Chapter 23- Protein turnover and AA catabolism Flashcards
Why must proteins be degraded?
To provide a steady supply of amino acids to the cell, dietary proteins are digested in the intestine and proteins are degraded in the cell. In response to changing metabolic demands, cellular proteins are constantly degraded and resynthesized. Additionally, misfolded, damaged, or unneeded proteins have to be degraded.
Ubiquitin
A protein that attaches to and marks unneeded or damaged proteins for destruction in the proteasome
Use of amino acids provided through degradation/digestion
They are used as building blocks for the synthesis of proteins and other nitrogenous compounds like nucleotide bases
What happens to excess amino acids?
They can’t be stored or excreted. They are used as metabolic fuel. The α-amino group is removed, and the resulting carbon skeleton is converted into a major metabolic intermediate. Then, the amino groups mostly go through the urea cycle
What happens to the carbon skeletons of amino acids?
The carbon skeleton is converted into a major metabolic intermediate. They can be transformed into acetyl CoA, acetoacetyl CoA, pyruvate, or one of the intermediates of the citric acid cycle. The carbon skeletons are then converted into glucose, glycogen, and fats
Pyridoxal phosphate
A coenzyme that forms Schiff-base intermediates- they allow alpha amino groups to be shuttled between amino acids and ketoacids.
What are essential amino acids?
Amino acids that can’t be synthesized and must be acquired in the diet
Essential amino acids in humans (9)
- Histidine
- Isoleucine
- Leucine
- Lysine
- Methionine
- Phenylalanine
- Threonine
- Tryptophan
- Valine
Fate of dietary proteins
Dietary proteins are degraded to amino acids, which are
absorbed and distributed throughout the body via the
blood.
Where does protein digestion begin?
In the stomach- the acidic environment denatures proteins into random coils. Denatured proteins are more accessible as substrates for proteolysis than folded proteins.. They are degraded by pepsin
Pepsin
The main proteolytic enzyme of the stomach. It is a nonspecific protease that is maximally active at a pH of 2, so it can function in the acidic environment of the stomach
Protein digestion in the small intestine
Partly digested proteins move from the stomach to the small intestine. The low pH of the food, as well as the polypeptide products of pepsin digestion stimulate the release of hormones that promote the secretion from the pancreas of sodium bicarbonate (NaHCO3) and a variety of pancreatic proteolytic enzymes. The enzymes have a wide range of specificity, so the substrates are degraded into free amino acids as well as di- and tripeptides. Digestion is also enhanced by proteolytic enzymes like aminopeptidase N
Function of sodium bicarbonate (NaHCO3)
It neutralizes the pH of the food during protein digestion in the small intestine
Aminopeptidase A
A proteolytic enzyme located in the plasma membrane of the intestinal cells. Aminopeptidases digest proteins from the amino-terminal end.
How do amino acids enter the intestinal cells?
Through transporters- there are 7 different transporters, and each one is specific to a different group of amino acids. Single amino acids, as well as di and tripeptides, are transported into the intestinal cells. Then, the transporters release free amino acids into the blood for use by other tissues
Ubiquitin
A small protein present in in all eukaryotic cells. It is a tag that marks proteins for destruction, acting as a signal for death
How does ubiquitin tag a protein for destruction?
The carboxyl-terminal glycine residue of ubiquitin becomes covalently attached to ɛ-amino groups (NH3 at the end of the molecule) of several lysine residues on a protein that needs to be degraded. ATP hydrolysis provides the energy for the formation of these isopeptide bonds
3 enzymes that participate in the attachment of ubiquitin to a protein
- E1- ubiquitin- activating enzyme
- E2- ubiquitin conjugating enzyme
- E3- ubiquitin protein ligase
Ubiquitin- activating enzyme (E1)
The C-terminal carboxylate group of ubiquitin becomes linked to a sulfhydryl group of E1 by a thioester bond. This is an ATP driven reaction- an acyl adenylate is formed at the C terminal carboxylate of ubiquitin with the release of pyrophosphate, and ubiquitin is therefore transferred to a sulfhydryl group of a key cysteine residue in E1. The ubiquitin is then considered activated
Ubiquitin conjugating enzyme (E2)
Activated ubiquitin is shuttled from the cysteine residue of E1 to the sulfhydryl group (cysteine residue) of E2- this reaction is catalyzed by E2 itself
Ubiquitin protein ligase (E3)
E3 catalyzes the transfer of ubiquitin from E2 to an ɛ-amino group on the target protein. It uses the E2-Ub complex as a substrate. During the ubiquitination reaction, E3 remains bound to the target proteins and generates a chain of ubiquitin molecules by linking the ɛ-amino group of lysine residue 48 of one ubiquitin molecule to the terminal carboxylate of another ubiquitin molecule. A chain of 4 ubiquitin molecules effectively signals the need for a protein’s degradation, and Ub is transferred to a lysine residue on the target protein. E3 enzymes are the readers of N-terminal residues. E3 is one of the largest gene families, as there is a diverse range of target proteins to be tagged for destruction and many E3 proteins are required as readers
Amino acid structure
An alpha amino acid contains a central carbon atom (an alpha carbon), which is bound to an amino group (NH2), a carboxylic acid (COOH), a hydrogen atom, and a distinct R group
Polyubiquitin
An especially
effective destruction signal- like 4 ubiquitin in a chain
Degron
A specific sequence of amino acids that indicates a protein should be degraded, and therefore that it should be tagged with ubiquitin.
Examples of degrons
For many cytoplasmic proteins, the N-terminal amino acid is an
important degradation signal. For example, a protein with a methionine at its N terminus may have a longer half life that one with arginine. A destabilizing residue like arginine or leucine favors rapid ubiquitination, but stabilizing residues like methionine or proline don’t. In some cases, the destabilizing amino acid is added to the protein after the protein is synthesized. Other degrons include cyclin destruction boxes and PEST sequences (the amino acid sequence proline, glutamic acid, serine, and threonine)
Pro-N-terminal degrons
N-terminal degrons that are only exposed after the protein is proteolytically cleaved. The protein must be cleaved to expose the signal.
Importance of E3 proteins to normal cell function
Proteins that are not broken down due to a defective E3 may accumulate to create a disease of protein aggregation such as juvenile or early onset Parkinson disease, cervical carcinomas, or Angelman syndrome
Angelman syndrome
A neurological disorder characterized by an unusually happy disposition, cognitive disability, absence of speech, uncoordinated movement, and hyperactivity. This is due to a defect in a member of the E3 family. If the same ligase is overexpressed, it can cause autism
How does inappropriate protein turnover lead to cancer?
Human papillomavirus encodes a protein that activates a specific E3 enzyme. The enzyme ubiquitinates the tumor suppressor p53 and other proteins that control DNA repair, which are then destroyed. The activation of this E3 enzyme is observed in more than 90% of cervical carcinomas
Proteasome
A large protease complex that digests ubiquitinated proteins. It is a complex of 2 components- a 20S catalytic unit and a 19S regulatory unit. The regulatory subunit binds to polyubiquitin, cleaves off intact ubiquitin (so it can be reused), unfolds the condemned protein, and inserts it into the catalytic subunit.
3 functions of the 19S regulatory unit of the proteasome
- Components of the 19S unit are ubiquitin receptors that bind specifically to polyubiquitin chains, ensuring that only ubiquitinated proteins are degraded
- An isopeptidase cleaves off intact ubiquitin molecules from the proteins that they can be reused
- The ubiquitinated protein is unfolded and inserted directly into the catalytic core of the proteasome
20S proteasome
A component of the proteasome. It is made up of 28 homologous subunits (including α and β type subunits). The subunits are arranged in 4 rings of 7 subunits each. Some of the β type subunits include protease active sites at their amino termini.
26S proteasome
Two 19S complexes bind to the 20S proteasome core, one at each end, to form the complete 26S proteasome
Generation of free amino acids
Ubiquitinated proteins are processed to peptide fragments. Ubiquitin is removed and recycled prior to protein degradation. The peptide fragments are further digested to yield free amino acids, which can be used for biosynthetic reactions, mostly protein synthesis. Alternatively, the amino group can be removed and processed to urea, and the carbon skeleton can be used to synthesize carbohydrate or fats, or used directly as fuel for cellular respiration
Bortezomib (Velcade)
A proteasome inhibitor used as a therapy for multiple myeloma
HT1171
A suicide inhibitor of the proteasome of M. tuberculosis and shows promise as a treatment for tuberculosis. It does not affect the proteasomes of the human host and therefore may not require the prolonged treatment that is required with conventional drugs. This reduces the risk of drug resistance due to the interruption of the treatment protocol
Processes regulated by protein degradation (8)
- Gene transcription
- Cell-cycle progression
- Organ formation
- Circadian rhythms
- Inflammatory response
- Tumor suppression
- Cholesterol metabolism
- Antigen processing
Ureotelic organisms
Organisms, like terrestrial vertebrates, where excess NH4 (ammonium) is converted into urea and then excreted. In terrestrial vertebrates, urea is synthesized by the urea cycle
Urea cycle
During this cycle, excess NH4 (ammonium) is converted into urea (CO(NH2)2) and then excreted. In humans, the urea cycle occurs in the liver.
Where are the 2 nitrogen atoms of urea derived from during the urea cycle?
One of the nitrogen atoms is transferred from an amino acid (aspartate). The other nitrogen atom is derived directly from free NH4
Where does urea’s carbon come from in the urea cycle?
The carbon atom comes from HCO3 (bicarbonate). The bicarbonate is derived by the hydration of carbon dioxide
Carbamoyl phosphate synthetase 1
Catalyzes the reaction where free NH3 (ammonia) and HCO3 (bicarbonate) react to form carbamoyl phosphate. This reaction is essentially irreversible due to the consumption of two molecules of ATP. The reaction occurs in the mitochondria
Synthesis of carbamoyl phosphate (3 steps)
- HCO3 is phosphorylated to form carboxyphosphate
- Carboxyphosphate reacts with NH3 to form carbamic acid
- A second molecule of ATP phosphorylates carbamic acid to form carbamoyl phosphate
N-acetylglutamate (NAG)
Required for carbamoyl phosphate synthetase activity
N-acetylglutamate synthase
Synthesizes N-acetylglutamate (NAG). This enzyme is activated by arginine. Therefore, NAG is only synthesized when amino acids (arginine, glutamate) are readily available, and carbamoyl phosphate synthetase is then activated to process the generated ammonia
How is carbamoyl phosphate synthetase inhibited?
N-acetylglutamate synthase is activated by arginine. Therefore, NAG is only synthesized when amino acids (arginine, glutamate) are readily available, and carbamoyl phosphate synthetase is then activated to process the generated ammonia. When ammonia is not being generated, the synthetase is inhibited by acetylation.
How is carbamoyl phosphate synthetase activated?
An energy poor state is indicated by a rise in mitochondrial NAD+. This stimulates a deacetylase that removes the acetyl group, activating the synthetase and preparing the enzyme to process ammonia from protein degradation.
Ornithine transcarbamoylase
Carbamoyl phosphate’s carbamoyl group is transferred to ornithine to form citrulline. The synthesis of citrulline takes place in the mitochondrial matrix. Citrulline is transported out of the mitochondria into the
cytoplasm in exchange for ornithine.
Ornithine and citrulline
Amino acids that are not used as building blocks of proteins
Argininosuccinate synthetase
Catalyzes the reaction where Citrulline is transported to the cytoplasm, where it condenses with aspartate. Aspartate is the donor of the second amino group of urea. This reaction synthesizes argininosuccinate. It is driven by the cleavage of ATP into AMP and pyrophosphate, and by the subsequent hydrolysis of the pyrophosphate
Argininosuccinase (lyase)
Cleaves argininosuccinate into arginine and fumarate. Therefore, the carbon skeleton of aspartate is preserved in the form of fumarate.
Arginase
Hydrolyzes arginine to generate urea and ornithine. Then, ornithine is transported back into the mitochondria to begin another cycle. The urea is excreted.
How many ATP are used to synthesize one molecule of urea?
4 ATP. Pyrophosphate is rapidly hydrolyzed, so the equivalent of 4 ATP are consumed in these urea cycle reactions to synthesize one molecule of urea.
Fumarate
Fumarate is synthesized by the urea cycle. This is important because it is a precursor for glucose synthesis. Fumarate is hydrolyzed to malate, which is then oxidized to oxaloacetate. Oxaloacetate can be converted into glucose by gluconeogenesis or transaminated to aspartate, linking the urea cycle to gluconeogenesis
Isozymes of carbamoyl phosphate synthetase (2)
Carbamoyl phosphate synthetase 1 and 2
Carbamoyl phosphate synthetase 2
Catalyzes the first step in pyrimidine biosynthesis, and is different from synthetase 1 in 2 ways. CPS 2 uses glutamine as a nitrogen source instead of NH3 (ammonia). In this enzyme, NH3 is supplied by the hydrolysis of glutamine. Also, this enzyme is part of a large complex that catalyzes several steps in pyrimidine biosynthesis. The glutamine binding site in CPS I has evolved into an allosteric site for binding N-acetylglutamate.
Which enzymes are urea cycle enzymes evolutionarily related to? (2)
- Carbamoyl phosphate synthetase 2
- Ornithine transcarbamoylase is homologous to
aspartate transcarbamoylase, which catalyzes the first (and the committed) step in pyrimidine biosynthesis, and the structures of their catalytic subunits are quite similar
How is the pyrimidine biosynthetic pathway adapted for urea synthesis?
CPS 1 and CPS 2 are homologous, as is ornithine transcarbamoylase and aspartate transcarbamoylase. This shows that two consecutive steps in the pyrimidine
biosynthetic pathway were adapted for urea synthesis.
How is the purine biosynthetic pathway linked to the urea cycle?
The steps in the urea cycle that catalyze addition of aspartate
and removal of fumarate are also observed in purine
nucleotide synthesis. In all, four of the five enzymes in the urea cycle were adapted from enzymes taking part in nucleotide biosynthesis.
Homologous enzymes
The structure of the catalytic subunit of ornithine transcarbamoylase is quite similar to that of the catalytic subunit of aspartate transcarbamoylase, indicating that these 2 enzymes are homologs
Why are urea cycle disorders so dangerous?
The synthesis of urea in the liver is the major route for the removal of ammonium (NH4). A blockage of any of the 4 steps of the urea cycle has devastating consequences because there is no alternative pathway for the synthesis of urea. All defects in the urea cycle lead to an elevated level of NH4 in the blood (hyperammonemia)
Symptoms of urea cycle disorders
Within a day or two of birth, an affected infant may become lethargic and vomit. Hepatic encephalopathy may occur and result in coma and irreversible brain damage can result
Why are high levels of NH4 toxic?
NH4 may inappropriately activate a sodium-potassium-chloride-cotransporter. This activation disrupts the osmotic balance of the nerve cell, causing swelling that damages the cell and results in neurological disorders
Argininosuccinate deficiency
Treated by supplementing
the diet with arginine. Excess nitrogen is excreted in the
form of argininosuccinate- in the liver, arginine is split into urea and ornithine, which then reacts with carbamoyl phosphate to form citrulline. Citrulline is a urea cycle intermediate, and it condenses with aspartate to yield the argininosuccinate, which will then be excreted. Basically, argininosuccinate substitutes for urea in carrying nitrogen out of the body
Carbamoyl phosphate synthetase deficiency/ornithine transcarbamoylase deficiency
Lead to the accumulation of nitrogen in glycine and glutamine. In this case, citrulline and argininosuccinate cannot be used to dispose of nitrogen atoms because their formation is
impaired. The body needs to get rid of the nitrogen accumulating in these 2 amino acids. Addition of benzoate to the diet leads to the excretion of glycine-nitrogen as hippurate, while the addition of phenylacetate results in the excretion of phenylacetylglutamine. These conjugates substitute for urea in the disposal of nitrogen. Therefore, latent biochemical pathways can be activated to partly bypass a genetic defect
Ketogenic amino acids
Amino acids that are degraded to acetyl CoA or acetoacetyl CoA. They can give rise to ketone bodies or fatty acids once they are degraded and their carbon skeletons are transformed to metabolic intermediates
Glucogenic amino acids
Amino acids that are degraded to pyruvate, α ketoglutarate, succinyl CoA, fumarate, or oxaloacetate. From there, they can be used to synthesize glucose. Oxaloacetate can be generated from citric acid cycle intermediates like pyruvate, and can then be converted into phosphoenolpyruvate and then into glucose.
Which amino acids are solely ketogenic? (2)
Leucine and lysine
What is the entry point of 3 carbon amino acids into the metabolic mainstream?
Pyruvate is the entry point of alanine, serine, and cysteine into the metabolic mainstream. Pyruvate is also the point of entry for tryptophan (Tryp is converted to alanine)
Transamination
the transfer of an amino group from one molecule to another, especially from an amino acid to a keto acid.
Pyruvate formation from alanine
The transamination of alanine directly yields pyruvate. This reaction uses alanine and α-ketoglutarate to yield pyruvate and glutamate. Glutamate is then oxidatively deaminated, yielding NH4+ and regenerating α-ketoglutarate
Serine dehydratase
Deamination of serine to pyruvate
Alanine aminotransferase
Converts alanine into pyruvate
Oxaloacetate is the entry point into metabolism for which amino acids?
Aspartate and asparagine
Conversion of aspartate into oxaloacetate
Aspartate is a 4 carbon amino acid that is directly transaminated to oxaloacetate. This reaction uses aspartate and α-ketoglutarate to produce oxaloacetate and glutamate
Asparaginase
Hydrolyzes asparagine to NH4 and aspartate, which is then transaminated to oxaloacetate
Entry point to the citric acid cycle for 5 carbon amino acids
The carbon skeletons of several 5 carbon amino acids enter the citric acid cycle at α-ketoglutarate. These amino acids are converted into glutamate, which is then oxidatively deaminated by glutamate dehydrogenase to yield α- ketoglutarate
Glutamate dehydrogenase
Oxidatively deaminates glutamate to convert it to α-ketoglutarate, so it can enter the citric acid cycle
How does histidine enter into metabolism?
Histidine is converted into 4-imidazolone 5-propionate. The amide bond in the ring of this intermediate is hydrolyzed to the N-formimino derivative of glutamate, which is then converted into glutamate when its formimino group is transferred to tetrahydrofolate. The reaction sequence requires the coenzyme tetrahydrofolate, which is a carrier of activated one carbon units
How does glutamate enter metabolism?
Glutamine is hydrolyzed to glutamate and NH4 by glutaminase. Proline and arginine are each converted into glutamate γ-semialdehyde,
which is then oxidized to glutamate
How do proline and arginine enter metabolism?
Proline and arginine are each converted into glutamate γ-semialdehyde, which is then oxidized to glutamate
Glutaminase
Hydrolyzes glutamine to glutamate and NH4
Succinyl coenzyme A is a point of entry for which amino acids?
It is a point of entry for some of the carbon atoms of methionine, isoleucine, threonine, and valine.
Succinyl CoA formation
Propionyl CoA and then methylmalonyl CoA are intermediates in the breakdown of isoleucine, threonine, and valine. Methionine is converted to succinyl CoA in a separate reaction. The reaction is dependent on vitamin B12. This pathway from propionyl CoA to succinyl CoA is also used in the oxidation of fatty acids that have an odd number of carbon atoms
Conversion of methionine into succinyl CoA (7 steps)
- Methionine is adenylated to form S-adenosylmethionine (SAM), which is a common methyl donor in the cell
- SAM loses a methyl and group to form 5- adenosylhomocysteine
- Homocysteine is formed due to the loss of an adenosyl group
- Cystathionine is formed
- α-ketobutyrate is formed
- α-ketobutyrate is oxidatively decarboxylated to form propionyl CoA
- Propionyl CoA is processed to form succinyl CoA
α-ketoacid dehydrogenase complex
Oxidatively decarboxylates α-ketobutyrate to form propionyl CoA
Threonine deaminase (threonine dehydratase)
A pyridoxal-dependent enzyme that converts threonine into α-ketobutyrate. α-ketobutyrate then forms propionyl CoA, which is metabolized to succinyl CoA
How is leucine degraded?
Leucine is transaminated to the corresponding α-ketoacid, ketoisocaproate. Ketoisocaproate is oxidatively decarboxylated to isovaleryl CoA by the branched chain α-ketoacid dehydrogenase complex
What is required to degrade aromatic amino acids?
Molecular oxygen is used to break the aromatic ring of aromatic amino acids. Oxygenases are required for the degradation of these amino acids
Monooxygenases
Use O2 as a substrate and incorporate one oxygen atom into the product and one into water
Phenylalanine hydroxylase
A monooxygenase that converts phenylalanine into tyrosine with the assistance of the cofactor tetrahydrobiopterin
Dihydropteridine reductase
Regenerates tetrahydrobiopterin, which is the reductant for the phenylalanine hydroxylase catalyzed reaction. When phenylalanine is hydroxylated to make dihydrobiopterin, is is reduced back to tetrahydrobiopterin by NADPH in a reactional catalyzed by dihydropteridine reductase
Tetrahydrobiopterin
An electron carrier that is derived from the cofactor biopterin. Biopterin is synthesized by the body and therefore is not considered a vitamin. Tetrahydrobiopterin acts as a reducing compound (takes on electrons) in the phenylalanine hydroxylase catalyzed reaction
Metabolism of tyrosine and phenylalanine
Tyrosine and phenylalanine are metabolized to fumarate and acetoacetate
Tryptophan degradation
Tryptophan degradation requires both monooxygenases
and dioxygenases to metabolize the amino acid to
acetoacetate
Dioxygenases
Incorporate both atoms of O2 into the product, are used to cleave aromatic rings. p-hydroxyphenylpyruvate
hydroxylase is one example- it catalyzes the reaction in the degradation of phenylalanine and tyrosine where p-hydroxyphenylpyruvate reacts with O2 to form homogentisate.
Homogentisate oxidase
Another dioxygenase- catalyzes the reaction where the aromatic ring of homogentisate is cleaved by O2 to yield s 4-maleylacetoacetate
Alcaptonuria
A disease that results from the absence of homogentisate oxidase, an enzyme in the tryptophan degradation pathway. Homogentisate is a normal intermediate in the degradation of phenylalanine and tyrosine, but in this disease its degradation is blocked. Homogentisate accumulates and, upon excretion, turns the urine dark, as the homogentisate is oxidized. However, alcaptonuria is a relatively harmless condition
Maple syrup urine disease
Results when the oxidative
decarboxylation of α-ketoacids derived from branched-
chain amino acids (valine, isoleucine, and leucine) is blocked due to lack of activity of the branched chain dehydrogenase complex. Therefore, the levels of the α-ketoacids and the branched chain amino acids that give rise to them are markedly elevated in the blood and urine
Symptoms of maple syrup urine disease
Patients’ urine smells like maple syrup, hence the name of the disease. The disease also leads to cognitive and physical disabilities unless the patient is placed on a diet low in valine, isoleucine, and leucine early in life.
How can maple syrup urine disease be screened for in newborns?
The disease can be detected by screening newborn urine
with 2,4-dinitrophenylhydrazine, which reacts with α-
ketoacids to form 2,4-dinitrophenylhydrazone derivatives. A definite diagnosis can be made through mass spectrometry
Citrullinemia
Due to a deficiency in arginosuccinate lyase. Symptoms- lethargy, seizures, reduced muscle tension
Tyrosinemia
Patients have a deficiency in various enzymes of tyrosine degradation. Symptoms- weakness, liver damage, cognitive disability
Albinism
Patients have a deficiency in tyrosinase. Symptoms- absence of pigmentation
Homocystinuria
Patients have a deficiency in cystathionine beta-synthase. Symptoms- scoliosis, muscle weakness, cognitive disability, thin blond hair
Hyperlysinemia
Patients have a deficiency in alpha-aminoadipic semialdehyde dehydrogenase. Symptoms- seizures, cognitive disability, lack of muscle tone, ataxia
Phenylketonuria (PKU)
Results if phenylalanine hydroxylase activity is missing or deficient. Excess phenylalanine accumulates in all body fluids because it can’t be converted into tyrosine. Phenylalanine is mostly converted into phenylpyruvate, which occurs much less commonly in healthy people.
PKU symptoms
Untreated phenylketonurics show severely impaired mental ability. They have low brain weight, defective myelination of nerves, and hyperactive reflexes. They also have a drastically shortened lifespan. Phenylketonurics appear normal at birth but are severely defective by age 1 if untreated.
PKU treatment
The therapy for phenylketonuria is a low-phenylalanine diet supplemented with tyrosine, because tyrosine is normally synthesized from phenylalanine. The aim is to provide just enough phenylalanine to meet the needs for growth and replacement. A low-phenylalanine diet must be started very soon after birth to prevent irreversible brain damage
How is PKU diagnosed?
Early diagnosis has been accomplished by mass screening programs of all babies born in the US and Canada. The blood phenylalanine level is measured
What is the basis of the neurological symptoms of PKU?
The bases for the clinical features of phenylketonuria are
still obscure. Possibilities include a lack of tyrosine, a precursor for certain neurotransmitters (like dopamine). Moreover, the high concentration of phenylalanine in the blood may inhibit transport of any tyrosine present, as well as tryptophan (precursor of serotonin), into the brain. It is also believed that high brain phenylalanine
concentration inhibits glycolysis at pyruvate kinase, disrupts myelination of nerve fibers, and disrupts synthesis of several neurotransmitters.
Ub isopeptide bond
A bond that forms between the nitrogen of a lysine side chain (on the target protein) and the carbonyl group of ubiquitin
Peptide bond
The alpha carboxyl group of one amino acid is linked to the alpha amino group of another amino acid through hydrolysis. The amino group loses 2 hydrogens and the carboxyl group loses one oxygen. These bonds are kinetically stable because the rate of hydrolysis is very slow
