Protein Metabolism Flashcards
What are the three types of amino acids?
Essential, conditionally essential, and nonessential amino acids
How can certain nonessential amino acids become essential?
Under certain conditions and states
What is the daily protein requirement for high-quality protein?
0.8 g per kg ideal body weight
What is the term for the constant breakdown and synthesis of body proteins?
Turnover
What is the range of half-lives for proteins?
From 11 minutes to life-long
How are extracellular and membrane proteins catabolized?
Via endocytosis and fusion with lysosomes
What system degrades intracellular proteins?
Ubiquitin Proteasome System (UPS)
What is the primary waste product from excess nitrogen?
Urea
What are the daily unavoidable nitrogen losses?
Must be replaced by synthetic reactions using dietary amino acids
What is the first form of Protein-Energy Malnutrition (PEM)?
Kwashiorkor
What characterizes Kwashiorkor?
Protein deficiency with sufficient carbohydrates, edema
What is the second form of Protein-Energy Malnutrition (PEM)?
Marasmus
What characterizes Marasmus?
Deficiency in both calorie and protein, no edema
What is the mnemonic for essential amino acids?
PVT TIM HALL
What are the essential amino acids represented by the mnemonic?
- Phe
- Val
- Thr
- Trp
- Ile
- Met
- His
- Arg
- Leu
- Lys
What is the role of gastric parietal cells?
Secrete HCl to partially denature proteins
What activates pepsin in the stomach?
The acidic environment through self-cleavage
What activates trypsinogen in the small intestine?
Enteropeptidase
What is the primary transport mechanism for free amino acids into cells?
Na+-dependent transport
What condition is characterized by defective transport of large neutral amino acids?
Hartnup disease
What condition is characterized by defective transport of basic amino acids?
Cystinuria
What is the function of ubiquitin in protein degradation?
Targets proteins for degradation by the proteasome
What are the FDA-approved proteasome inhibitors for treating multiple myeloma?
- Velcade (Bortezomib)
- Kyprolis (Carfilzomib)
What is the acidic environment in lysosomes primarily maintained by?
Vacuolar H+ ATPase
What are the two types of autophagy?
- Micro-autophagy
- Macro-autophagy
What is the purpose of amino acid catabolism?
- Provide materials/presursors for synthesis
- Provide intermediates for TCA cycle
- Provide intermediates for glucose or lipid biosynthesis
What are glucogenic amino acids?
Amino acids that produce pyruvate or TCA intermediates
What are ketogenic amino acids?
Amino acids that produce ketone bodies
What are the main enzymatic reactions involved in amino acid catabolism?
- Aminotransferases
- Glutamate Dehydrogenase
What is the role of glutamine in the body?
Non-toxic plasma transporter for ammonium to the liver
What amino acids are related to α-ketoglutarate?
- Glutamine
- Glutamate
- Proline
- Arginine
- Histidine
What amino acids are related to oxaloacetate (OAA)?
- Aspartate
- Asparagine
What is FA oxidation?
Fatty acid oxidation process that breaks down fatty acids to generate energy
What does TCA cycle stand for?
Tricarboxylic Acid Cycle
Which amino acid is a non-toxic plasma transporter for ammonium to the liver?
Glutamine
Name two amino acids related to TCA cycle intermediates OAA.
- Aspartate
- Asparagine
List three amino acids related to TCA cycle intermediates fumarate.
- Phenylalanine
- Tyrosine
- Glutamate
What is the Krebs bi-cycle?
The common steps between the TCA cycle and urea cycle
Identify two amino acids that are related to the TCA cycle intermediate Succinyl-CoA.
- Methionine
- Threonine
Which important vitamin is involved in the synthesis of Methionine?
B12
Fill in the blank: The five cofactors involved in branched-chain α-keto acid dehydrogenase are TPP, riboflavin, lipoic acid, pantothenic acid, and _______.
niacin
What is the main substrate of branched-chain α-keto acid dehydrogenase?
Branched-chain α-keto acids
What is Maple Syrup Urine Disease (MSUD)?
A deficiency of the branched-chain α-keto acid dehydrogenase leading to abnormal metabolism of leucine, isoleucine, and valine
What is a treatment for MSUD?
Strict dietary control of BCAA and possible supplementation with thiamine
Which amino acids are exclusively ketogenic?
- Leucine
- Lysine
What condition is characterized by defective transport of large neutral amino acids like tryptophan?
Hartnup disease
What is Phenylketonuria (PKU)?
A genetic disorder caused by a deficiency in the enzyme that metabolizes phenylalanine
What unusual metabolites appear in the blood and urine of PKU patients?
- Phenylpyruvate
- Phenylacetate
- Phenyl lactate
What is the musty urine odor in PKU patients due to?
Unusual metabolites of phenylalanine
What is the incidence of classical PKU in newborns?
About 1 in 15,000 newborns
What dietary treatment is recommended for pregnant women with PKU?
Maintain low plasma levels of phenylalanine during gestation
What causes urine to darken in Alcaptonuria?
Oxidation and polymerization of homogentisate
Name two symptoms of Alcaptonuria.
- Homogentisic aciduria
- Arthritis
What is the clinical relevance of amino acid metabolism?
Understanding nitrogen balance, glucogenic and ketogenic amino acids, and related diseases
What is the treatment for cystinuria?
Dietary restriction of cysteine and methionine, increase fluid intake
What is the condition characterized by excessive phenylalanine levels in infants?
Phenylketonuria (PKU)
What is the main characteristic of lysosomal storage disorders?
Defects in lysosomal enzyme targeting or function
What is the purpose of the Urea Cycle?
To dispose of nitrogen and excrete ammonia.
Which substrates are involved in the Urea Cycle?
- NH4+
- HCO3-
- Ornithine
- Aspartate
What are the main reactions of the Urea Cycle?
Involves the conversion of ammonium to urea in the liver through specific enzymatic reactions.
What is the rate-limiting enzyme of the Urea Cycle?
Carbamoyl Phosphate Synthetase I (CPS-I)
How is the Urea Cycle regulated?
- Allosteric effectors
- Substrate availability
- Enzyme levels
What are the causes of hyperammonemia?
- Excess protein intake
- Fasting
- Trauma
- Liver disease or toxins
- Genetic defects in Urea Cycle enzymes
- Intestinal bacteria
True or False: High levels of ammonium are toxic to the CNS.
True
What role does glutamate play in amino acid metabolism?
It is formed from the transfer of amino groups and can release ammonia.
Fill in the blank: The Urea Cycle occurs primarily in the ______.
Liver
What is the major nitrogenous excretory product of amino acid degradation?
Urea
What is the significance of the Krebs bi-cycle in relation to the Urea Cycle?
It recycles fumarate back to aspartate, replenishing TCA cycle intermediates.
What is the effect of a high protein diet on the Urea Cycle?
It induces the synthesis of urea cycle enzymes.
How does the body transport ammonium to the liver?
Through glutamine and alanine as nitrogen carriers.
What happens to urea excretion during fasting?
It is high during the first few days due to muscle proteolysis.
What is the role of arginine in the Urea Cycle?
It stimulates the synthesis of N-Acetyl-Glutamate, activating CPS-I.
What are the three main enzymatic reactions converting NH4+ to organic forms?
- Glutamate Dehydrogenase (GDH)
- Glutamine Synthetase
- Carbamoyl phosphate synthetase I (CPS-I)
What are the symptoms of hyperammonemia?
- Tremors
- Slurred speech
- Blurry vision
- Somnolence
- Vomiting
- Coma
- Death
What is the main function of aminotransferases?
To transfer amino groups to α-ketoglutarate, forming glutamate.
What is the clinical significance of Blood Urea Nitrogen (BUN)?
High in kidney disease but generally low in liver failure.
What happens to glutamine levels during acquired hyperammonemia?
They are generally high in the blood due to urea cycle backup.
What is the first step in the Urea Cycle?
Formation of Carbamoyl Phosphate by CPS-I.
What is the role of Nitric Oxide Synthase (NOS) in relation to arginine?
It uses arginine to synthesize Nitric Oxide (NO).
What is a common defect in congenital hyperammonemia?
Defects in Carbamoyl Phosphate Synthetase I (CPS I) or Ornithine TransCarbamoylase (OTC).
What happens to muscle proteolysis as the brain adapts to ketone bodies during fasting?
The rate of muscle proteolysis and gluconeogenesis from muscle amino acids drops.
What is the result of Ornithine TransCarbamoylase deficiency?
Excessive orotic acid in the urine
Orotic acid is an intermediate of the pyrimidine biosynthetic pathway.
What symptoms do infants with urea cycle defects typically develop shortly after birth?
Lethargy, irritability, vomiting, and coma.
What happens to ornithine levels in Argininosuccinate lyase deficiency?
Ornithine quickly becomes depleted.
How can oral arginine help individuals with Argininosuccinate lyase deficiency?
It regenerates ornithine from arginine and stimulates the removal of carbamoyl phosphate.
What does the buildup of carbamoyl phosphate lead to in Ornithine transcarbamoylase deficiency?
Increased synthesis of orotic acid.
What is the main treatment strategy for hyperammonemia?
Low protein diet.
What is one consequence of prolonged fasting in patients with hyperammonemia?
Increased muscle proteolysis.
Which drugs are administered to dispose of excess glutamine and other amino acids in hyperammonemia?
Phenyl Butyrate, Phenyl Acetate, Benzoic Acid.
What is the role of phenyl acetate in treating hyperammonemia?
It is activated to a CoA derivative, attaches to glutamine, and is excreted.
What is the primary carrier of nitrogen atoms generated from amino acid catabolism?
Urea.
Where does urea synthesis occur?
In the liver.
Which amino acids carry nitrogen from peripheral tissues to the liver?
Alanine and Glutamine.
What does the urea cycle incorporate to form urea?
One nitrogen from free ammonia and another from aspartate.
What condition results from disorders of the urea cycle?
Hyperammonemia.
What clinical symptoms were observed in the 5-month-old female infant with a urea cycle defect?
Periodic bouts of vomiting, failure to gain weight, irritability, and lethargy.
What were the laboratory findings in the infant with urea cycle defect?
Increased plasma ammonia, increased glutamine, and low citrulline.
Why was orotate noted to be excreted in the urine of the infant?
Due to the deficiency in Ornithine transcarbamoylase.
What was the treatment provided to the infant upon hospital admission?
Intravenous phenylbutyrate and benzoate.
Why was the infant put on a low protein diet?
To avoid increased ammonia levels from protein metabolism.
What does the level of ornithine transcarbamoylase activity in the patient’s liver indicate?
About 10% of normal activity.
True or False: The further down the urea cycle the defective enzyme is located, the more toxic effect is observed in the patient.
False.
Fill in the blank: The urea cycle consists of ______ steps.
four
Which enzyme is responsible for the conversion of glutamate and Acetyl CoA to N-Acetyl Glutamate?
N-Acetyl Glutamate Synthase.
What is the pathogenesis of PKU
cells are not able to convert phenylalanine to tyrosine; Tyr becomes an essential amino acid for these pts.
What vit. deficiency can result from insufficient or impaired transportation of tryptophan
niacin Vit. B3
cytoplasmic membrane bound materials targeted for lysosomal degradation are transported into the lysosome via what cytosis mechanism
endocytosis
large particles like bacteria cytosed into the lysosome via
phagocytosis
pinocytosis into the lysosomal compartment is for what matter
fluid and small particles
UPS functional inadequacy has been implicated in which 2 neurodegenerative diseases
Huntington’s & Alzheimer’s
UPS functional inadequacy contributes to the oncogenesis of what protooncogenes
HMD2/MDM2 for p53
Aminotransferases require what Vit.
Vit. B6/PLP
ammonium is converted into what non-toxic metabolite
glutamine
alpha-ketoglutarate, a TCA intermediate, can be used to synthesisze what amino acids
Glutamine
glutamate
proline
arginine
histidine
what AAs rely on TCA intermediate oxaloacetate for synthesis
aspartate & Asparagine
what AA rely on TCA intermediate fumarate for synthesis
phenylalanine & tyrosine
what AAs rely on TCA intermediate succinyl-CoA for synthesis
methionine; threonine; isoleucine; valine
what important vit. are invovled in the Succinyl-CoA AA pathway
B12 & folate for Met. synthesis
B6
Biotin
Thiamine
what vit.s are required for activation of the branched-chain alpha-keto acid dehydrogenase
Thiamine (B1)
Riboflavin (B2)
Niacin (B3)
Pantothenic acid (B5)
List the branched AAs
Leu; Ile; val
what AAs are linked to intermediates of glycolysis
glycine; serine; cysteine; alanine
what AAs are both glucogenic & ketogenic
ALL OF THE AROMATICS: F, W, & Y
Isoleucine
Tyrosine is degraded into what TCA intermediate
fumarate
what are clinical manifestations of alcaptonuria
spinal arthritis; dark ochronotic pigmentation of cartilage and collagenous tissue
What affect does alcohol have on ammonium metabolism
decreases hepatic capacity to convert NH4 to urea
What AA is the amino group donor for the urea cycle
aspartate
what AA is the carbon donor for gluconeogenesis
most of them except lys & Leu
does the rate of urea production increase or decrease during fasting state
it decreases
what role do proteins play during the fasting state
their carbons are used for gluconeogenesis
what enzyme converts gluamate to ammonium
glutamate dehydrogenase
what AA carries ammonium from the muscle into the liver
alaline & glutamine
what is the rate-limiting step for the Urea cycle
formation of Carbamoyl phosphate by CPS-I
What Urea Cycle enzymes are invovled in the first 2 steps of Urea synthesis that take place in the mitochondria
CPS-I & OTCase
describe the process by which the Urea Cycle is initiated
Arginine allosterically stimulates synthesis of NAG which allosterically activates CPSI
Arginine is also used to produce what endothelial anti-inflammatory modulator
NO
BCAAs are great for muscle fuel during times of fasting; how are they used for hepatic gluconeogenesis
amino groups on BCAAs are transferred to pyruvate & alpha-ketoglutarate to form alanine & glutamine; these are released into the blood and travel to the liver for gluconeogenesis
where does the formation of CPS-I occur
in the mitochondria
Describe how aspartate is used to produce arginine
N combines w/ citrulline to form Arginine from its amino group and fumarate from its remaining carbons
what enzyme regenerates’ ornithine for another round of the urea cycle
Arginase
how can fumarate be recycled back into the urea cycle
Fumarate conversion to aspartate via oxaloacetate
describe the mitochondria-cytosol transport system for the urea cycle
In the cytosol, arginine gets converted back to ornithine by arginase; ornithine gets transported back into the mitochondria where it gets converted to citrulline; citrulline then shuttles back into the cytoplasm where it gets converted to aspartate to initiate another round of the urea cycle
what mitochondrial substrate is required for activation of the ornithine transcarboxylase to convert ornithine into citrulline
carbamoyl phosphate
what stimulates the urea cycle
fasting; high protein diet; NAG stimulation via arginine activates CPSI
Transformation of Arginine to citrulline realses what byproduct
NO
the argininosuccinate lyase converts arginosuccinate to what molecules
arginine & fumarate
would you expect levels of alanine & glutamine to be high or low during fasting? Explain.
High
Explanation:
prolonged fasting results in increased muscle proteolysis to utilize amino acids for gluconeogenesis. this is going to increase serum levels of ammonia
How does increasing colonic pH contribute to management of hyperammonia?
bacterial flora in the gut will favor formation of ammonium when pH of colon decreases; unlike ammonia which is neutrally charged, its conjugate base is + charged and therefore cannot pass through the colonic tight junction barriers; ION TRAPPING
what substances can be administered to promote excretion of excess glutamine in hyperammonia?
phenylbutyrate; phenyl acetate; benzoic acid
what gets excreted in urine from phenylbutyrate
phenylacetylglutamine
describe the MOA for benzoic acid induced excretion of excess nitrogen
benzoyl CoA attaches to glycine and excretes it as hippuric acid
when nitrogen is in excess, the body will divert nitrogen to synthesize serine which is subsequently converted to glycine
a pt. has been fasting for 4 days. what primary energy source is predominating?
what source will predominate over a week
gluconeogenesis
over a week: ketogenesis
