Week 2 - Metabolism - Skildum Flashcards
what’s your favorite color?
blue!
2,3 Bisphosphoglycerate is only made under what conditions?
Conditions of hypoxia
(Like high altitude or heavy smoking)
You don’t want to do it at other times because it requires energy to do.
Describe the mechanism by which 2,3 biphosphoglycerate is activated by hypoxia
1,3 bisphophoglycerate is converted to 3 phosphoglycerate. 3 phosphoglycerate then builds up if there is no oxygen to power the electron transport chain.
When 3 phosphoglycerate builds up it actually activates bisphosphoglycerate mutase. This enzyme create 2,3 bisphosphoglycerate from 1,3 bisphosphoglcerate
If there are problems downstream of pyruvate, where does the cell get ATP from?
The cell will have to get all its ATP from glycolysis with lactic acid as the end product.
What is the turnover rate like in fatty acids?
VERY high. Turned over about 180 times per 12 hr. It’s because there is a lot in storage, but only a small amount in circulation. Constantly creating and burning.
Fatty acids: Unsaturated or saturated have higher melting points? why?
Unsaturated that have a lower melting point!
Example: butter (saturated) is solid at room temp, whereas olive oil (unsaturated) is more liquid.
What is the protein in serum that transports fatty acids and transports them to needy cells.
Albumin
How is adipocyte stored Fatty acids different from dietary ones in the way its transported?
Albumin takes the ones from adipocytes. There are specific molecules for the dietary ones. (Chylomicrons, i think… etc)
What do the lipase molecules in adipocyes genereally respond to?
Hormones
Insulin - inhibits the lipase
Glucagon, epinephrine, and noreprinephrine - activate it
Sum up what happens to the Fatty Acid from when it arrives at the cell to when it arrives at the mitochrondria
- FA-albumin complex binds to receptor at surface and the FA is brought into the cell
- Coenzyme A is added through fatty acyl CoA synthetase (GIVE IT A HANDLE)
- This can then easily pass through the outer membrane of the mitochondria
How do we get the fatty-acyl CoA across the impermeable inner membrane of the mitochrondia
- CPT1 Switches out the CoA for a carnitine molecules that the fatty acyl group will be able to ride across the inner membrane
- The carnitine translocase is a symporter that trades a fatty-acyl-carnitine for a carnitine
- CPT2 Then switches the carnitine for a CoA and the fatty-acyl-CoA is now ready to be beta-oxidized
How does Acetyl CoA carboxylase (ACC) regulate fatty acid trasnport into the mitochrondria?
It converts acetyl CoA into malonyl CoA, which inhibits CPT1
Insulin activates it if there is a lot of glucose around because it is unecessary to make energy through beta oxidation.
AMP inactivates it if there is not a lot of excess energy around, so that more energy can be created by beta oxidation without interference from ACC
How do you get CPT 2 deficiency and what would be the problems associated?
Inherited recessive disorder
Adult onset: Characterized by muscle pain, weakness and myoglobinuria after prolonged exercise or fasting.
Neonatal/Infant Onset: Irritabilty, failure to thrive, death
Causes problems because carb supplies just aren’t enough to meet all the caloric needs, burns up too fast and you cant use FA’s
In serum lipid profiles they will not show elevated ketone bodies like what would be seen in normal starvation because beta-oxidation is required to produce them. YOu would see a lot of acyl carnitine in their lipid profile.
4 steps of fatty acid oxidation:
Oxidation
Hydration
Oxidation
Carbon-carbon bond cleavage
alpha, beta, and w-ish carbon. What are they on the fatty acid chain?
a carbon: first carbon away from a functional group
b carbon: second carbon from the functional group
w carbon: furthest carbon from the functional group
Do you get more ATO from glycolysis or fatty acid b-oxidation?
beta oxidation
Palmitic acid (16:0) is beta oxidized. How many oxidation reactions will this require? How many acetyl-CoA groups will it create?
7 oxidations (NOT 8)
8 acetly CoA ‘s
Let’s say you have medium chain acyl CoA dehydrogenase deficiency. What is the right name for that? What are the symptoms?
Reye Syndrome
Symptoms:
fasting hypoketotic hypoglycemia
(Not normal to be hypoketotic when you are hypoglycmeic)
Hepatic encephalopathy
sudden infant death syndrome
Diagnosed by lipid profiles of mutation identification
What would you see in the blood serum of someone with Reye Syndome?
A lot of medium length fatty-acyl-CoA ‘s
Why should you watch out for unripe fruit in Jamaica?
Ackee fruit that is not ripe has a chemical called hypoglycin.
Ingesting a lot can inhibit acyl-CoA-dehydrogenase similar to MCAD(REYE)
So you could get Jamaican vomiting sickness.
Usually not fatal, but also not fun.
Are cis or trans double bonds needed in order for fatty acid catabolism to occur?
TRANS!
Enoyl-CoA hydratase only accepts trans double bodns
What has to be done to catabolize a fatty acid with unsaturation?
Enoyl-CoA isomerase can move the double bond to the right positiion and 2,4-Dienoyl CoA reductase can reduce the fatty acid
(This is a crappy answer…)
What can be done in the case of odd-chain lengthed fatty acids?
Basically the oxidation is all the same until the very last cycle when instead of 2 acetyl-CoA’s you get 1 acetyl-CoA and 1 Propionyl-CoA
Downstream the propionyl CoA can be converted to succinyl CoA (An exact intermediate in the TCA cycle)
That’s wild.
What happens to all those ridiculously long fatty acid chains?
They are degraded in peroxisomes in a similar manner to beta-oxidation. Once they hit a 4-6 carbon chain then they are trasnferred to mitochondria for the regular beta oxidation
What about fatty acid chains with branches coming off of the chain? waht happens to them?
They are beta oxidized the same way but can produce different end prodcucts. For example, any carbons with methyl chains will make propionyl CoA, whereas the ones without branches can still prodcue normal propionyl CoA.
What is w oxidation?
It is a sosrt of inefficient way of doing oxidation where they make both ends carboxylic acids and then metabolize from both ends.
Cytochrome P450 enzymes do it.
I think this happens when there is a disruption of normal metabolism and things have to go down in the endoplasmic reticulum instead
Outline where these parts of your body can get energy and where they prefer to get energy:
Red Blood Cells:
Brain:
Skeletal Muscle:
Red Blood Cells: Glucose ONLY (no mitochondria)
Brain: Prefers glucose, can use ketone bodies
Skeletal Muscle: Glucose/ Fatty Acids/ Ketone Bodies
Where in the body are ketone bodies produced from fatty acids?
the liver! yep.
If a patient comes in with ketoacidosis, what would you expect is their condition?
Also, what is Ketoacidosis?
Starvation or diabetes
Ketoacidosis is a depression in blood pH caused by excessive ketone body prodcution
A couple examples of ketone bodies that can be used as fuel by brain heart and skeletal muscle?
3-hydroxybutyrate and acetoacetate
They are first converted to acetly CoA and then go into the TCA cycle
Describe three types of transport systems:
Antiporters:
Symporters:
Uniporters:
- Antiporters transport one molecule in and another molecule out. (ATP / ADP)
- Symporters transport two molecules in or out. (pyruvate + H+, Pi + H+)
- Uniporters transport one molecule in or out. (calcium)
Which membrane of the mitochondria can create a chemical gradient??
WHY???
The inner mitochorndial membrane BECAUSE it is impermeable. (this allows voltage or proton concentrations to be established)
Almost everything small enough just passes through the outer mito membrane without any problem at all
How do we inheriit mitochondrial DNA?
Maternally
What kind of things do mitochondiral DNA code for?
They encode for a few proteins for the electron transport chain and the tRNA’s needed to translate these proteins.
(13 genes)
HOWEVER: most mitochondrial proteins are encoded by nuclear DNA and transported over later
Why is mitochondrial DNA hypermutable?
It is more likely to get breaks and become mutated because:
- Mitochondrial DNA is “naked” (not bound to histones) so its unprotected
- exposed to a lot of ROS reactive oxygen species (not to be confused with ROUS’s)
- Mitochondrial genome has milited ability to repair genome when probs occur
How does the heterogenous quality of mtDNA dampen the effects of hypermutability?
There are multiple copies of the mtDNA in each mitochondria and mutliple mitochrondria in each cell. So unless the probs are wide-spread there is a dampening effect
This also leads to a range of phenotypes spanning from mild to very severe problems depending on how much of the mitochondrial genome has been damaged.
Mitochondrial disease tend to get better or worse?
Diseases which result from mitochondrial dysfunction tend to be progressive– they get worse with age.
Which enzyme links glycolysis to the TCA cycle?
Pyruvate dehydrogenase
PDH
Where in the cell does glycolysis happen?
TCA?
Pyruvate dehydrogenase
Glycolysis: Cytosol
TCA: Mitochondria
PDH: Mitochondria
What protein complex transports pyruvate into the mitochondria?
Mitochondrial Pyruvate Carrier (MPC)
Point mutations affecting MPC can cause lactic acidosis and hyperpyruvatemia
Pyruvate Dehydrogenase (PDH) has some complicated regulation:
Give an overview of how this regulation works
In the active unphosphorylated state, PDH converts pyruvate to acetly CoA for the TCA cycle
To inactive PDH, an enzyme called PDH kinase can phosphorylate the E1 subunit
PDH Kinase is activated or inhibited by indicators of the cell’s energy balance
Acetyl CoA and NADH activate PDH Kinase
Pyruvate and ADP inhibit PDH Kinase
In this way PDH is active when the cell needs to produce ATP in the TCA cycle.
Got it?
ACetly CoA can be produced from what sources?
Fatty acids
Ketone Bodies
Sugars
Amino acids
Ethanol
Which steps in the TCA cycle have large deltaG’s?
The converson of malate to oxaloacetate and the converson of citrate to isocitrate
Which step in the TCA cycle is the KEY rate-limiting step in the cycle?
Isocitrate dehydrogenase
(Converts isocitrate to alpha-ketoglutarate)
At what point in the TCA cycle do we go from 4 carbons to 6?
The first step where oxaloacetate is combined with acetly CoA to make citrate
When in the TCA cycle do we lose the first carbon. Going from 6 carbons to 5
In the 3rd step from isocitrate to alpha-ketoglutarate. Its an oxidative decarboxylation using a dehydrogenase
When in the TCA cycle do we lose the second CO2. Going from 5 carbons to 4?
The 4th step. Where we go from alpha-ketoglutarate to succinyl-CoA
This is an oxidative decarboxylation using a dehydrogenase
Which steps of the TCA cycle contribute to the electron tranport chain?
3,4,6,8
Is this important?
Which step of the TCA cycle produces GTP?
the 5th step from succinyl Coa to succinate.
You get this much energy from cleaving that thioester bond attached to the CoA
Which enzyme in the TCA cycle is actually part of the electron transport chain?
Seems like a possible question. Too hard?
Succinate dehydrogenase
(Maybe you can remember that because FAD is a prosthetic cofactor, so in order to get the electrons into the transport chain it makes sense it would have to be a part of it)
How can succinyl dehydogenase be a tumor suppressor?
Maintains low [succinate] which aids in signalling blood vessel generation (TB)
It affects the HIF (oxygen sensing) pathway
Maybe look at this again i didn’t finish the reason in my notes……..
How many ATP prodcued per acetyl CoA?
Carbon dioxides?
10 ATP
2 CO2
How does an increase in NAD have on oxaloacetate?
More oxaloacetate will be produced as these substrate levels increase
Increasing NADH or oxaloacetate would do the opposite.
How would increased NADH affect citrate?
Citrate is actually going to increase a bunch because the TCA cycle will get stalled and the negative delta G to in the opposite direction will make this easy.
How is isocitrate dehydogenase regulated
This is the main regulatory enzyme of the TCA cycle:
ADP binds to IDH and decreases its Km (activates it)
IDH is allosterically inhibited by NADH
What is a method to form oxaloacetate to replsnish the TCA cycle?
Pyruvate carboxylase converts pyruvate to oxaloacetate and plugs it into the TCA cycle.
How is oxaloacetate realted to exercise?
It is often the limiing factor in the production of energy from TCA during exerise.
What is myoadenylate Deaminase Deficinecy?
It is characterized by a lack of the enzyme AMP deaminase.
The hallmark of the disease is exercise intolerance, muscle pain, and muscle probelms because this enzyme is part of the pathway used to recharge stores of oxaloacetate.
Overview of Eletron transport chain:
