Week 2 - Metabolism - Skildum Flashcards Preview

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Flashcards in Week 2 - Metabolism - Skildum Deck (147)

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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.



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?


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

  1. FA-albumin complex binds to receptor at surface and the FA is brought into the cell
  2. Coenzyme A is added through fatty acyl CoA synthetase (GIVE IT A HANDLE)
  3. 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

  1. CPT1 Switches out the CoA for a carnitine molecules that the fatty acyl group will be able to ride across the inner membrane
  2. The carnitine translocase is a symporter that trades a fatty-acyl-carnitine for a carnitine
  3. 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:




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


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?


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:


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 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??



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?




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:

  1. Mitochondrial DNA is "naked" (not bound to histones) so its unprotected
  2. exposed to a lot of ROS reactive oxygen species (not to be confused with ROUS's)
  3. 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



Where in the cell does glycolysis happen?




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


Amino acids



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?


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.


In the electron transport chain:

Going from NADH to H2O, how many protons are transported across the inner mitochondrial membrane?

10 protons


How many protons do complexes 1,3, and 4 tranport across the inner mito membrane?

I - 4H+

III - 4H+

IV - 2H+


What are the main reactive oxygen species (ROS)

Why are they dangerous

superoxide, hydrogen peroxide, and hydroxyl radicals


They cause a lot of damge to the cell. THey canoften cause damage without terminating, which allows them to damage widely.


Overview of Eletron transport chain:


ATP synthase:

What does it do?

What part do protons go through?

It uses chemical gradeint energy of protons to make ATP.


Protons go though F0 portion


What makes human warm blooded?

Heat energy produced by the electron trasnport chain


What is uncoupling?

This is when the trasnfer of electrons from NADH to O2 does NOT produce ATP. 

3 cases:

adaptive thermogenesis

chemcial uncoupling (toxins transport stuff through mito membrane)

mechanical uncoupling (mechanical damage)


How does adaptive thermogenesis happen?

Noreprinephinre activates UCP1


UCP1 is a channel that can open and re-realse H+ back into the inner space of mitochondria without ATP being made

IMPORTANT for babies, cuz they just hang out a lot


What is an example of a chemcial uncoupler?

DNP Dinitrophenol


Transports H+ across the membrane  without going through ATP synthase


chemcial in explosives, people int he facory got fevers and lost a lot of weight


Common cause of mechanial uncoupling?

Peroxidation by ROS's!!!!!!!!

or mitochondrial swelling due to high water influx!


BAsically a dmaged membrane doesn't provide a means to make a good gradient


Main form of fatty acid storage in the body?



what molecule is integral to the firs step of fatty acid biosynthesis?

Citrate, which is created in the first ste of the TCA cycle


What substrates form the TCA cycle signal the entrance of citrate into fatty acid biosynthesis?

In conditions of excess energy, isocitrate dehydrogenase is inhibited by a high NADH/NAD+ ratio.  This drives citrate towards fatty acid synthesis rather than through the TCA cycle


How do the cofactors produced from converting citrate back into pyruvate affect glycolysis and fatty acid synthesis?

When oxaloacetate is converted to malate, NAD+ is produced which helps power glycolysis forward.

When malate is converted to oxaloacetate NADPH is produced which helps to power beta oxidation


THe pyruvate malate cycle has 2 important functions in lipogensis. What are they?

1)  Transports acetyl CoA from the mitochondria to the cytosol.

2)  Malic enzyme generates NADPH to power fatty acid synthesis.


Acetyl CoA carboxylase is used to convert acetyl CoA to malonyl CoA in the first step of liogenesis. What must be the cofactor involved?


(used in carboxylations)


What step is the rate limiting step in fatty acid biosynthesis?

The first step where acetyl-CoA is converted to malonyl-CoA.

Acetyl-CoA carboxylase catalyzes this rxn using biotin



How is acetyl CoA carboxylase regulated???

Do the activators!

This is THE rate-limiting step in FA synthesis!

  • Citrate allosterically activates ACC (this is called feed-forward and Dr.Skildum mentioned this is the most important regulator
  • Xyulose 5 phosphate increases transcription
  • Insulin activates it by stimulating dephosphorylation


How is acetyl CoA carboxylase regulated???

Do the inhibitors!

  • Palmitoyl CoA(a product) allosterically inhibits
  • AMP-PK phosphorylates to inhibit
  • Glucagon --> cAMP -->PKA --> inhibitory phosphorylation


  • Malonyl-CoA inhibits carnitine palmitoyl transferase I (CPT1)
  • This prevents beta oxidation of newly synthesized fatty acids
  • The body would not want to synthesize and break down FA's at the same time, so this makes sense


Give the 4 step sequence of fatty acid synthesis!!!!!!

Bond formation





Fatty acid synthase has a mode of action that derives from its structure. Explain what that is

It has two important exposed sulphur atoms that it uses to extend the fatty acid chain.

2 carbons are added at a time going back and forth between the two

At the beginning of each cycle phosphopantetheinyl continues to recieve a malonyl CoA which then gets the full chain from cysteine transferred to it. The chain is solidified and then tranferred back over to the cystien so that the phosphapantetheinyl can recieve another malonyl CoA.

Sort of an oversimplification I guess....


Which cofactor powers the reduction step of fatty acid synthesis?


That's what I'm talking about!


In the 2nd reduction step where the carbon double bond is formed, what is the cofactor powers the reaction?



What enzyme catalyzes each subsequent step of fatty acid synthesis?




All threee catalyzed by fatty acid synthase


What is the body's limit for saturating Carbon-carbon bonds

They must be at least 9 carbons away from the w-carbon end

This is why dietary w-3 and w-6 fatty acids must be obtained from plant and fish oils in order for the body to synthesize eicosonoids. (our body can't make those doubles bonds itself




Most important dietary unsaturated fatty acids? 

linoleic and linolenic acids


What is the enzyme and energy source for unsaturation of fatty acids in the body?

fatty acyl-CoA desaturase

energy ultimately through NADH


Explain that two ways and locations that glycerol-3-phosphate can be created in order to store fatty acids!

In the liver:

LIpolysis of triacylglycerides (TAG) will free a glycerol-3-phosphate


In adipocytes (and the liver):

Glycolysis can occur

Dihydroxyacetone phopshate (an intermediate) can be converted into glycerol -3-phosphate


Why must FA's be attached to a glycerol in order to be stored?

It makes them soluble ( they are very insoluble otherwise)


Storage of TAG in adipocytes requires two important conditions! What are they???

Excess carbohydrates




Explain what happens to triacylglycerides in the Golgi, how they circulate in the blood, and how they enter cells for storage or beta-oxidation!!!!!!

Explain it now!

The golgi packages TAG's with the apoprotein B-100 to become Very Low Density Lipoproteins (VLDL).


VLDL's circulate in the blood until their fatty acids are cleaved at the lumen of capillary endothelial cells by lipoprotein lipase (LPL)

The fatty acids can then enter the cells

In muscle cells they undergo beta-oxidation for energy

In adipocytes they are stored as TAG's again.


Do dietary fatty acids travel the same way as synthesizd ones?

NOPE. They travel in chylomicrons (and other kidns of structures)



How are glycerophospholipids different from a triacylglycerol and where are they found?

They are similar, but have a head group.


Found in cell membranes, lipoproteins, bile, lung surfactants etc...


What glycerophopsholipd is an important part of the inner mitochondiral membrane??



Tell me about sphingolipids.

They use ceramid isntead of glycerol for their backbones


The most important sphingolipid is sphingomyelin, which is present in the myelin sheaths of nerve fibers


Clinical importance of cerebrosides?

Most important clinical significance discussed in class:

The inability to break them down is often correlated with severe mental retardation. LEads to accumulation in neurons

ex. Tay Sachs disease


Function of Dipalmitoylphosphatidylcholine?

Other than memorizing a very long word?

It is a lung surfactant

Like soapy water in a balloon, helps those alveolar walls stay open


What is an interesting way to use surfactants to guess gestational progress?

The ratio of sphingomyelin to phosphatidylcholine in amniotic fluid is an indicator of gestational progress.

with more time, the ratio switches to favor phosphatidyl choline


What hormones are release by adipocytes and what do they do?


The satiety hormone, released when TAGs levels high

Acts through JAK/STAT receptors in the hypothalamus to release factors depressign appetite



Complements leptin. Acts thru AMP-PK and PPAR to inhibit acetyl-CoA carboxylase

This stops fatty acid oxidation

In obesity adiponectin decreases! Crazy!


Are ammonium or ammonia ions able to cross membranes????

Ammonium ions (NH4+) CANNOT cross


Ammonia (NH3) CAN cross


What is the equation for nitrogen balance?

Nitrogen balance [grams] = nitrogen intake [g] – urinary urea nitrogen [g] – X [g]


The constant X ranges from 2g to 4 g, and depends on:
the route of nutrition intake (oral vs. perenteral)
age (X is higher in children).


.16g of N per gram of protein = the constant


What does it mean to fix nitrogen?

It means to make it organic.


What can be problematic about ammonium and ammonia in the blood?

Ammonia and ammonium are toxic, especially to neurons


They can cause lethargy, headaches, seizure, etc.


This is why the body is always attachign stuff to free nitrogens - to avoid toxicity


How does pepsin act in the digestive system?

Preferentially cleaves peptide bonds of aromatics but some hydrophobic

Single, di-, adn tri- peptides can then move into the blood where they first go to the liver


How is transport of Amino acids into the intestinal lumen similar to the SGLT glucose transport system???

They both make use of a symporter for transport and the second molecule going through the symporter is an ion that is pumped into a gradient using ATP.


The intestinal epithelial cell actively transports Na out of the endothelial cell and into the gut lumen to create a high concentration gradient of Na outside.

The Amino Acid/Na+ symporter makes use of this energy gradient to push amino acids into the cell.

The amino acids can then easily go through facilitated transport into the portal vein


What are the key amino acids of the urea cycle!?

Also name their deaminated form and their main role. This seems hard...

  • Glutamate - alpha ketoglutarate - represents the amino group pool in the cell
  • Aspartate - oxaloacetate - Donates nitrogen to the urea cycle
  • Alanine - pyruvate - key role in gluconeogenesis (when muscles working hard)
  • Glutamine - glutamate - transports nitrogen to liver for irea cycle
  • Arginine - important transporter in the urea cycle (can even be used as therapy in certain diseases)


Explain what happens to dietary proteins starting at the gut.

In the FED metabolic state

-Dietary protein enters the gut and is digested to AA's

-It enters pools of AA in the blood

-Insulin will then promote storage pathways for proteins in the liver and cells

-Excess amino acids can be stored as glycogen or turned into triacylglycerols that are subsequently turned to VLDL

-VLDL can be stored as TAG in adipose tissue and later used by muscles

-Glycogen will be stored until it is needed to be released as glucose in the blood


Explain what happens to proteins :

In the FASTING metabolic state

Glucagon, cortisol, epinephrine, and noreprinephrine mobilize stored fuels

Protein pools in the muscle will be broken down into amino acids

Branched chain AA's will be used in the TCA cycle

Glutamine can be used in the gut and kidney

Glutamine/Alanine used in the liver to create ketone bodies and glucose to make energy


Let's get a little more specific.

Can you explain how the alanine/ glucose cycle is able to use amino acids as fuel

  1. Cortisol stimulates muscle protein breakdown
  2. Alpha-ketoglutarate is a universal amine acceptor and removes the amine from an amino acid to form glutamate and an alpha-keto acid
  3. Glutamate then donates the amine to pyruvate to form alanine and reform alpha-ketoglutarate
  4. Alanine can then be trasnsported to the liver where it undergoes gluconeogenesis and the nitrogen converts to urea for excretion


What are the three enzymes that can fix free ammonium?

Glutamate dehydrogenase - (alpha-ketoglutarate to glutamte)

glutamine synthetase - (glutamate to glutamine)

carbamoyl phosphate synthetase - 


These are NOT transaminases, so they require energy to form


Basics about glutamate dehydrogenase: go!

Using NADPH as an energy source it can fix ammonium to alpha-ketoglutarate to form glutamate. 

It is also capable of performing the reverse reaction, which would reform NADPH from NADP


How can liver failure cause brain problems?

This is called hepatic encephalopathy.

Liver failure (occurring for many reasons) can cause ammonia accumulation in the blood because it canot be fixed. As we know, ammonia accumulations can be toxic, especially to the brain


What is the main fucntion of the urea cycle?

Convert nitrogen to urea, which can easily be excreted in the urine.


How does nitrogen enter the urea cycle?

(2 ways)

It can enter as free ammonium from deamination of amino acids

(it then must be incorportaed into carbamoyl phosphate by carbamoyl pops)


It can also enter from aspartate -which results from transamination of amino acids

(It is then combined with citrulline by arginosuccinate synthetase to form arginosuccinate)


What enzyme converts NH4+ and HCO3- to carbamoyl phopshate?


Carbamoyl phopshate synthetase 1


Ornithin plays a similar role to what substrate from the TCA cycle?



Which two molecules are antiported between the cytosol and mitochondrion in the urea cycle?


What happens if this antiporter is defective?

Ornithine and citrulline


HHH syndrome!

hyperammonaemia, hyperornithaemia, homocitrullinaemia



What is the main regulator of the Urea cycle????

The availability of substrates is the main regulator! So not so sophistaicated. Just simple feed-forward regulation


Some modulation by allosteric regulation of CPS-1 and transcriptional regulation of urea cycle enzymes


How does arginine regulation the urea cycle?

Well arginine is actually an indicator of urea cycle back-up, and would encourage things to get going again.

It stimulates the urea cycle by increasing the synthesis of N-acetyl-glutamate (NAG)

NAG then allosterically activates carbamoyl phosphate synthetase-1 (CPS-1) which we know fixes NH4+ to make carbamoyl phopshate in the urea cycle's first step


So you could say that arginine NAGs the urea cycle forward...


Symptoms of ammonium toxicity in the brain?

(Hepatic encephalopathy)

refusal to eat (protein aversion)






Failure to thrive


Elevated orotic acid in the urine is a characteristic of?

Urea cycle disorders!

Particularly ones downstream of CPS-1


Step 1 of diagnosing an inherited disorder when you see hyperamonaemia?

Obtain blood pH and blood HCO3


When a newborn has hyperamonaemia

and blood pH and HCO3 show no acidosis

What is your next step?

You need to check plasma amino acids to see if there is s specific amino acid elevation


Main treatment possibilities for inherited irea cycle disorders:

low protein diet

N-Carbamoylglutamic acid (CPS-1 allosteric activator)

Arginine, Benzoic Acid, Phenylbutyrate (eliminate nitrogen in alternative pathways)

liver transplant/hepatocyte transfusion



Phenyl butyrate and benzoic acids work by?

basically just allowing nitrogen-filled amino acids to be excreted in the urine to get rid of the nitrogen load


How does arginine therapy work?

ONLY works for arginosuccinate lyase deficiency


Basically arginine can power the ureas cycle forward because the mssing enzyme would normally create arginine. And having arginine allows you to get ornithine (which is crucial)

It allows arginosuccinate to be excreted in urine once it is full of nitrogens because a lot of it will build up


When you see liver enzyme in the blood, what should you suspect?


That liver cells have been damaged and their contents spilled out.


What are the three key cofactors for enzymes in amino acid metabolism? What kinds of reactions do they catalyze?

PLP - transamination, deamination, carbon chain transfer

Tetrahydrofolate (TH4) - One carbon transfers

Tetrahydrobiopterin (BH4) - ring hydroxylations - (like Phe to Tyr)


Is M.V.Pitthall actually a useful thing to memorize?

No. That's my opinion. sorry.


How can you create Tyrosine without ingesting it in your diet?


Make sure to name the cofactor!

Phenylalanine hydroxylase is an enzyme that hydroxylates phenylalanine


The cofactor is tetrahydrobiopterin


Amino acids can be turned into and drieved from?


glycolysis intermediates

TCS cycle intermediates

Acetyl CoA and Acetoacetate


Lets look at glycolytic intermediates

What glucolytic intermediates can be tuned tinto amino acids?

Pyruvate to Alanine

3-phosphoglycerate to Serine


Name 2 amino acids that cen be turned to glycine in one step.

What cofactors do they use?

Serine to glycine using PLP and FH4



Threonine to glycine using PLP


Intersting biproducts of cysteine degradation?

Sulfuric Acid


PAPS (an activated sulfate that can be used to negatively charge stuff)


What happens if you have a recessive mutation in your SLC carrier?

Hint: painful

cysteine wil begin to precipitate in your renal tubules. Forming kidney stones

Called cystinuria


What enzyme is used to transaminate alanine to pyruvate?

alanine aminotransferase (ALT)



What TCA intermediates can be turned into amino acids?





What AAs can oxaloacetatebe converted to?

aspartate and asparagine


What AAs can alpha-ketoglutarate be converted to?

Glutamate, glutamine, proline, arginine


What can you assume if you find ALT and AST in the blood???

Liver damage

Alanine aminotrasnferase and aspartate aminotransferase are only found in the liver normally


What cofactor does AST use?



Describe the cause, symptoms, lab results, and treatment of an infant with maple syrup urine disease.

  • recessive deficinecy in branched-chain alpha-keto acid dehydrogenase


  • Symptoms: 1 week old, convulsions, vomiting, maple syrup urine odor


  • Labs: elevated plasma/urine of Val, Iso, and Leu + hypoglycemis + ketoacidosis


  • Treatment: Hydration, transfusion, low branched cahin amino acid diet


Why could high doses of thiamine be an effective treatment for mild Maple Syrup Urine Disease?

You have a problem with a decarboxylase enzyme. loading up with more TPP will help the enzyme be as effective as it could be.


A missing kinase that normally inhibits aplha keto acid dehydrogenase (enzyme responsible for Maple Syrup Urine) causes a problem. What is it?

A combined seizure/ autism disorder resulting from a lack of available branched chain amino acids.


Supplment these BCAA's and symptoms lessen


What is the problem in PKU?

A defect in phenylalanine hydroxylase. What normally produces tyrosine.

Phenylalanine then accumulates in the blood and brain eventually causing seizures, cognitive problems, and mousy odor

Treatment: No Phe in diet!


How would somone get Tyrosinemia Type 2? Symptoms? treatment?

Tyrosinemia (Type II)

A rare autosomal recessive mutation of tyrosine aminotransferase. (build-up of tyrosine)

Patients develop plaques on the hands and feet, corneal ulcers, and frequent mental retardation.

Treatment:  Synthetic diet low in phenylalanine and tyrosine.


What is the cause, symptoms, and diagnosis of alcaptonuria?

A rare autosomal recessive deficiency in homogentisate oxidase.

Homogentisate accumulates and is excreted in urine, giving it a dark color.  Patients are asymptomatic until middle age, when they develop arthritis, back pain, renal calculi.

Ochronosis (dark spots of polymerized homogentisic acid in the sclera and ear cartilage)
Homogentisic acid in urine.


How do you get Tyrosinemai Type 1? Problems? Diagnosis? Treatment?

An inherited disorder of fumaryloacetoacetate hydrolase (FAH)

results in accumulation of succinlyacetone.

(Lots of LIVER problems!)

acute hepatic crisis at 2-4 months of age, Jaundice, hepatomegaly, elevated AST & ALT, hypoglycemia

Diagnosis:  Succinylacetone in urine and blood

Treatment:  Nitosinone