by MAT enzyme
KS enzyme the join both acetly and malonyl together to form 4 C compound due to CO2 also made to drive the process
What are steps 2-4 of the fatty acid anabolism pathway
Step 2 is the reduction stage
Step 3 is the dehydration stage
Step 4 is another reduction stageaqnd they all work to turn a C=O into a CH2 molecule on the Beta Carbon
The final product made is Butyryl ACP + 2NADP+ + H2O
What is the elongation step of fatty acid anabolism
This process keeps happening where the finshed product is recycled back to the KS enzyme for S1 to happen again
This is done until the 16C long to make Palmitic acid that is then released by enzyme thioesterase by breka ther bond with ACP arm
In Mammary tissue there is different thioesterase so cleaves off a shorter fatty acid to go into milk to make it easier for the baby to digest
How are lipids stored and transported
In an anabolic state the new fatty acids will be converted to triglycerides and then stored as these
If they are stored in the liver then lipoproteins are used to export the triglycerides to adipose and other types of tissue
Lipoprotein will vary depending on the surface proteins that they have on their shell
What are the types of lipoproteins
Chlyomicrons, very low denstiy lipoprotein, intermediate density lipoprotein, low density lipoprotein and high density lipoprotein
What will determine the density of a given lipoprotein
The largerthe lipoprotein then the lower the density of it and if they are denser then they will be smaller sized lipoprotein
All of the larger lipoprotein will offload cargo and unload some proteins and be converted to a smaller lipoprotein except for HDL
The Chylomicrons are much larger than liver lipoproteins but have the shortest life span due to being the largest
What is gluconeogenesis
It is the synthesis of new glucose from other non carbohrdate molecules
Why is gluconeogenesis important
This is due to in absence of insulin most of theb body need fatty acid for energy as have no mitochondria but brain and blood need glucose for TCA cycle
Glycogen stores in the liver are limited and muscles cant release glucosee from glycoegn to the blood
Gluconeogenesis is needed for long term survival if no food available
How to make new glucose when low blood glucose levels
The best way is to convert FA to glucose due to large stores of Fatty acid in the body but we dont have the necassary enzyme to be able to do this
There is then the option to reverse the 3 irreversible steps of glycolysis by using ,6 ATP
How to reverse the 1 irriversible step of glycolysis
Pyruvate will need to be converted to PEP by the first enzyme Pyruvate Carboxylase along with Co2 to produce OAA that then will combine with the enzyme PEP Carboxykinase and GTP to then make the PEP
Overall reaction = Pyruvate + Co2 + ATP + GTP ==> PEP + Co2 + ADP + GDP
PEP is a 3 Carbon compound
This take place in the cytoplasm so need to use Malate shuttle tranfer to move the OAA into cytoplasm for 2nd stage
What is the the 2n irriversible step of glycolysis
This is where fructose 1,6 bisphosphate is converted to Fructose 6 Phosphate and will use the enzyme Fructose 1,6 bisphosphatase
There is the hydrolysis of the 1 of the 2 phosphate groups and happens in the cytoplasm
How to reverse the 3rd irreversible step of glycolysis
This is where glucose 6 phosphate will be converted to glucose as their is the hydrolysis of the phosphate group by the enzyme glucose 6 phosphatase in the ER
Glucose 6 phosphate cant cross the cell membrane so tissues without the phosphatase cant export glucose out of them during gluconeogenesis
What is the solution to having no Pyruvate stores in the body
Lactate is produced in cells that dont have mitochondria so dont feed pyruvate to the TCA cycle but instead use the Cori Cycle
Amino acids can also be used
What is the Cori Cycle
This is where in some tissues the glucose is fed to then make pyruvate and then that will produce lactate rather than going to the TCA cycle.
The lactate can then be used to be converted back to pyruvate that can then be used to make glucose
There is a low ATP usage until turning pyruvate to Glucose due to have to undo the 3 irreverisble steps of glycolysis
What are the glucogenic amino acids
These are all the amino acids that can be used to make glucose and the others that cant are used to make jetone bodies so are called ketogenic amino acids
Why is Alanine the most important amino acid for making glucose
Alanine is important for making glucose as alanine is released from the catabolism of muscles that havnt eaten for a while and alanine is released as they are broken down and this can then be converted to pyruvate
How is alanine converted to pyruvate
This is done by the enzyme alanine aminotranferase and at the same time in a side reaction there is alpha Ketoglutarate being converted to glutamate
The pyruvate can then be used to make glucose
There is the ability to combine the alanine and the cori cycle with an overall cost of 10ATP of glucose
How is glycerol used in gluconeogenesis
In the body there is an enzyme to convert glycerol to glucose to then be releases
This is an overall better method due to an energy balance of only 1 ATP used and 1 NADH made so will make more energy in the process
How is glycerol converted to glucose
Glycerol is turned to Glycerol 3 phosphate by the enzyme Glycerol Kinase
This is then turned to Dihydroxyacetone phosphate by glycerol phosphate dehydrogenase
This can then be turned to glucose in gluconeogenesis or then turned to glyceraldehyde 3 phosphate that is fed into the glycolsis reversal method
How are other sugars used to make new glucose and enter gluconeogenesis process
Fructose is converted to G3P and in non liver tissues to G6P
Mannose can also enter process as G6P by being turned to mannos 6 phosphate then G6P
Galactose will enter one stage above G6P by using galactokinase to make G1P then use UDP Glucose to make UDP galactose to make glucose 1 phosphate to then make G6P
What happens to excess amino acids in the body
There are no amino acids to be stored in the body and then they cant be lost in the urine due to being too valuable
What is the nitrogen balance
Most of the nitrogen in the body is in amino acids so the Nitrogen balance refers to the number of amino acids
There is an amino pool of free amino acids that are used to make proteins as well as equal protein degradation to refill the amino acid pool
The pool get bigger if eat more protein but wont get bigger due to break down of amino acids
Where do amino acids go to
They are being used in protein synthesis, the dirtect use of the amino acid and also for the breakdown and redeployment elsewhere in the body
They can be used as neurotransmitters and also hormones
Why cant amino acids be broken down to ammonia
This is due to ammonia being toxic and so what happen is that the amino acids are converted to alpha ketoglutarate via transamination and then these are converted to Glutamate
Any ammonia produced is converted to urea in the liver and extrected in the urine
What is transamination
This is where all amino acids are turned to alpha ketoglutarate which is then converted to Glutamate due to the gaining of an amino group with the enzyme aminotransferase
The actual amino acid is then made into a alpha ketoacid
How does the amino acid change the product of transamination
There may be a different product instead of a Ketoacid formed
Asparatoic acid break down will lead to oxaloacetate and alanine will lead to pyruvate being formed
There is the overall production of glutamate no matter what due to the use of V6 prosthetic group PLP to move the amino group as intially the amino group added to alpha ketoglutartae that then lose amino to make glutamte
What is deamination
This is where the amino group that funneled to glutamate is then removed to then make alpha ketoglutare
This is done by adding water and then reducing NAD+ and the removal of NH4+ to then go to the urea cycle
It will be activated by ATP and inhibited by GTP
What is urea synthesis
Co2 + NH4 + H2O + 2ATP in the mitochondria
This will use the enzyme carbamoyl phosphate synthetase 1 and lead to the prodiction of Carbamoyl phosphate + 2ADP + 2Pi
What is the urea cycle
This is where carbamoyl phosphate is fed into the cycle and it will first lose the phosphate group to form citruline
This will then be converted to argino succinate due to the additon of arginine and then ATP will be hydrolyised to AMP
The succinate is then removed to leave just arginine where then the urea is then removed from the arginine to leave Ornithine to then combine with carbamoyl phosphate to restart the cycle
Why cant be urea be removed by the liver
This is due to tghe 4ATP cost to produce a urea molecule and so it it less efficient to add to the urine to remove
The urea cyckle will compensate this due to the Carbon Skeleton production
What is extraphatic tissue
This is tissue that will be catabolise amino acids to NH3 but wont make urea as they will reverse the deamination process due to add NH3 to make glutamate from a-ketoglutarate
There is then the option to add NH3 to glutamate to make glutamine and this is good as can remove 2 urea molecules
In the Kidney glutamine can be deaminated back to glutame to release NH3 into urine to then neutralise the urine acid
What does the breakdown of the carbon skeleton lead to
Lead to the production of Pyruvate, Acetly CoA, Acetoacetly Coa , alpha ketoglutamate, Succinyl CoA, Fumarate and oxaolacetate
This is all dependent of the type of amino acid used to make the carbon skeleton
How are sulfur amino acids broken down and disposed of
Cysteine and Methione both have Sulfur in their R group and can remove the amino acid just the same way as normal
For methione it is turned to Cysteine so making methione is an essential amino acid can cysteine is not as can be made from other amino acids
How is Cysteine broken down
It has the Carbon Skeleton of Pyruvate so has the amino and the sulfur to remove to then produce pyruvate
There are 2 pathways that both will lead to the production of the pyruvate
1= Cys goes to B-mercaptopyruvate tpo then go to pyruvate
2= Cys goes to Cysteinsulphinayte that then go to B sulphinylpyruvate that then go to pyruvate
Both are transamination processes
What are esential amino acids
These are ones that cant be made in our body so have to eat them to get them in the body and there are 9 of them
The other 11 can be made from other processes
What is the rate determing step
This is the slowest recation of the pathway and will determine the overall flux through the pathway by acting as a bottleneckl
Usually the 1st unqiue enzyme in a pathway is the rate determing step and in a branched pathway this will happen after the branch so then the products are made independent of each other so then will be deliberate slowed down to allow independent products to be made
How do you find the rate determing step
Can measure the Vmax of all enzyem in the pathway as lowest may be the RLS
Compare the equilibirum constant and the Mass action ratio and if they arent the same then the cell is modifying the the reaction so will be the RLS
Test if step is at the crossover point that will identify the regulatory step and if pathway flux increases then the enzyme has also increased so must be the RLS
Why is enzyme control needed
To ensure that the pathway is active when the product is needed and so that competing pathways are simulataeneously acitve as may need both for same reactant
Ensures that co-ordinated activoty in multiple pathways
Why is glycolysis and gluconeogenesis bad at the same time
Due to very energy costly due to the Futile cycle between F6P and F1,6P where ATP is hydrolysed to add a phsophate that is then lost in other direction
Neither of the process are completed due to both being a cycle and this may be used on cold days to help raise body temp in small organisms
What are the types of enzyme control
Intrinsic control by metaboliyes by changing metabolic cell activity via inhibitors and allosterism
Can have fast extrinsic control by covalent modification of hormones as well as slow extrinsic control by gene expression change of hormones
How is there control via metabolites
This can be either done by product inhibition or by allosterims which can be inhibitory or increase product production into another thing so then dont get full product if have too much of it can be used to make more
What is allosterism
If there is a side reaction if the original product is being produced too much
An example is if too much glucose 6 phosphate then there is a side reaction to make fructose 2,6 bisphosphate instead, this will the reactivate the enzyme phosphofructokinase to then restart fructose 1 phosphate production and also inactivate gluconeogenesis enzyme to make glucose 6 phosphate
What enzymes do ATP inhibit
PKF1 , Pyruvate dehydrogenase, citrate sythnase, isocitrae dehydrogenase, pyruvate kinase, a-ketoglutarte dehyodrgenase
Can also be then be activated by AMP,ADP
What can hormones alter
The activity of enzymes is rapid vai dephosphorylation of the enzyme and this is very short lived and much quicker
Can also change the number of enzymes which is slower due to change gene expression so change enzyme active site shape and this is long lived effect
How can there be control via phosphorylation
The phosphorylation can cause a conformational change of the enzyme that cause the inactivation of the enzyme
The phosphorylation will overide the any allosterism taking place
Phosporylase in muscles will be activated by AMP and inhibited by ATP and Glucose 6 phosphate
In glycogen synthesis there are 7 muscle phosphorylation sites and in the liver there are 7 and as 1 is made active the others are inactive
When is insulin released
When there is a high levels of blood glucose so need to store glucose and not break it down so does the opposite of adrenaline that makes glucose for the blood
It will stop the phosphorylation of glycogen synthase and active PP! to remove phosphate from glycogen synthase to allow glycogen production to store excess glucose
What is the difference between insulin and glucagon
Insulin will cause the dephosphorylation and glucagon cause phosphorylation
Insulin acitvate enzymes phosphorylase kinase + glucagon phosphorylase to then lead to increas in gluconeogenesis
There can be no fat broken down if insulin is present due to perilipin protein memrbane is round the the triglycerides
When there is adrenaline present then the perilipin is phosphorylated and then the lipase can access the triglycerides and break them down to fatty acids
What is the side reaction from glycolysis when fructose 1,6 bisphosphate is made
Fructose 6 phosphate is converted to fructose 2,6 bisphosphate due to the enzyme phospofructokinase 2 and fructobisphosphatase 2 will produve fructose 2,6 bisphosphate to then activate the enzyme needed to turn fructose 6 phosphate tp fructose 1,6 bisphosphate that is useful
How can phosphoryaltion regulate enzymes
When insulin is present the PFK2 is active to turn fructose 6 phosphate to fructose 2,6 bisphosphate and then when adrenaline is present there will be phosphorlyation of FBPase2 to make it active to then remake fructose 6 phosphate
How does multiple enzymes lead to greater control
Pyruvate will carry CoA then when the PDH Kinase is dephosphophorylated it will then release the CoA + ADP + NAD+
Then when the pyruvate is phosphorlyated it will lead to enzyme PDH phosphatase will then become active and so convert the pyruvate to carry acetyl CoA
ATP and NADH will go to the dephosphorylated pyruvate to inhibit the reaction and push reaction forward and activate PDH kinase
CoA,ADP,NAD+ inhiit PDH kinase to then limit forward reaction
What is AMP activated protein kinase
It will link the allosterism to phosphorylation and carry out both processes
It is an energy sensor when we are hungy and shift all the enzyme to survival mode as AMP is a trigger for hunger to make more ATP
It is able to phosporylate multiple targets like enzymes and transcription factors
How can there be control via expression
Transcription factors bind to genes and lead to an increased or decreased gene expression
If there are more enzymes so then Vmax and V will increase and vice versa as well
It can change the activation as transcription factors are receptors for metabolites so if they bind to metabolote lead to activation so then greater expression and if no metabolite bind then less gene expression
There can be phsophorylation of transcription factors that the lead to more gene binding
How does lipoprotein lipase work
This is done due to lipoprotein lipase will cleave off the the fatty acid that then enter the cell but there are low levels of enzymes in the blood on the muscle wall so then greater increase in fat level after eating
How does excerise effect muscle stress
If undergo excersie then there is muscle ill stress and be more short of energy so then this will lead to increase in the lipoprotein lipase on the capillaries so then more fatty acids will be cleaved off and used for energy purposes so less fat in the blood after excersize and eating
How does all 3 enzyme metabolic controls work as 1
This will lead to the highest level of control if allosteric, phosphorylation and gene expression are all being used at once
How does enzymes be indirectly regulated
Enzyme can be regulated indirectly due to dietary deficiency will lower Vmax and so the enzymes that need the vitamins to activate them wont be able to be turned on as quick so then lower Vmax of the enzymes, so too low enzyme activated concentrations
Can have dietary additions such as caffeine that is a purine and similar to adenine and guanine and can act as allosteric inhibitor or activator
how does the body decide if catabolic or anabolic state
This will be decided depending on the ATP levels of the body as ther are mutliple control tissues being used to decie this
Food molecules go to anabolic pathways and storage molecules for catabolic pathways and all used to recycle ATP and ADP
What are the tissues for anabolic state control
Brain - Wont store anything and wont export anything either
Liver - Storage of glycogen and Triglyceride and will ecport TG and glucose
Adipose tissue - Stores of TG and export glycerol and fatty acid
Muscles - Store of TG and carbohydrates and only export lactate during intense excersise
What are Metabolic tissue oddities
Heart- Preferred fuel of Ketone bodies not glucose
Eyrthrocytes – Only carry out glycolysis to generate lactate under all conditions
Cancer cells – They only carry out aerobic respiration to make lactate = Warburg effect
Kidneys- use 8g of lactate per day for ATP production
Intestines – Have a preferred fuel of glutamine as do the immune cells
Spermatozoa- Prefer a fuel of Fructose
What is the anabolic state
This will take place when we are eating and having the uptake of glucose where 60% to glycolysis, 10% for storage asnd 30% for TG production
Amino acid mainly go to make protein but some for carbon skeletons
Fatty acids all go to the production of triglycerides
What happens in storgage organs
There are higher levels Glycogenesis and Lipogenesis so there can be long term storage of glucose and fatty acids as glycogen and Triglycerides and so there is no energy wasted and there are high insulin levels In the high anabolic state
What happens if high glucose levels in the anabolic state
There will be high insulin levels that cause the liver to increas glycogenesis, decrease glycogenolysis, increase glycolysis, decrsse gluconeogenese and also more fatty acid synthesis
How does insulin effect other organs in anabolic state
Adipose tissue there will be more acetly CoA so then more fatty acids as well as lower lipolysis
In the liver there will be more glucokinase + Malic enzyme + ATP citrae lyase
What are Glucose transporters enzyme isotopes + Hexokminase isozymes
In most tissues
GLUT 1+3 has a low Km and HK1-3 has a low Km
This means take up glucose slowly and when there is low amount of glucose due to high affinity all the time
In the liver and Beta pancreas cells
GLUT 2 has high Km + HK 4 has high Km that cant be inhibited but glucose 6 phosphate
This means lower affinity so only take out glucose from the blood when very high blood glucose levels
In the muscle + Adipose tissue
There is GLUT 4 that has medium KM and is induced by insulin + HK 2 has a low Km
GLUT 4 is triggered by insulin and when its not there, there is no GLUT 4 channels so can only take up glucose when insulin is present so needs to be high blood glucose levels
What does insulin do to glucose
Insulin will turn glucose to Glucose adipose tissue as well as blocking fat breakdown this then means there will be more fat for the stores but then no fat will be lost in the strorage organs causing them to then swell up
It will ultimatly remove the ability to remove any fat stores
How can fructose corn syrup be used as sweetner instead of glucose
There is less glucose compared to sugar so then this will then cause there to be less insulin to be released so then leading to less fat storage and more fat will be broken down in storage organs
However due to fructose being metabolised quicker than glucose in the liver so then in the long term lead to greater levels of fat
What can fructose sweetners lead to as a replacement for glucose
Means that due to fructose being fed into glycolysis after the 2 slow points of glycolysis meaning then there is no more regulation of glycolysis after this
This then means you get greater levels of pyruvate building up leading to excess acetly CoA spo then there will be greater fatty acid and triglyceride synthesis so thne more fat being stored in organs so then overal a weight gain
What can alcoholsim cause
There will be a greater ethanol levels in the body that will cause more acetly CoA to be produced and there is no regukation of the due to no regulated enzymes and will happen quickly to remove ethanol from the bodhy
Due to no regulation the preffered method will get energy via the oxidation of ethanol leading to more NADH and less NAD+
Why is ethanol oxdiation bad caused from alcoholism
Due to more ethanol oxidation so then more NADH made and less NAD+ and this will then inhibit the TCA cycle as well as more lactate to increase so then pyruvate is inhibited so then the body enter an acidic state when higher ethanol levels and so there is more ATP used but glycolysis is inhibited and so then lead to less pyruvate and glucose being made leading to hypoglycemia
This then will cause less NAD+ and then B oxidation is inhibited so cant break down fatty acid to get energy and there are higher levels of acetly CoA so more triglyceride production leading to a fatty liver
How is ethanol converted to acetly CoA
Ethanol is converted to acetaldehyde by the enzyme alcohol dehydrogenase and NAD+ is reduced to NADH
This is then turned to acetate by aldehyde dehydrogenas and NADH is made
Acetate is then turned to acetly CoA by Acetly CoA synthetase
What is the catabolic state
This will happen when havnt eaten for a while and so low blood glucose levels so need to make glucose from other sources
Glucose in the blood for the brain but rest of the body will have to use fatty acid for energy in this state
What is the 1st metabolic priority
This is too maintain the blood glucose levels so the brain has enough glucose to make ATP for survival and this is done by releasing adrenaline and glucagon to trigger glucogenolysis and gluconeogenesis in the liver
There will also be lipolysis at the same time to provide rest of the body with ATP as well as to make glycerol so more gluconeogenesis
What is the catabolic response to long term fasting
Cortisol will be released that will lead to protein degradation to then increase gluconeogenesis for long term fasting
How does adrenaline act on muscles in the catabolic state
It will lead to less glycogen synthesase so less glycogenesis and also greater phosphorylase so more glycogenolysis
There will be more phosphofructokinase 2 so then more phosphofructose 1 so then quicker glycolysis and more glucose
Greater lipoproten lipase so more fatyy acid uptake from blood for more energy and there will be more hormone sensitive lipase in the adipose tissue so more lipolysis
How does adrenaline act on the liver in the catabolic state
There will be less glycogen synthase so less glycogenesis and also more glycogenolysis due to more phosphorylase
Lower rate of glycolysis due to less phosphofructokinase 2 but more fructose1,6 bisphosphate so then more gluconeogenesis
Less acetly CoA carboxylase so then stop malonly CoA so less fatty acid synthesis so less TCA cycle
What does glucogaon do in the catabolic state
It will do the same as adrenaline but for a long term effect and last longer
Also be lower glucokinase and stop glycolysis to preserve glucose levels
Also lower pyruvate kinase to stop pyruvate production for more gluconeogenesis to happen
Increase PEP carboxykinase so more gluconeogenesis as well as fructose 1,6 bisphosphate and glucose 6 phosphate to increase gluconeogenesis
Less Acetly CoA so then less fatty acid made and more ketone bodies will be made
What does cortisol do in the catabolic state
Increase PEP carboxykinase so more gluconeogenesis and an increase in amino acid catabolising enzymes so more amino acid breakdown to release more urea so more of the urea cycle takes place
Greater glycogen synthase so more glycogensis due to the limited levels of glycogen in the liver by the time cortisol is used and also due to extreme level of glucose so then get exfess that needs to be stored as glycogen
What is starvation as the 2nd metabolic priority
This will happen to preserve fucntional proteins and not break them so dont lose vital protein in the body
If fasting goes for long time then enter starvation by dropping the body glucose requirements
This can be done due to brain convert ketone bodies to ATP so then less need for glucose and lower usage of it
What does excersise do for catabolic pathways
There will be a sudden drop in ATP due to more muscle contraction
If short term intense activity the major ATP drop and then very large decrease in creatine phosphate to remake ATP and a gradual glucose increase to get energy
Possible to make ATP without the ETC and is much quicker
For long term excersie then use fatty acids and glycogen to provide energy fro muscle contraction but has to be done in anareobic condtions so get lactic acid build up
What is thermogenesis
This is the generation of heat from metabolic pathways via shivering and uncoupled respiration in animals
It is done by wasteful ATP usage so loss of energy as heat to keep core body temp stable
How does uncoupled respiration come about
Will happen due to the uncoupling of a protein called thermogenin to match thermogenesis as well as attaching fatty acid to amino acid
What is brown adipose tissue
This is a modified adipose tissue that is used to generate heat by wasting the energy that the are storing in fats by breaking down the triglycerides
Hibernating animals need to keep minimal body temp so they dont freeze inside so generate heat by metabolic pathways
How is brown adipose tissue different to white adipose tissue
There are many smaller triglyceride droplets in the cytoplasm as well as their being more mitochondria present
Also more sympathetic innervations so more noradrenaline leading to the uncoupling of ETC and ATP synthesis for thermogensis to happen
UCP1 is present when noradrenaline released and then they will be activated by free fatty acids and then open to allow proton to enter membrane so less proton renter and less ATP made so energy lost as heat
What does N-acly amino acids do in the catabolic state
In the mitochondria membrane there is an ATP/ADP translocase carrier so 1 ATP enter and 1 ADP leave, when this is the in the presence of N acyl amino acid it will become permeable to proteins as well
This means that Energy not being captured as ATO so then will be lost as heat energy
What is diabete
In a healthy person the glucose coming into the body will be diverted to the muscle, liver and adipose tissue
But before get diabetes the person will become insulin resistant which at the start glucose distribution is the same
But as conditions gets worse then the muscle stops taking up glucose and the liver will release glucose to the blood
This then means the adipose tissue is then taking up all excess glucose so then they swell and so gain weight is first sign of developing type 2 diabetes