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Flashcards in Protein Biochemistry Deck (72):
1

what are the 4 important versions of amino acid side chains you should be thinking about?

(in terms of the breakdown from dietary protein and stuff)
*1. Sulfur containing amino acids
2. Amino acids with nitrogen in the side chain which are involved in nitrogen transport.
3. Branched chain amino acids
4. Aromatic amino acids which are precursors for a number of neurotransmitters and hormones.

2

What are the specific PTMs on proteins that matter in the land of protein biochemistry?

1. Hydroxy-Proline and Hydroxy Lysine which are structural components of collagen, Vitamin C is needed for their synthesis. Vitamin C deficiency causes scurvy because of a failure to synthesize sufficient quantities of these amino acids.
2. Gamma carboxyglutamate: Prothrombin uses this to target membranes
3. Ornithine: part of the Urea cycle

3

Describe the process of protein absorption from the gut:

Protein in the diet is broken down in the GI tract by a group of peptidases.
*These enzymes need to be activated in the gut lumen to be functional.
*Once activated, these different peptidases have different specificities for specific types of peptide bonds.
*They are categorized by the type of enzyme they are and the type of bond that they cleave.
*These peptidases work sequentially to break down long peptide chains into their component amino acids which are then absorbed and enter the circulation.

4

what are the two primary ways proteins are turned over within the cells?

At some point, these proteins will be inactivated and broken down. The half-life and mechanisms by which a protein is broken down will vary depending on the protein. However, there are two intracellular pathways for protein degradation that are particularly important:
1. Ubquination which targets proteins for degradation in proteasomes
2. Degradation in lysosomes

5

What is a transaminase reaction? where do they occur?

For an amino acid to be used as a precursor for gluconeogenesis, the NH2 group must be removed.
*For an amino acid to be made from a carbon skeleton, an NH2 group must be added.
*Actually these NH2 groups are transferred from another nitrogen containing molecule to the carbon skeleton, or from an amino acid to an acceptor molecule.
*These so called “transamination reactions” are typically bidirectional depending on the availability of substrates and acceptors.
*These reactions typically take place in the liver (and to a lesser extent in kidney, intestine and muscle).

6

what is the prototypical transaminase reaction?

In the prototypical reaction, an amino acid donates an NH2 group to alpha-ketoglutarate to produce L glutamate and an alpha-keto acid.
*The enzyme that catalyzes this reaction is an aminotransferase.
*Different aminotransferases have different specificities for different amino acids.
*The nitrogen that has been accepted by alpha-ketoglutarate with the production of glutamate can then be released as NH3 with the regeneration of alpha-ketoglutarate.
*This ammonia is toxic and needs to leave the body. It does so through the process of urea synthesis.

7

Describe in general the urea cycle

In the first step of the urea cycle, the ammonia that was produced from transamination reactions is converted to carbamoyl phosphate
*The production of carbamoyl phosphate is catalyzed by carbamoyl phosphate synthase 1 which is the key regulated step in protein catabolism.
*KEY ENZYME = carbamoyl phosphate synthase 1
*The nitrogen from the carbamoyl phosphate enters the urea cycle, and ultimately is combined with an NH3 from aspartate to form urea which contains 2 nitrogen atoms.

*The nitrogen thus transferred from amino acids to urea can then leave the body in urine as urine urea nitrogen. Urinary nitrogen in the form of urea then represents a marker of amino acid catabolism and oxidation

8

Why is glutamine an important amino acid in the biochemistry of amino acid catabolism?

Glutamine is an important nitrogen containing amino acid (has 2 nitrogen atoms) because it accepts nitrogen from other amino acids in peripheral tissues, carries the nitrogen to the liver and kidney where it is donated to glutamate and from there to alpha-ketoglutarate.
*The conversion of glutamate to alpha-ketoglutarate is catalyzed by glutamate dehydrogenase. This is the second key regulated step in protein catabolism

9

Why are the sulfur-containing amino acids important?

1. Cysteine can form disulfide bridges that change protein conformation.
2. S-adenosylmethionine (SAM) is an energy source for a number of important biochemical reactions. In addition, it is a methyl donor for a number of important reactions.
3. SAM is a precursor for homocysteine which is important in vascular disease, wound healing, and is involved in B12 and folate metabolism.
4. Glutathione is a tri-peptide that contains cysteine, and serves as an important redox buffer, and protects against free radical injury.

10

When you see vitamin C, what do you think?

ASCORBATE, COLLAGEN, SCURVY
♣ Collagen is the most abundant protein in human body that forms a triple-stranded helix, which is comprised of both hydroxyproline (Hyp) and hydroxylysine (Hyl):
♣ Hyp used in collagen for H-bonding that increases collagen strength. Prolyl hydroxylase converts Pro to Hyp.
♣ Hyl use in collagen for interchain cross-links. Lysyl hydroxylase converts Lys to Hyl.
♣ Prolyl hydroxylase, Lysyl hydroxylase rely on Vit-C (ascorbate) as coenzyme, thus, lack of Vit-C leads to Scurvy (i.e. reduced collagen strength).

11

What enzyme is responsible for the formation of hydroxyproline?

♣ Hyp used in collagen for H-bonding that increases collagen strength. Prolyl hydroxylase converts Pro to Hyp.

12

What enzyme is responsible for the formation of hydroxylysine?

Hyl use in collagen for interchain cross-links. Lysyl hydroxylase converts Lys to Hyl.

13

What is Gla and why is it important?

♣ g-Carboxyglutamate (Gla) used to target proteins to membranes via Ca chelation. G-glytamyl carboxylase converts Glu to Gla, which is Vit-K dependent.

14

While there are too many aminotransferases to know, what are some pretty dang important ones? what co-factor do they use/depend upon?

¬ For protein degradation, aminotransferases move nitrogen to Asp & ammonia for Urea Cycle.
¬ Two specific aminotransferases are:
♣ Alanine aminotransferase (Alt)
♣ Aspartate aminotransferase (Ast)
¬ Pyridoxal phosphate (PLP) is a derivative of Vit-B6 and is used by aminotransferases to “hold”/transfer the amino groups.

15

What is the overall reaction of the urea cycle?

3ATP + HCO3- + NH4+ + aspartate --> 2ADP + AMP + 2Pi + PPi + fumarate + urea

16

what are the two entry points for nitrogen into the urea cycle?

¬ There are two entry points for Nitrogen in urea cycle:
1) Aspartate.
2) Free ammonia (incorporated into carbamoyl phosphate

17

When arginine is made into ornithine, what is released?

UREA. this is part of the urea cycle

18

what molecule is moved from the mitochondria to the cytoplasm during the urea cycle?

citrulline. Ornithine and carbamoyl phosphate are the substrates of the reaction that makes citrulline

19

What catalyzes the conversion of glutamate to alpha-ketoglutarate? Is this a regulated reaction?

*The conversion of glutamate to alpha-ketoglutarate is catalyzed by glutamate dehydrogenase. This is the second key regulated step in protein catabolism

20

What are the 4 steps of the Urea Cycle?

• Ornithine --> citrulline
○ Carbamoyl phosphate synthetase I
○ Citrulline + Aspartate --> argininosuccinate
§ Arginonosuccinate synthase
○ Argininocussinate --> arginine
§ Argininosuccinate lyase
○ Arginine --> Ornithine + urea (catalyzed by arginase)

21

What is important about the reaction catalyzed by Carbamoyl phosphate synthetase I?

• This is the initial step in the Urea Cycle, and is what creates the species for ENTRY into the cycle
• Found in the mitochondria
• Bicarbonate + ammonia --> carbamoyl phosphate
○ Uses 2 of the 3 ATPs used in Urea Cycle
• N-acetylglutamate is an allosteric activator of Carbomoyl phosphate synthetase I
• Arginine is an activator of N-acetylglutamate synthase
○ Acetyl CoA + glutamate --> N-acetylglutamate
○ Which in turn will potentently stimulate the action of CPS-I which initiates the urea cycle

22

Describe in general the transport of ammonia through the body

¬ Ammonia cannot be transported through blood, so alternative mechanisms are needed such as those that rely on urea.
¬ Glutamine serves as a means of transport, since it can “hold” two ammonia groups.
¬ Glu dehydrogenase serves as a regulator modulator for protein metabolism specifically by controlling the direction of either nitrogen removal or incorporation into amino acids
¬ Most tissues use glutamine synthetase to convert glutamate to glutamine for transport to the liver (to enter the urea cycle).

*Muscle is different where alanine is used instead of glutamine for transport in the Alanine-Glucose Cycle. This is because in muscle there is a build-up of pyruvate from glycolysis and pyruvate can be converted to alanine for transport to liver (transamination). The liver, in turn, can use the alanine to convert back to pyruvate (transamination) and glucose remade (gluconeogenesis) can then be delivered back to the muscle

23

What amino acid functions as a "transport" molecule for ammonia?

Glutamine - it can "hold" two ammonia groups
*¬ Most tissues use glutamine synthetase to convert glutamate to glutamine for transport to the liver (to enter the urea cycle).

24

Many tissues use glutamine as a way to transport ammonia back to the liver. What does muscle tissue do?

*short = alanine instead of glutamine b/c it can be used in gluconeogenesis
*Muscle is different where alanine is used instead of glutamine for transport in the Alanine-Glucose Cycle. This is because in muscle there is a build-up of pyruvate from glycolysis and pyruvate can be converted to alanine for transport to liver (transamination). The liver, in turn, can use the alanine to convert back to pyruvate (transamination) and glucose remade (gluconeogenesis) can then be delivered back to the muscle

25

Describe the role of arginine in nerve and muscle tissue (ammonia handling and energy production)

¬ NO synthase converts arginine --> citrulline to produce NO, an important molecule used as a neurotransmitter. (nerve tissue) - this is essentially a shortcut through the urea cycle that bypasses the mitochondrial phase
¬ In the urea cycle, arginine --> ornithine can either be catalyzed by arginase or alternatively can be catalyzed by several enzymes to produce creatine phosphate for energy (muscle).

26

Creatine Phosphate is used by what tissue for energy, and where does this reactant come from?

¬ In the urea cycle, arginine --> ornithine can either be catalyzed by arginase or alternatively can be catalyzed by several enzymes to produce creatine phosphate for energy (muscle).
*different from nerve tissue when arginine is often converted into citrulline to produce NO

27

Give an example of a glucogenic amino acid metabolism

♣ Glucogenic: Oxaloacetate in Kreb Cycle comes from aspartate transamination

28

Give an example of a ketogenic amino acid metabolism reaction

Ketogenic: Lysine and leucine are the ketogenic amino acids since breadown gives Acetyl-CoA (i.e. only 2 carbons

29

What are the amino acids that, when metabolised, should be recognized as ketogenic?

Ketogenic: Lysine and leucine are the ketogenic amino acids since breadown gives Acetyl-CoA (i.e. only 2 carbons

30

How does the body metabolize the branched chain amino acids?

¬ Branched Chain Amino Acids include leucine, valine, and isoleucine.
¬ First, these three amino acids are deaminated by branched-chain aminotransferase to produce a-keto acids.
¬ Second, they are decarboxylated by branched-chain a-ketoacid dehydrogenase complex.
♣ Maple Syrup Urine Disease (MSUD) occurs when this dehydrogenase complex is deficient and there is consequently a build up of the a-keto acids in urine (“sweet smelling”).

31

What would a build-up of alpha-keto acids in teh body indicate?

a problem in the metabolism of branched chain amino acids can lead to a rise in alpha-keto acid concentration
♣ Maple Syrup Urine Disease (MSUD) occurs when this dehydrogenase complex is deficient and there is consequently a build up of the a-keto acids in urine (“sweet smelling”).

32

Tyrosine is an important amino acid for the immune system. Why?

¬ Tyrosine is used to make T4 (prohormone) that is converted to T3 (hormone). - these are thyroid hormones
¬ Thyroid stimulating hormone (TSH): Stimulates iodide (I-) uptake and stimulates release of T4,T3.
♣ Thyroid peroxidase (enzyme): Oxidizes iodide (I-) to (I2).
♣ Thyroglobulin (Tg): Contains Tyr residues iodinated to form T4,T3.
♣ Thyroxin binding globulin (TBG): Transports T4,T3.

33

Heme is synthesized by the production of porphyrin rings. How is this process accomplished?

¬ To produce a porphyrin the following reactions take place:
1. Gly + succinyl CoA --> alpha-Aminolevulinic acid (ALA) (catalyzed by alpha-Aminolevulinate synthase)
2. 2x ALA --> Porphobilinogen (catalyzed by by alpha-Aminolevulinate dehydratase)
3. Porphobilinogen --> Protoporphyrin IV (catalyzed by 4 enzymes)
4. Protoporphyrin IX --> Heme (catalyzed by Ferrochelatase)

34

Lead poisoning can lead to a porphyria. What is this and why does Lead mess with porphyrin?

¬ Porphyrias are the general term for diseases in porphyrin synthesis.
¬ Lead inhibits two enzymes in porphyrin synthesis (alpha-Aminolevulinate dehydratase, AND ferrochelatase)

35

Describe how porphyrin is broken down

¬ Porphyrin (Heme) degradation:
♣ Reactions Heme --> biliverdin (green) --> bilirubin (red-orange), -->bilirubin diglucuronide --> urobilinogen --> stercobilin (brown)
♣ Bilirubin is transported in blood via albumin.
♣ In liver, bilirubin is conjugated with glucuronic acid --> bilirubin diglucuronide (or otherwise known as conjugated bilirubin).
♣ In intestine, bilirubin diglucuronide is oxidized --> stercobilin.
♣ Jaundice occurs when bilirubin cannot be processed properly (i.e. hemolytic jaundice occurs when too many RBCs lyse, neonatal jaundice when bilirubin diglucuronide is not produced fast enough by low levels of bilirubin glycuronyltransferase).

36

Which amino acids contain sulfur?

Met and Cys comprise the two sulfer-containing amino acids

37

What is super important about cysteine?

¬ Cysteine (an unessential amino acid) is unique in that the –SH can form disulfides with another Cys, which is important for the structural integrity of many proteins (especially extracellular proteins).
♣ Glutathione (GSH): tripeptide that controls redox potential via GSH GSSG, where cysteine is the central amino acid that actually does the work here.

38

what is important about methionine?

¬ Methionine (an essential amino acid) is unique in that it is used to produce S-adenosylmethionine, which is also an intermediate in the production of cysteine.
♣ S-adenosylmethionine (SAM): produced in the first step of methionine degradation and converted to S-adenoyslhomocysteine (SAH). SAM is major Carbon donor and a “high energy storage unit” like ATP.

39

If a patient's GI is messed up and if they have a weird diet, what important sulfur amino acid can they be deficient in?

Methionine is an essential amino acid

40

What is the process of methionine recycling?

¬ Recycling Met reactions: Met --> SAM --> SAH --> Homocysteine --> Met
♣ Homocysteine --> Met needs THF and Vit-B12 to transfer back CH3 group.

41

What is SAM?

S-adenosylmethionine (SAM): produced in the first step of methionine degradation and converted to S-adenoyslhomocysteine (SAH). SAM is major Carbon donor and a “high energy storage unit” like ATP.

42

Methionine can be made into cysteine how?

¬ Met --> SAM --> SAH --> Homocysteine --> Cystathionine --> Cysteine

43

What are the three diseases of sulfur-containing amino acids that we need to know about it?

¬ Hyperhomocysteinemia:
*Homocystinuria
*Cysteinuria

44

Describe what's going on in the three sulfur amino acid disorders we need to know

¬ Hyperhomocysteinemia: elevated levels of homocysteine cause multiple problems that include cardiovascular disease. Results from low levels of folate, B6, & B12 (vascular disease). Cysteine is now essential and treat with folate, B6, & B12. - this will drive the reaction toward the production of methionine from homocysteine and reduce the homocysteine levels

*Homocystinuria: results from defect in cystathionine-b-synthase (CBS) and cannot convert homocysteine to cystathionine (and eventually cysteine). Leads to mental retardation, osteoporosis, & vascular disease. Cysteine is now essential. Can treat with Vit B6 to “force” CBS activity.

*Cysteinuria : kidney stones (renal failure), due to defective in transporter of cysteine (& Ornithine, Lysine, Arginine) that leads to crystallization in urea, treat with acetazolamide that makes cysteine more soluble.

45

What is up with hyperhomocysteinemia?

¬ Hyperhomocysteinemia: elevated levels of homocysteine cause multiple problems that include cardiovascular disease. Results from low levels of folate, B6, & B12 (vascular disease). Cysteine is now essential and treat with folate, B6, & B12.

46

what is up with homocystinuria?

*Homocystinuria: results from defect in cystathionine-b-synthase (CBS) and cannot convert homocysteine to cystathionine (and eventually cysteine). Leads to mental retardation, osteoporosis, & vascular disease. Cysteine is now essential. Can treat with Vit B6 to “force” CBS activity.

47

what is up with cysteinuria?

*Cysteinuria : kidney stones (renal failure), due to defective in transporter of cysteine (& Ornithine, Lysine, Arginine) that leads to crystallization in urea, treat with acetazolamide that makes cysteine more soluble.

48

What cofactors and amino acids are highly utilized to transfer carbon atoms?

Several cofactors are used for transferring carbons (Fig 3):
¬ SAM - high energy metabolite and carbon donor
*Tetrahydrofolate (THF) is synthesized in bacteria and its precursor, folate, is a vitamin for mammals. The one-carbon group, in any of three oxidation states, is bonded to N-5 or N-10 or to both.
*we should recognize that this carbon can be in several different states of oxidation, and might need to be "regenerated" before it can be added to another skelaton
*The most reduced form of the cofactor carries a methyl group, a more oxidized form carries a methylene group, and the most oxidized forms carry a methenyl, formyl, or formimino group.
*The different forms of tetrahydrofolate are interconvertible and serve as donors of one-carbon units in a variety of biosynthetic reactions

49

Glutathione is super important for the cell why?

*main importance = protection from reactive oxygen species
*¥ GSH is a highly soluble tripeptide as opposed to Cys.
¥ As high as millimolar in some tissues.
¥ Functions:
i) thiol acts as redox buffer (“SH buffer”) to maintain proteins in their reduced forms (i.e. intracellular proteins) and regulate activity (i.e. enzymes)
ii) Cofactor for several enzymes (i.e. Glutathione transferase, GST).
iii) Reduce hydrogen peroxide (H2O2) to water and general protection against ROS (radical oxidizing species).

50

you see ORNT1 and ORNT2 and you think what?

the antiporters will transport ornithine in (mitochondria), citrulline is transported out (to cytoplasm)
*important to fuel the first step of the urea cycle (formation of carbamoyl phosphate)

51

While CPS-1 might be the more important control point for protein catabolism, what is the first control point?

the first control point for protein catabolism is the relative concentrations of substrates and reactants
*in particular, the substrate concentrations that dictate teh directionality of the aminotransferases

52

Glutamate can be produced from what other amino acid that can cross the BBB?

glutamine can be made into glutamate, and this is super important for nerve tissue (glutamatergic neurons)

53

you see Glu Dehydrogenase and you think....?

*important control point for urea cycle and for protein catabolism
*also, think FREE AMMONIA (can go both ways, either shuttling or removing the ammonia) - thus the relative substrate concentrations will dictate the directionality of these reactions
*glutamate --> alpha-ketoglutarate is an example of freeing ammonia
*this particular reaction is regulated by ATP/ADP ratios
*inhibited by high energy state, stimulated by low energy state
*this enzyme, when mutated, can result in hyperinsulinemia????

54

what are the amino acids that are both ketogenic AND glucogenic?

tyrosine, valine, isoleucine, leucine (branched chain plus tyrosine)

55

What is thyroglobulin (tg?)

*important for the production of thyroxine
This is a giant protein complex that has 140 tyrosines, only a couple of which are iodinated
*T3 and T4 come off of this large complex through protealysis
*transferred to thyroxine binding protein for shuttling through the blood
*think of this as the sacrificial goat, which is destroyed to release the hormones T3 and T4

56

ALAS1 and ALAS2 are inhibited by what?

*their end products, there is feedback inhibition in heme synthesis
*lead will act like a constant presence of heme production feedback-inhibition

57

what is important about tryptophan metabolism?

¬ Trp is metabolized to pyruvate or acetyl-CoA. (ENERGY) - glucogenic
¬ Trp is first hyroxylated by tryptophan hydroxylase using tetrahydrobiopterin (BH4) as a cofactor
¬ Trp is used to produce serotonin (neurotransmitter), melatonin (hormone), and niacin (energy).

58

What neuronal complications can result from a problem in tryptophan handling?

¬ Trp is used to produce serotonin (neurotransmitter), melatonin (hormone), and niacin (energy).
¬ BH4 deficiency - Trp is first hyroxylated by tryptophan hydroxylase using tetrahydrobiopterin (BH4) as a cofactor
*symptoms = affected patients typically have hyperphenylalaninemia (HPA) and/or progressive neurologic deterioration during infancy due to decreased production of the neurotransmitters dopamine, epinephrine, norepinephrine, and serotonin
*Untreated patients typically die before reaching one year of age

59

What is important about Phe and Tyr metabolism?

¬ Phe, Tyr are metabolized to fumerate or acetoacetate. (ketogenic AND glucogenic)
¬ Phe is hydroxylated by phenylalanine hydroxylase to produce Tyr using BH4 cofactor (so can be a problem in PKU and BH4 deficiency) - so it's one pathway, just one extra step for Phe to make Tyr
¬ Tyr is hydroxylated by tyrosine hydroxylase to produce DOPA using BH4, which is subsequently metabolized to:
♣ Catecholamines, which include DOPA, dopamine, norepinephrine, epinephrine.
♣ Melanin, which is a pigment produced as a complex combination of several molecules derived from Tyrosine metabolism.
¬ Metabolic diseases in Tyr metabolism include:
♣ Phenylketonuria (PKU), which is a defect in phenylalanine hydroxylase that leads to build-up of alternative byproducts (phenyllactate, phenylacetate, and phenylpyruvate).
♣ Tyrosinemias are defects in the mutli-step tyrosine degradation categorized as types I, II, and III that refer to the particular dysfunctional enzyme involved.

60

What are the metabolic diseases in Tyr metabolism that we are expected to know?

¬ Metabolic diseases in Tyr metabolism include:
♣ Phenylketonuria (PKU), which is a defect in phenylalanine hydroxylase that leads to build-up of alternative byproducts (phenyllactate, phenylacetate, and phenylpyruvate).
♣ Tyrosinemias are defects in the mutli-step tyrosine degradation categorized as types I, II, and III that refer to the particular dysfunctional enzyme involved.

61

SAM synthase uses what for energy?

ATP is used in Met --> SAM

62

what is cyclical about methionine degradation?

homocysteine can be made back into methionine, this can reproduce SAM
*the enzyme that does this is dependent on THF and vitamin B12
*methyl group is transferred B12 from THF
*thus you need both of these enzymes to remake methionine

63

What's the difference between SAH and SAM?

SAH is one methyl group less than SAM. this is produced by methyl transferases (the methyl group is put on some other carbon skeleton)

64

when you see PLP, you think...

vitamin B6! PLP is made from vitamin B6
*thus, B6 is important for cysteine synthesis from methionine (and methionine breakdown)

65

what enzyme can be super mutated and thus lead to hyperhomocysteinemia?

cystathionine-beta-synthase (CBS)
*intellectual disability, osteoporosis, vascular disease

66

an intermediate in the pathway of cysteine formation from methionine is important for what "carrier" function?

When you think cysteine, think sulfur amino acid.
*think disulfide bonds, Glutathione, protection from ROS
*also, think about methionine handling and SAM
*it is SAM that is the high energy intermediate used by cells to carry a methyl group that is easily extractable
*thus, SAM is a carbon carrier molecule

67

what is vitamin B9?

B9 = folic acid
*THF is produced from B9
*THF is another carbon carrier for cells, (SAM is the other)

68

Glutamate, Glycine and Cysteine make what important molecule?

Glutathione. Important for ROS reduction (in particular neutralization of H2O2) and keeping proteins reduced
*the goal is solubilization of cysteine to maintain the reduction state of proteins
*chaperone molecule for protein folding process
*important for keeping Fe in the ferrous state
*Fe in the ferrous form (2+) is the only form that can bind oxygen

69

What does a problem in amino acid breakdown have to do with Parkinson's Disease?

Lecture topic, in the lecture slides but not in the lecture notes
*DOPA, problem in dopamine synthesis essentially. Since Parkinsons is a dopamine problem in the Substantia nigra, any problem in the production of dopamine might have parkinsons manifestations
*monoamine oxidase will deaminase these NT and lead to their inactivity (thus the treatment of parkinsons with MAOI)

70

PKU can be caused a problem in what?

could the phe hydroxylase enzyme OR the cofactor (BH4)

71

Tyrosine can be made into what glucogenic species?

fumarate and acetoacetate

72

BH4 should make you scream...?

Aromatic amino acid catabolism!
*phe, tyr, formation of NT
*manifestations are progressive neuronal degradation and buildup of phenylketones