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_____________ is one of the most common metabolic disorders. It results in severely impaired mental ability.
Phenylketonuria
Phenylketonuria is caused by absent or deficient ___________ __________ activity, which causes excess phenylalanine to be converted into phenylpyruvate.
Phenylalanine Hydroxylase
Proteins tagged with __________, a small (76 aa), highly conserved protein, are targeted for destruction.
Ubiquitin
Degradation of Cellular Proteins:
1. Removal of __________ from amino acids
2. Conversion of ammonia to ______
3. Generation of _______ atoms as major metabolic intermediates.
Ammonia, Urea, Carbon
Degradation of Ingested Proteins:
1. Ingested proteins are denatured in acidic environments and cleaved by ________ at pH 2
2. Beginning in the small intestine, secretion of NAHCO3 and pancreatic _________ enzymes degrade substates into free amino acids, dipeptides, and tripeptides.
3. Amino acids are transported into the intestinal cells and released into the blood by _____ amino acid antiporters.
Pepsin, Proteolytic, Na+
Multiple copies of ubiquitin, known as __________, are attached to proteins by an isopeptide bond and are effective destruction signals
Polyubiquitin
_________ residues, including ___________ _____, are the major site for linking addition ubiquitin molecules
Lysine, Lysine 48
Ubiquitin has an extended _____________ terminus, which is activated and linked to proteins targeted for destruction.
The carboxyl-terminal ___________ residue of ubiquitin becomes covalently attached to the ε-amino groups of several ___________ residues on a protein destined to be degrade
Carboxyl, Glycine, Lysine
Mechanisms of Ubiquitin Conjugation:
1. Ubiquitin ___________ enzyme (_____) adenylate Ub and transfers it to a cysteine residue on E1.
2. Ubiquitin ________ enzyme (_____) then transfers Ub to one of its cysteine residues
3. Ubiquitin-________ _______ (_____) uses the E2-Ub complex as a substrate, transferring the Ub to the target protein.
Activating, E1, Conjugating, E2, Protein Ligase, E3
__________ are the specific amino acid sequences that determine the half-life of proteins.
Degrons
The ____-__________ ______ is that the N-terminal amino acid is an important degradation signal in a protein.
N Terminal rule
N-terminal _________ or ________ residues favor rapid ubiquitination, whereas methionine or proline does not
Arginine, Leucine
Aside from certain amino acid residues, degrons include _______ _______ ________ and ___________ sequences
Cyclin destruction Boxes, PEST
The __________ is the organelle responsible for the degradation of ubiquitinated proteins. It consists of two components:
1. The ________ regulatory subunit
2. The _______ catalytic subunit
Proteasome, 19S, 20S
The _______ subunit of the proteasome is made up of 19 smaller subunits. It can recognize ubiquitin, and its receptors bind to _____________ chains
19S, Polyubiquitin
Three Functions of 19S Regulatory Subunit:
1. Its receptors bind to __________ chains
2. An __________ cleaves intact ubiquitin from the target protein for reuse.
3. The doomed protein is unfolded and directed into the catalytic core, ______ subunit.
Polyubiquitin, Isopeptidase, 20S
The 19S complex has six AAA class __________. ATP hydrolysis assists the 19S complex in unfolding the substrate and inducing conformational changes.
ATPases
The proteasome's _______ catalytic subunit is composed of 28 smaller subunits arranged into 4 ____________ rings forming a sealed barrel.
The peptide fragments are further digested to yield free amino acids, which will be used for _____________. Or, the amino group can be removed and processed to _________.
20S, Heteroheptameric Biosynthesis, Urea
The amino acids produced by the proteasome and proteolysis have multiple possible fates:
1. They can be left intact for __________
2. Their _______ ________ can be used for nitrogen disposal by the urea cycle
3. Their ______ _______ can be used in metabolism.
Biosynthesis, Amino Groups, Carbon Skeletons
The major site of amino acid degradation in mammals is the _________
Liver
The first step of amino acid degradation is the removal of ___________.
Amino groups from many amino acids are transferred to ___-___________ to form glutamate, which is then deaminated to form ________
Removal of Nitrogen, a ketoglutarate, NH4+
_______________ (____________) transfer amino groups from an amino acid to α-ketoglutarate to generate glutamate
Aminotransferases, transaminases
Aminotransferases (transaminases) transfer amino groups from an amino acid to α-ketoglutarate to generate ___________
Glutamate
In terrestrial vertebrates (ureotelic organisms), the ultimate fate of the NH4+ is the formation of __________.
Urea
____________ _________ is an enzyme that releases NH4+ by oxidative deamination using NAD+/NADH or NAP+/NADPH.
Glutamate Dehydrogenase
___________ by the help of liver-specific mitochondrial enzymes helps to sequester toxic NH4+
Compartmentalization
________ and ________ are two residues that have dehydratase enzymes that directly deaminate their their respective amino acids.
Serine, Threonine
__________ precedes deamination
Dehydration
Some of the NH4+ formed in the breakdown of amino acids is consumed in the ______________ of nitrogen compounds.
Excess NH4+ is converted into _______ in the liver.
Biosynthesis, Urea
In the formation of urea, one of the nitrogen atoms comes from ___________, while the other nitrogen atom comes from free ________ .
The carbon atom comes from ________ (derived by the hydration of CO2).
Aspartate, NH4+, HCO3-
Urea Cycle:
1. ___________, produced from the breakdown of amino acids, enters the cycle.
2. Ammonia combines with carbon dioxide (CO₂) and ATP to form __________ _________
3. The previous product combines with ornithine to produce ___________, which moves out of the mitochondria.
4. The previous product combines with aspartate to form _______________.
5. The previous product splits into arginine and fumarate. Arginine is then converted to _______ (excreted) and __________ (recycled).
Ammonia, Carbamoyl Phosphate, Citrulline, Argininosuccinate, Urea, Ornithine
Muscle uses branched-chain amino acids as fuel. The first step is NH4+ generation, but the muscle lacks the enzymes of the urea cycle. The nitrogen from these amino acids is transported to the liver by either __________ or _________
Glutamine, Alanine
The urea cycle is linked to ___________ via fumarate
Gluconeogenesis
_____________ can be converted into oxaloacetate by the citric acid cycle and then into glucose by the gluconeogenic pathway.
Fumarate
Fumarate can be converted into ______________ by the citric acid cycle and then into glucose by the gluconeogenic pathway
Oxaloacetate
____________ and ________ are amino acids, but they are not used as building blocks of proteins.
Ornithine, Citruline
(BIG QUESTION) The urea cycle, gluconeogenesis, and the transamination of oxaloacetate are linked by ___________ and _________
Fumarate, Aspartate
The carbon atoms of degraded amino acids emerge as major _____________ ____________.
Metabolic Intermediates
The carbon skeletons of the amino acids are metabolized to ___ major metabolic intermediates
7
Amino acids metabolized to acetyl CoA and acetoacetyl CoA are called ____________ amino acids because they can form fats but not glucose.
Amino acids degraded to the remaining major intermediates are called __________ amino acids because they can be used to synthesize glucose.
Ketogenic, Glucogenic
____-_____________ is an entry point into metabolism for five-carbon amino acids
___________ is an entry point into metabolism for three-carbon amino acids
a ketoglutarate, Pyruvate
Pyruvate is an entry point into metabolism for many (3-carbon) amino acids
Alanine is converted into pyruvate by the action of _________ _______________
___________ is subsequently oxidatively deaminated.
Serine is easily converted into pyruvate by the action of __________ ___________
Other amino acids require more complicated pathways to form pyruvate.
Alanine Aminotransferase, Glutamate, Serine Dehydratase
_______________ is an entry point into metabolism for aspartate and asparagine
Oxaloacetate
Oxaloactate is an entry point into metabolism for ___________ and __________.
Aspartate, Asparagine
Asparagine is hydrolyzed by ____________ to NH4+ and aspartate, which is converted into _____________.
Asparaginase, Oxaloacetate
a-ketoglutarate is an entry point into metabolism for five-carbon amino acids
Step 1: The 5-carbon amino acids are first converted into ____________.
Step 2: This product is deaminated to form ___-_____________.
Glutamate, a ketoglutarate
_____________ is converted into α-ketoglutarate in a reaction sequence that requires the coenzyme tetrahydrofolate.
Glutamine is hydrolyzed by glutaminase to form ____________.
Proline and arginine are converted into glutamate γ-semialdehyde and then to __________
Histidine, Glutamate, Glutamate
Four amino acids are converted into glutamate and eventually a-ketoglutarate:
1. ____________
2. __________
3. __________
4. __________
Glutamine, Proline, Arginine, Histidine
_____________ ________ is a point of entry for several nonpolar amino acids.
Succinyl CoA
_________, ________, and ________ are all amino acids that are ultimately converted to Succinyl CoA in a vitamin B12 dependent reaction
Methionine, Leucine, Valine
The degradation of aromatic amino acids requires _____________.
Oxygenases
The degradation of the aromatic amino acids yields the common intermediates _______________, __________, and __________.
Acetoacetate, Fumarate, Pyruvate
The aromatic amino acids require ________________ for degradation.
monooxygenases
Monooxygenases use ______ as a substrate and incorporate one ___ atom into the product and one into the water
O2, O
Degradation of ________________ begins with hydroxylation to tyrosine. The monooxygenase (phenylalanine hydroxylase) requires the cofactor tetrahydrobiopterin
Phenylalanine
____________ is metabolized to fumarate and acetoacetate.
Tyrosine
____________ degradation requires both monooxygenase and dioxygenase enzymes to metabolize the amino acid to acetoacetate
Tryptophan
_________________ incorporates both atoms of O2 into the product, are used to cleave aromatic rings. Helps with tryptophan cleavage
Dioxygenases
Dioxygenases incorporate both atoms of O2 into the product and are used to cleave __________ ________
aromatic rings
Inherited defects of the urea cycle cause _______________ due to elevated NH4+ in the blood and can lead to brain damage
Hyperammonemia
___________________ deficiency is treated by supplementing the diet with arginine.
Argininosuccinate
Carbamoyl phosphate synthetase deficiency and ornithine transcarbamoylase deficiency lead to the accumulation of __________ in glycine and glutamine
Nitrogen
The addition of ____________ to the diet leads to the excretion of glycine-nitrogen as hippurate, whereas the addition of phenylacetate results in the excretion of phenylacetylglutamine.
Benzoate
______________ is a disease that results from the absence of homogentisate oxidase, an enzyme in the tryptophan degradation pathway.
Homogentisate accumulates and upon excretion, turns the urine dark
Alcaptonuria
In _________ _________ _________ disease, the oxidative decarboxylation of α-ketoacids derived from valine, isoleucine, and leucine is blocked because the branched-chain dehydrogenase is missing or defective. Leads to mental and physical retardation.
Maple Syrup Urine
In Phenylketonuria, _____________ hydroxylase activity is missing or deficient.
Therefore, no ___________ is produced.
Phenylalanine, Tyrosine
________________ is a chemical inhibitor of the proteasome that is used to treat multiple myeloma
Bortezomib
_____________, an inhibitor of the proteasome of M. tuberculosis, shows promise as a treatment for tuberculosis.
HT1171
_____________ (dietary and cellular) are degraded to amino acids.
Proteins
Protein turnover is tightly regulated by mechanisms such as ____________ (______)
Ubiquitination, E1
The first step in amino acid degradation is the removal of ___________.
Nitrogen
In the second step of amino acid degradation, ammonium is converted into _________ in most terrestrial vertebrates
Urea
In the third step of amino acid degradation, the degradation of amino acids generates carbon atoms that become ____________ __________
Metabolic intermediates
____________ errors of metabolism can disrupt amino acid degradation.
Inborn
What two amino acids are essential for blood transport?
Alanine (Ala) and Glutamine (Gln)
Carbamoyl phosphate synthetase deficiency and ornithine transcarbamoylase deficiency lead to the accumulation of nitrogen in _______ and ________
Glycine, Glutamine
___________ __________ _________ deficiency and ornithine transcarbamoylase deficiency lead to the accumulation of nitrogen in glycine and glutamine.
Carbamoyl Phosphate Synthase
The two types of subunits for the proteasome that digests the ubiquitin-tagged proteins are the _______ __________ subunit and the _____ _________ subunit.
19S, 20S
The 2 stages of Amino Acid Degradation:
1. ________________
2. Oxidative deamination of __________ to ammonia
Aminotransferases, Glutamate
In the conversion of ammonium to urea, one of the nitrogen atoms comes from _________ while the other comes from _________
Aspartate, NH4
___________ and _________ are the only purely ketogenic amino acids. All others are either glucogenic or both
Leucine, Lysine
Alcaptonuria is caused by the absence of ___________ ___________.
Homogentisate Oxidase
Maple syrup urine disease is caused by the decarboxylation of _________-___________.
Alpha Ketoacids