Amino Acid Degradation and the Urea Cycle - General

Question 1

What two storage forms of energy in the body are the primary storage depot for amino acids?

Answer 1

Fatty acids (TAG) and glucose (glycogen)

Question 2

Why is protein not the main storage depot of amino acids?

Answer 2

When rapid degradation of muscle occurs in order to provide amino acids to the body for other purposes, it is in response to a severe metabolic or physiological disorder, such as severe starvation or untreated diabetes. Thus, in the normal state, we have no reservoir of amino acids to synthesize proteins, and thus need them in our diet every day.

Question 3

What are the 3 sources of amino acids for humans?

Answer 3

1. Turnover, or degradation, of cellular proteins that are either damaged, defective, or in excess of what is needed by the cell
2. Dietary protein
3. Synthesis of amino acids by the cell using precursors

Question 4

_____ and _____ can produce all 20 amino acids, while _____ can only synthesize some and require the rest through diet.

Answer 4

Yeast and bacteria can produce all 20 amino acids, while mammals can only synthesize some and require the rest through diet.

Question 5

What 4 things are amino acids used for in the body?

Answer 5

1. Make new proteins
2. Synthesize other nitrogenous compounds
3. Metabolized by different pathways to biomolecules such as glucose, ketone bodies, and fatty acids
4. Oxidized through the citric acid cycle to CO₂ and H₂O, producing ATP in the process

Question 6

The average person requires _____ g of dietary protein per day to maintain the amino acid pool.

Answer 6

70-100 g

Question 7

How are amino acids absorbed into the body from proteins? What is the breakdown of proteins called?

Answer 7

Intact proteins are too large to be absorbed in our small intestine so the digestion process breaks down proteins into primarily amino acids, as well as a small amount of di- and tri-peptides. The process whereby peptide bonds within proteins are cleaved is called proteolysis, which is a hydrolytic reaction where a water molecule is added across a peptide bond. During digestion, proteolysis begins in the stomach and continues on in the small intestine, where protein digestion is completed.

Question 8

What are the 2 roles of the mouth in protein digestion?

Answer 8

1. Liquefies the protein in the food that increases its surface area and makes it a better substrate for the proteases it will encounter in the stomach in small intestine
2. Chewing and having the protein in your mouth for a certain period of time triggers neural effects that prepare the stomach for the protein that is on its way (cephalic phase [208]).

Question 9

What is the role of the stomach in protein digestion?

Answer 9

The neural effects that result from chewing food stimulate special cells in the stomach to secrete gastric juice, in amounts up to one litre in volume. (Gastric juice combines with pepsinogen to form pepsin, an endoprotease [208])

Question 10

What is the pH of gastric juice? What 2 purposes does this serve?

Answer 10

Around 2.

1. Denaturation of proteins, which facilitates the degradation of proteins, since unfolding of proteins makes the peptide bonds, many of which are buried in the interior of the folded protein, accessible to proteases.
2. Antiseptic function, destroying many bacteria and viruses that are ingested when we eat.

Question 11

What are the 2 enzymes of gastric juice? What are their roles?

Answer 11

1. Gastrin: peptide hormone that is secreted by special cells in the stomach. Its primary role is to stimulate acid secretion into the stomach.
2. Pepsin: protease that cleaves the peptide bonds involving hydrophobic amino acids, breaking it up into smaller segments which facilitates the next round of proteolysis that occurs in the SI.

Question 12

What issue does the chyme from the stomach pose when it needs to be moved to the small intestine? How is this remedied?

Answer 12

It’s very acidic and needs to be neutralized so that the cells lining the small intestine aren’t damaged and so that the digestive enzymes present in the small intestine aren’t denatured. This is accomplished by the secretion of pancreatic juice by the pancreas into the small intestine. This solution contains bicarbonate, which neutralizes the gastric juice to around a pH of 7.0.

Question 13

Pancreatic juice also contains several additional _____, each recognizing different types of peptide bonds.

Answer 13

Proteases

Question 14

What are the 6 proteases of the GI system? What do they cause?

Answer 14

1. Pepsin: cleaves peptide bonds following a hydrophobic amino acid
2. Trypsin: cleaves bonds following arginine or lysine.
3. Chymotrypsin: cleaves bonds following aromatic amino acids.
4. Elastase: cleaves bonds after amino acids that have smaller, hydrophobic side chains.
5. Carboxypeptidases and 6. aminopeptidases: cleave bonds working from either end of peptides with little specificity.

This array of proteases causes proteins to be rapidly degraded into free amino acids.

Question 15

What happens to the free amino acids after they have been broken up by the pancreatic juice proteases?

Answer 15

They are absorbed by the endothelial cells and then moved into the portal vein, where they are transported throughout the body for utilization.

Question 16

All of the proteolytic enzymes involved in protein digestion are synthesized as _____, stored in _____ after they are synthesized and released when they are needed.

Answer 16

zymogens, granules

Question 17

Since these proteolytic enzymes are proteins, how are the enzymes themselves protected from being degraded by their own proteolytic activity?

Answer 17

All of the proteolytic enzymes are initially synthesized in an inactive form called a zymogen and are activated by having a small portion of their polypeptide backbone cut off which allows them to properly fold into active enzymes.

Question 18

Describe the modification needed to convert pepsinogen to the active form pepsin.

Answer 18

In order for the active site to be properly formed, it needs to be activated which involves cutting off part of the protein. Pepsinogen has a 44 amino acid masking sequence on one end of the protein, and when this is cut off, the protein changes conformation and forms a cleft which is the active site where polypeptide regions fit and are cleaved by pepsin.

Question 19

What triggers the removal of the masking sequence on pepsinogen? What is this process called?

Answer 19

When pepsinogen is secreted in the gastric juice, the low pH causes a small degree of conformational change in pepsinogen which allows it to self-cleave the masking sequence, forming a small number of active pepsin molecules. These active proteases molecules in turn attack other pepsinogen molecules, converting them to active pepsin molecules.

This self-activation process is called autocatalysis.

Question 20

After digestion of protein is accomplished, continued activity of proteases is not desirable as they will start attacking proteins on the surface of cells. How is this combatted?

Answer 20

Proteases self-inactivate; they chemically-attack and degrade each other when there is no dietary protein to act on, ensuring that protease activity is terminated when not needed.

Question 21

How do most GERD cases occur?

Answer 21

Most GERD cases result from an over-active proton pump in the stomach, causing the production of too much acid.

Question 22

What is the normal series of events in regards to the insertion of K+/H+ pumps into the cell surface (3 steps)? How does GERD change this?

Answer 22

1. The K⁺/H⁺ pump is actually kept sequestered in intracellular membrane compartments until it is needed at the cell membrane.
2. Signalling molecules such as gastrin and histamine bind to receptors on parietal cells, which directly or indirectly lead to activation of protein kinase A by increasing cAMP in the cell.
3. This kinase phosphorylates the K⁺/H⁺ pump, which causes the pump to move to the surface of the cell and to begin pumping protons into the lumen of the stomach, lowering the pH.

In GERD, this signalling pathway becomes dysregulated, resulting in too much acid secretion which lead to symptoms of heartburn.

Question 23

What 3 drugs treat GERD? How do each work?

Answer 23

1. Antacids such as TUMS (calcium carbonate) act as sponges for protons, thus reducing acidity.
2. Histamine H2 receptors (e.g. Zantac) by preventing the binding of histamine, which puts the brake on the cAMP signalling pathway and slows the translocation of the proton pump to the cell surface.
3. Proton Pump Inhibitors (PPIs) bind directly to the proton pump and inhibit its ability to pump protons into the lumen of the stomach.

Question 24

What is the first step of the degradation of amino acids?

Answer 24

Nitrogen removal. (transamination)

Question 25

What are the two key components of amino acids that need to be considered during amino acid breakdown? How are each of these handled by the body?

Answer 25

1. Amino group: excess amino groups are eventually secreted from our bodies in the form of urea
2. Carbon skeleton: converted into a-keto acids, which can be oxidized for energy production or in some cases converted to glucose via gluconeogenesis.

Question 26

The amino groups from the amino acids are funneled into one amino acid, _____, through a process called _____.

Answer 26

glutamate, transamination.

Question 27

The amino group from glutamate is then released as _____ in a process called _____.

Answer 27

ammonium (NH₄⁺), oxidative deamination

Question 28

The combined reactions of transamination and oxidative deamination are collectively referred to as _____.

Answer 28

transdeamination

Question 29

The ammonium from transdeamination is then used to synthesize _____, which is excreted from the body. Production of this occurs only in the _____.

Answer 29

urea, liver

Question 30

Transamination

1. What is it?
2. Where does it occur?
3. What is this reaction catalyzed by?
   
   • What do these require?
4. Where are the groups transferred?
5. What happens to the amino acid once the amino group is removed?

Answer 30

1. The gathering of the amino groups from 17 amino acids (excluded are glutamate, lysine, and threonine; the latter two are catabolized differently) into the amino acid glutamate
2. Cytosol
3. Aminotransferases, which are specific for the amino group donor
   
   • These require a coenzyme pyridoxal phosphate, which is derived from vitamin B6
4. a-ketoglutarate, creating glutamate
5. The amino acid from which the amino group was removed is converted to a corresponding a-keto acid

Question 31

What are the two aminotransferases explicitly mentioned in class? What reaction do they carry out?

Answer 31

1. Alanine aminotransferase (older name was alanine transaminase): the enzyme that transfers the amino group from alanine to a-ketoglutarate, producingglutamateandpyruvate as products
2. Aspartate aminotransferase: the enzyme that transfers the amino group from aspartate to a-ketoglutarate, producing glutamate and oxaloacetate as products

Question 32

Why can the presence of aminotransferases in blood be useful diagnostic tools?

Answer 32

Blood samples from people suspected of having a heart attack, or liver damage, or muscle diseases are often screened for tissue-specific aminotransferases. This is because when tissues are damaged, the contents of the cells that are damaged end up in the blood, including enzymes. Because of this, elevated levels of these isoform enzymes in blood can be used to diagnose different types of medical conditions, depending on the origin of the tissue they came from.

Question 33

What is the second step of the degradation of amino acids? Where does this occur?

Answer 33

The oxidative deamination of glutamate. This occurs in the liver.

Question 34

What part of the cell does the oxidative deamination of glutamate in the liver occur? What are the products of this reaction?

Answer 34

The mitochondria, releasing the amino group as ammonium (NH₄⁺) and a-ketoglutarate.

Question 35

Why is it important that ammonium is produced in the mitochondria rather than the cytosol during oxidative deamination?

Answer 35

Ammonium is very toxic if levels get too high in the blood. By producing free ammonium in the mitochondria, the very place where it will be used to form urea, the ammonium is prevented from accumulating in the body.

Question 36

Oxidative deamination of glutamate is catalyzed by _____, located in the mitochondria of liver. How does this enzyme change glutamate? Is the reaction reversible?

Answer 36

Glutamate dehydrogenase. This enzyme removes the amino group, and oxidizes glutamate in a two-step process. This reaction is potentially reversible; but in the liver it almost always proceeds in the direction of deamination since the ammonium is quickly incorporated into urea.

Question 37

How are the electrons captured from the oxidation of glutamate by glutamate dehydrogenase? Why is this unusual?

Answer 37

​The electrons removed are captured either as NADH or NADPH. This makes the enzyme very unusual, since it can use either NAD⁺ or NADP⁺ as a substrate.

Question 38

How is ammonium that is produced in tissues other than liver converted to urea? What are the 4 steps? What tissue is the exception?

Answer 38

​In most tissues, free ammonium is incorporated into glutamine by the enzyme glutamine synthetase.

Steps:

1. While most amino acids cannot get out of cells, glutamine can and it enters the bloodstream and is transported to liver.
2. In liver, there is an enzyme called glutaminase, a mitochondrial enzyme, which uses water to cleave ammonium off of glutamine.
3. The ammonium released is used to synthesize urea.
4. The glutamate in turn can be acted upon by glutamate dehydrogenase, which releases the second amino group.

Muscle tissue is the exception to this process.

Question 39

Why is the incorporation of free ammonium into glutamine an efficient process?

Answer 39

This strategy keeps free ammonium levels in peripheral tissues and blood low, and uses glutamine as an efficient, non-toxic carrier of ammonium from peripheral tissues to the liver.

Question 40

How is the ammonium produced in muscle converted to urea? What is this process called?

Answer 40

While a small amount of ammonium is incorporated into glutamine in this tissue, most of it gets transported out of muscle in the form of alanine. This is a cyclical process called the Glucose-Alanine Cycle.

Question 41

What are the 6 steps of the glucose-alanine cycle?

Answer 41

1. Initially, the excess amino groups in muscle are collected in the form of glutamate.
2. Glutamate then undergoes a transamination reaction with pyruvate, catalyzed by alanine aminotransferase, which transfers the amino group from glutamate to pyruvate, forming alanine (remember that transamination reactions are reversible).
3. Alanine leaves the muscle, goes to the liver through the blood, and in liver the alanine aminotransferase present there transfers the amino group from alanine to a-ketoglutarate, reforming glutamate.
4. The glutamate is then acted on by glutamate dehydrogenase in the mitochondria; this releases ammonium which is converted to urea.
5. The pyruvate released from this reaction is used as a substrate for gluconeogenesis.
6. The glucose produced goes back to the muscle (and other tissues) and is metabolized through glycolysis to pyruvate.

Question 42

Ammonium is converted into _____ in most terrestrial vertebrates. What is this process called? What happens to this product?

Answer 42

Urea. The Urea Cycle. Urea is released from the liver into the blood and filtered out by the kidneys and excreted from the body in urine.

Question 43

Why was urine an important commodity historically?

Answer 43

Urine was used for a variety of cleaning applications, to the point where it was collected in public bathrooms, so it didn’t go to waste.

Question 44

The urea cycle consists of reactions that occur in both the _____ and the _____. Where does the cycle start and why?

Answer 44

Mitochondria, cytosol. Because the ammonium is released in the mitochondria, this is where things start.

Question 45

The first and rate-limiting step in urea synthesis is catalyzed by _____. What occurs in this reaction?

Answer 45

Carbamoyl phosphate synthetase I. In this reaction, ammonium is fused to CO₂ and requires the cleavage of two ATP, forming carbamoyl phosphate. This step is where free ammonium is used in urea synthesis.

Question 46

Why is carbamoyl phosphatate synthase I slightly unusual? Define.

Answer 46

Carbamoyl phosphate synthetase I is a bit unusual in that it has an obligate allosteric activator, N-acetylglutamate. An obligate activator is one that is absolutely required for its target enzyme to have activity.

Question 47

Where is carbamoyl phosphate synthetase I found?

Answer 47

In the mitochondrial matrix

Question 48

N-acetylglutamate is synthesized from glutamate and acetyl CoA by the enzyme _____. What stimulates this enzyme? How will a meal effect the activity and what will occur as aresult?

Answer 48

N-acetylglutamate synthase. The presence of arginine.

Following a meal where protein is eaten, the influx of amino acids will increase the nitrogen balance which needs to be re-balanced. The arginine from dietary protein, as well as glutamate, will lead to an increase in N-acetylglutamate, which in turn will stimulate carbamoyl phosphate synthetase I, which will increase urea synthesis.

Question 49

What is the first part of the urea cycle (3 steps)?

Answer 49

Carbamoyl phosphate produced in the above step now feeds into the Urea Cycle.

1. Carbamoyl phosphate combines with ornithine to produce citrulline in the mitochondria catalyzed by ornithine transcarbamoylase.
2. Citrulline then passes out of the mitochondria into the cytosol where the next phase of the urea cycle occurs.
3. The aspartate is formed in the mitochondria through a transamination reaction catalyzed by aspartate aminotransferase; glutamate is the source of the amino group in aspartate.

Question 50

Urea has two amino groups, where do they come from?

Answer 50

One comes from free ammonium, the other one comes from aspartate.

Question 51

What are the two ways glutamate provides amino groups to urea synthesis?

Answer 51

1. Free ammonium is cleaved from it by glutamate dehydrogenase, which is used to form carbamoyl phosphate.
2. Glutamate transfers its amino group to form aspartate, which is used later in the urea cycle to add the second amino group onto urea.

Question 52

What is the aim of the second step of the urea cycle?

Answer 52

Produce urea and replenish ornithine

Question 53

What are the 4 steps of the second part of the urea cycle?

Answer 53

1. In the cytosol, citrulline reacts with aspartate to form argininosuccinate by argininosuccinate synthetase. ATP is cleaved to AMP + PPi which drives the reaction forward.
2. Argininosuccinate is then acted on by argininosuccinase, which cleaves the substrate into fumarate and arginine.
   
   • The fumarate is transported back into the mitochondria and can enter the citric acid cycle. The arginine is what we need to focus on with respect to the urea cycle.
   • In arginine, the end of the side-chain has a carbon to which two amino groups are attached and thus looks a lot like urea.
3. Arginine is acted upon by the hydrolase arginase, urea is produced along with ornithine.
4. The urea leaves the cell and goes into the blood, while ornithine re-enters the mitochondria and reacts with another molecule of carbamoyl phosphate and starts another round of the cycle.

Question 54

What are the three enzymes of the second part of the urea cycle and how are they arranged? What 2 benefits does this give?

Answer 54

Argininosuccinate synthetase, argininosuccinase, and arginase are clustered together in a complex.

1. It keeps the pathway intermediates trapped in or near the complex, with the products of one reaction quickly passed along to the next enzyme in the pathway. This keeps the local concentration of intermediates high, thus increasing the reaction rate of the cycle.
2. Keeping the intermediates sequestered in the complex prevents the intermediates from undergoing unrelated, side reactions which would slow the rate of flux through the urea cycle and inhibit the elimination of excess nitrogen from the cell.

Question 55

_____ and _____ link the urea cycle and the citric acid cycle. Where do each of these go once cleaved?

Answer 55

Aspartate and fumarate.

Fumarate can either go directly to the citric acid cycle or be first converted to malate, which can then move to the mitochondria.

Aspartate moves to the cytosol, where it is used to form argininosuccinate and ultimately provides one of the amino groups present in urea.

Question 56

Urea synthesis summary

1. It involves reactions in both _____ and _____
2. It is connected to the citric acid cycle by _____ and _____
3. The rate-limiting enzyme is _____
4. Regulation is through _____ and _____
5. Energy cost is ___ ATP (___ high energy bonds) per urea molecule formed
6. Overall reaction is: _____

Answer 56

1. Mitochondria and cytosol
2. Fumarate and aspartate
3. Carbamoyl phosphate synthetase I
4. N-acetylglutamate and arginine
5. 3, 4
6. Aspartate + NH₄⁺ + CO₂ + 3 ATP → urea + fumarate + 2 ADP + AMP + 2P_i + PPi

Question 57

What two other ways is nitrogen excreted? (fish and reptiles + birds). What are each of the classifications called?

Answer 57

1. Fish release ammonium directly through the gills into the surrounding water. They have no need to spend unnecessary ATP to convert ammonium into urea since the large surface area provided by gills allows fast release and disposal of ammonium.
   
   • Organisms that eliminate excess nitrogen as ammonium are termed ammoniotelic in contrast to ureotelic organisms which secrete urea.
2. Birds and reptiles dispose of excess nitrogen as uric acid, which is a degradation product of purines. It is relatively insoluble in water, and rather forms a paste.
   
   • Organisms that use this method of nitrogen disposal are termed uricotelic

Question 58

Most ammonium comes from the metabolism of _____, and much of this occurs in the liver not surprisingly since this is the site of urea synthesis.

Answer 58

Dietary and body protein

Question 59

What are the 4 major processes that produce free ammonium in the liver?

Answer 59

1. Transdeamination of amino acids produce glutamate, which is then acted on glutamate dehydrogenase
2. Serine and threonine, catalyzed by serine and threonine dehydratase
3. Glutamine hydrolysis by glutaminase
4. Amino groups from other tissues come to the liver in the form of alanine and glutamine; the free ammonium is released from these two amino acids by transdeamination and glutaminase

Question 60

There is also a fair bit of free ammonium produced in the kidney from the breakdown of _____ and _____, by the actions of , _____ and _____ respectively.

Answer 60

glutamine, glutamate, kidney-specific glutaminase and glutamate dehydrogenase

Question 61

What 3 mechanisms keep levels of free ammonium low?

Answer 61

1. Formation of urea
2. Formation of glutamate in muscle by glutamate dehydrogenase;
   
   • In this tissue, the reaction usually goes in the direct of glutamate synthesis because of the relative concentrations of substrate products
3. Formation of glutamine in many tissues by glutamine synthetase

Question 62

What is hyperammonemia? What does this primarily effect and why?

Answer 62

Abnormally high ammonium levels in the blood. While most tissues are affected to some degree, the most significant and dangerous effects are ones that impact the central nervous system (CNS). It is believed that the reason behind this is because the brain, in attempting to reduce the levels of free ammonium, synthesizes glutamine in high levels from glutamate using glutamine synthetase.

Question 63

How does hyperammonemia change the levels of glutamine and glutamate? What does this result in? What are the symptoms?

Answer 63

Hyperammonemia results in high levels of glutamine, and reduced levels of glutamate

• Glutamine is an osmolyte in astrocytes, which causes a large uptake of water and leads to swelling of the brain.
• Glutamate is a neurotransmitter, and is a substrate for a second neurotransmitter, GABA (gamma-aminobutyric acid).

An imbalance in both of these occurs, causing the CNS effects observed in hyperammonemia, which include tremors, slurring of speech, blurred vision, and eventually coma and death.

Question 64

What are the two forms of hyperammonemia? Describe each.

Answer 64

1. Acquired hyperammonemia: liver damage caused by things such as viral hepatitis (hepatitis C infection) or hepatotoxins such as excessive alcohol.
   
   • As the liver becomes damaged and cirrhotic, collateral blood circulation develops which bypasses the liver, resulting in elevated ammonium in the blood.
2. Congenital hyperammonemia: inheritance of mutations in one of the genes coding for any of the five enzymes of the urea cycle.
   
   • Defects in arginase, however, tend to be less severe since arginine itself can be excreted in the urine (has three nitrogen atoms so it is a rather efficient way of getting rid of excess nitrogen).
   • Symptoms appear shortly after birth as the infant begins ingesting protein through milk or formula.

Question 65

Most cases of hyperammonemia used to end in _____. Treatment for the disease includes these 2 methods. Describe each.

Answer 65

Death.

1. Reducing protein intake and increasing caloric intake, in the hopes that this would decrease amino acid catabolism.
2. Compounds have been developed that bind to amino acids, forming water-soluble compounds that are excreted in the urine.
   
   • Phenylbutyrate is one of these, which complexes with glutamine (two amino groups) to form phenylacetylglutamine

Question 66

The _____ which are produced by transamination are further metabolized through several steps and can be used to either form fuels such as glucose and fatty acids or can be oxidized completely through the citric acid cycle to produce ATP.

Answer 66

a-ketoacids

Question 67

What is a glucogenic amino acid? Give an example.

Answer 67

​Glucogenic amino acid: one that is catabolized to pyruvate or to an intermediate of the citric acid cycle, since these biomolecules can potentially serve as substrates to produce glucose through gluconeogenesis.

A good example is alanine. When alanine undergoes transamination, the a-ketoacid produced is pyruvate. Pyruvate can be used to produce glucose.

Question 68

What is a ketogenic amino acid? How are the breakdown products funneled?

Answer 68

Ketogenic amino acid: one that is catabolized to acetyl CoA and/or acetoacetate. Neither acetyl CoA nor acetoacetate can lead to the net synthesis of glucose, but rather to the formation of fatty acids, ketone bodies or their precursors.

Question 69

Which 5 amino acids are both glucogenic and ketogenic? What does this imply?

Answer 69

1. Tryptophan
2. Tyrosine
3. Threonine
4. Phenylalanine
5. Isoleucine

This implies that during the catabolism of these amino acids, the products consist of both acetyl CoA or acetoacetate, as well as pyruvate or a citric acid cycle intermediate.

Question 70

Tryptophan, alanine, serine and cysteine all have some of their carbons ending up in which molecule?

Answer 70

Pyruvate, thus making these amino acids glucogenic.

Note that acetyl CoA is also a product of tryptophan catabolism, making tryptophan both a glucogenic and ketogenic amino acid.

Question 71

What is the catabolic pathway for asparagine? Are asparagine and aspartate glucogenic or ketogenic? Why?

Answer 71

Asparagine is easily converted to aspartate via a hydrolysis reaction; aspartate can undergo transamination to form oxaloacetate, which is an intermediate of the citric acid cycle. Thus, both asparagine and aspartate are glucogenic.

Question 72

What is the catabolic pathway for phenylalanine? Are the products glucogenic or ketogenic?

Answer 72

Phenylalanine undergoes hydroxylation to form tyrosine, which is then degraded further to fumarate and acetyl CoA. Thus, both phenylalanine and tyrosine are glucogenic and ketogenic.

Question 73

What is the most common disease related to amino acid degradation?

Answer 73

Phenylketonuria

Question 74

What is phenylketonuria caused by? What does this result in? How does this present?

Answer 74

This disease results from a deficiency in the enzyme phenylalanine hydroxylase.

When the normal degradative pathway for phenylalanine is compromised, an alternative pathway is engaged which is normally inactive, which leads to significant elevations in phenylpyruvate, phenylacetate, and phenyl lactate.

The presence of these compounds in high amounts in urine gives off a strong musty smell, which was the way this disease was diagnosed before more sophisticated techniques became available

Question 75

When do the biochemical effects of phenylketonuria become evident? What do these changes consist of?

Answer 75

Right after birth (as soon as an infant start ingesting protein from breast milk or formula), consisting of elevations in phenylalanine and the three metabolites (phenylpyruvate, phenylacetate, and phenyl lactate), in the blood and urine.

Question 76

What are the effects on the CNS and the light pigmentation due to phenylketonuria caused by?

Answer 76

The effects on the CNS are likely due to the phenylalanine metabolites competing with and thus interfering with the transport of phenylalanine across the blood brain barrier.

The light pigmentation results from the reduction in tyrosine that occurs as a result of deficient phenylalanine hydroxylase. Tyrosine is a precursor for melanin, the pigment which gives skin and hair its dark color.

Question 77

What is the treatment for phenylketonuria?

Answer 77

1. Special diets that eliminate high protein foods in order to restrict dietary ingestion of phenylalanine
2. Avoidance of aspartame since as it undergoes degradation phenylalanine is produced.

Question 78

Maple syrup urine disease is the result of what? What does it cause?

Answer 78

Results from a deficiency in the dehydrogenase complex. Causes a build-up of the a__-ketoacids derived from the three branched-chain amino acids result in urine that gives off a strong maple syrup odor.

Question 79

What are the effects of maple syrup urine disease? How can these be prevented?

Answer 79

Effects on the CNS leading to vomiting, convulsions, mental retardation, and early death unless caught early and a special diet implemented.

Question 80

The general target of the symptoms of a genetic disease affecting amino acid catabolism is where? Why?

Answer 80

The CNS is a major target of the symptoms and effects.

This is likely due, at least in part, to disturbances in the uptake of amino acids into the CNS that results from the altered catabolism.

Question 81

What are the 5 specialized products amino acids can be converted to?

Answer 81

1. Porphyrins
2. Catecholamines
3. Histamine
4. Serotonin
5. Creatine

Question 82

What are porphyrins? What is the most common one? What are their conserved structural features?

Answer 82

Cyclic compounds that bind Fe²⁺ or Fe³⁺.

The most common and familiar porphyrin is heme but also include cytochromes and other molecules.

They have conserved structural features: they consist of four nitrogen-containing pyrrole rings that are linked together; and each pyrrole ring has a sidechain that are unique to different porphyrins.

Question 83

All carbon and nitrogen atoms in porphyrins are contributed by _____ and _____.

Answer 83

glycine, succinyl CoA

Question 84

The very first step in the synthetic pathway of porphyrins consists of what?

Answer 84

The very first step in the synthetic pathway consists of the fusion of succinyl CoA and glycine to form ALA.

Question 85

_____ are rare genetic diseases which lead to defects in the biosynthesis of certain porphyrins and result in the accumulation of intermediates.

Answer 85

Porphyrias

Question 86

Acute intermittent porphyria results from a defect in _____

Answer 86

PBP deaminase

Question 87

What allows us to diagnose different porphyrias?

Answer 87

The defects in a particular enzyme cause an increase in the intermediates prior to that point in the pathway because the pathway is blocked from proceeding.

It is the accumulation of these different intermediates that give each disease its own profile of symptoms.

Question 88

How do individuals with Acute Intermittent Porphyria present? When are symptoms most active?

Answer 88

Symptoms are uncommon, but when there are they include abdominal pain, motor weakness and neuropsychiatric problems such as insomnia, hysteria, anxiety, phobias, etc.

Symptoms are usually brought on by activating factors such as hormones, drugs, or nutritional changes.

Question 89

How do individuals with Porphyria Cutanea Tarda present?

Answer 89

Individuals with PCT present with skin lesions, anemia due to insufficient heme, and are also abnormally sensitive to light.

Their urine is also very red due to the high abundance of intermediates of the heme pathway caused by the defective enzyme; these same intermediates accumulate in the teeth, causing them to fluoresce strongly in UV light

Question 90

What are the 3 major catecholamines? What are they and what are they synthesized from?

Answer 90

1. Dopamine (NT)
2. Norepinephrine (NT)
3. Epinephrine (hormone from adrenal gland)

All three are synthesized from tyrosine through a series of sequential reactions.

Question 91

Histamine: how is it synthesized and what are its 2 major roles?

Answer 91

Synthesized in the body from histidine through a decarboxylation reaction.

1. Powerful vasodilator and mediates many responses associated with allergies and inflammation
2. Regulates gastric acid secretion

Question 92

Serotonin

1. Where is it found and how does it function?
2. What does it do in the CNS?
3. How is it synthesized?
4. What can it further be converted to?

Answer 92

1. Primarily in intestinal mucosa where it regulates intestinal movement, and to a lesser degree in the CNS, where it functions as a “feel good” neurotransmitter.
2. Mediates pain perception, sleep, blood pressure, appetite and mood.
3. It is synthesized from tryptophan through a decarboxylation reaction.
4. Can be further converted to melatonin in the CNS, which is known to maintain our circadian rhythm.

Question 93

Creatine

1. Where is it found and in what form?
2. What is it’s role?
3. What is it synthesized from?

Answer 93

1. Found in muscle, and its phosphorylated form, creatine phosphate (or phosphocreatine), is a high energy compound.
2. It serves as a small pool of energy source, a few minutes worth, that is readily available to replenish ATP levels by transferring its phosphate group to ADP.
3. Glycine, arginine and methionine

Question 94

What is MSG sensitivity likely attributed to?

Answer 94

While MSG sensitivity can’t be entirely dismissed, many cases may simply be a result of eating too much good food that we aren’t used to eating.