Amino Acid Metabolism Flashcards
What is the ratio of amino acids that are ketogenic: ketogenic and glucogenic: glucogenic?
2:5:13
What are the 2 ketogenic amino acids, and what can they be converted into?
Leucine
Lysine
Converted to acetyl coA or acetoacetate
What are the 5 “switch-hitter” amino acids, that can be ketogenic or glucogenic?
Phenylalanine Isoleucine Tryptophan Tyrosine Threonine
[mnemonic PITTT] - just remember these aren’t their one-letter codes!
Ketogenic amino acids are metabolized into alpha keto acids and ketone bodies, and both carbons are ultimately metabolized to ______ in the TCA cycle
CO2
What are glucogenic amino acids converted into?
Pyruvate
Or TCA cycle intermediates: Oxalaoacetate Alpha-ketoglutarate Succinyl CoA Fumarate
Glucogenic amino acids act to replenish TCA intermediates via __________ reactions
Anaplerotic
Every amino acid has a conjugate what?
Keto acid
Oxaloacetate is the keto acid of __________
Aspartate
Alpha-ketoglutarate is the keto acid conjugate to ___________
Glutamate
The shuffling of amine groups is referred to as ___________, which is catalyzed by enzymes called ______________
Transamination
Transaminases (aka aminotransferases)
Alanine aminotransferase (ALT) is responsible for what transamination reaction?
Pyruvate + Glutamate Alanine + alpha-ketoglutarate
Aspartate aminotransferase (AST) is responsible for what transamination reaction?
Oxaloacetate + Glutamate Aspartate + alpha-ketoglutarate
Transaminases require what coenzyme? What vitamin is this derived from?
Pyridoxyl-5’-phosphate (PLP) which is a derivative of Vitamin B6
Aminotransferases detected on lab tests can be indicative of tissue damage. What is ALT indicative of?
Increase in viral hepatitis, liver cell necrosis, or prolonged circulatory collapse
Aminotransferases detected on lab tests can be indicative of tissue damage. What is AST indicative of?
Myocardial infarction (increases 6-8 hrs after), biliary cirrhosis, liver cancer, pancreatitis, mono, alcoholic cirrhosis, strenuous exercise
Between ALT and AST, which one is more specific to liver disease?
ALT
The conversion of glutamate to glutamine acts as a ________ trap mechanism, by utilizing glutamine synthetase, ATP, and ________
Nitrogen; NH4+
Glutamine is converted to glutamate using what enzyme? What type of enzyme is this?
Glutaminase (hydrolase - because water is used and NH4+ is released)
Which amino acids are your branched chain amino acids? What are these metabolized into?
Val
Ile
Leu
Metabolized into succinyl coA (note that Met is also metabolized to succ. CoA)
What pathologic condition may result from a defect in the methionine pathway?
Homocystinuria
Note that this may be due to absence of PLP which is needed for cystathionine synthase OR absence of B12 which is needed for homocysteine methyltransferase
What is the difference between homocysteine and homocystine?
Homocysteine has a terminal thiol group
Homocystine is 2 homocysteine molecules bonded together via a disulfide bond using those thiol groups
What is the most common cause of homocystinuria?
Mutations in CBS (cystathionine B-synthase) which also requires PLP
Where does PLP (pyridoxal phosphate) come from?
Vitamin B6
Cysteine has one fewer ________ groups than homocysteine
Methyl
Hyperhomocysteinemia is a risk factor in what two pathological conditions?
Atherosclerotic heart disease and stroke
[but also in eye lens dislocation, osteoporosis, and mental retardation]
what are the 4 organ systems affected by hyperhomocysteinemia?
Eyes
Skeletal
CNS
Vascular
Deficiencies in branched chain amino acid metabolism readily lead to what inborn error of metabolism? What enzyme is likely defective?
Maple Syrup Urine Disease (MSUD)
Oxidative decarboxylation of the amino acid is not taking place, so deficiency is likely to be branched chain alpha-ketoacid dehydrogenase complex (BCKD)
What is the clinical presentation of MSUD and what is the most common treatment?
BCAA’s present in the urine, giving the hallmark maple syrup smell. They also accumulate in the blood causing toxic effects on brain function and eventually mental retardation
Treatment includes a synthetic diet that limits BCAAs (Val, Leu, Ile). The activity of BCKD may be restored with thiamine supplementation in milder forms
True or false: the incidence of MSUD is higher in Mennonite, Amish, and Jewish populations
True
Phenylketonuria (PKU) is an inborn error of metabolism characterized by a deficiency of what enzyme?
Phenylalanine hydroxylase (which would typically participate in the conversion of Phe to Tyr)
[majority are missense mutations in the catalytic domain]
What is the primary treatment for PKU?
It is controlled dietarily by avoiding phenylalanine and supplementing with Tyr
What is the most common inborn error of metabolism?
PKU
In PKU patients, phenylalanine is converted to phenylpyurvate and then to phenyllactate and phenylacetate instead of being converted to tyrosine. What symptom does this cause?
Musty odor in urine
Tyrosine bioavailability is critical to the production of ________ hormones and endocrine regulation
Thyroid
Is GABA inhibitory or activating?
Inhibitory
What is the primary neurotransmitter in mammalian CNS’s?
Ach
What are the 2 primary tryptophan derivatives?
Serotonin –> melatonin
Niacin –> NAD(P)+
What are the 3 primary Tyr derivatives?
Dopamine –> NE –> epinephrine
Thyroid hormones
Melanin
What is the primary glutamate derivative?
y-aminobutryic acid (GABA)
What is the primary serine derivative?
Acetylcholine
Fill in the blank with “high” or “low”
Hypothyroidism = _______ TSH, ______ T4
Hyperthyroidism = _______ TSH, _______ T4/T3
High; low
Low; high
What is the difference between T3 and T4 thryoid hormones?
Thyroid hormones are either mono or diiodinated
T4 = 2 diiodotyrosine
T3 = Monoiodotyrosine + diiodotyrosine
What are the 3 primary pathological conditions that may result from defective tyrosine metabolism?
Grave’s disease
Hypo/hyperthyroidism
Albinism
[also possible Parkinsonism]
How does a defect in tyrosine metabolism lead to albinism?
Albinism is due to a severe lack of melanin
This can result from a blockage in the conversion of tyrosine to melanin due to defects in the enzyme tyrosinase - resulting in partial or complete absence of pigmentation in the skin, hair, and eyes
What is the primary treatment used for hyperthyroidism?
Medications that block the iodination of thyroglobulin to decrease the production of T3 and T4
Ammonia is removed as ________ and _______ in the brain via the enzyme ____________ _____________.
However, it is removed as ________ and ________ in other tissues.
Glu; Gln
Gln; Ala
Increased entry of ____________ to the brain is a primary cause of neurologic disorders, such as congenital deficiencies of urea cycle enzymes, hepatic encephalopathies, Reye Syndrome, and some toxic encephalopathies
Ammonia
How is excess ammonium removed from the brain?
NH4+ is utilized in the conversion of a-KG to Glu, and again in the conversioin of Glu to Gln, which carries NH3 to the liver where NH4+ can be released to go through the urea cycle
So basically glutamate dehydrogenase continues to create glutamate from a-KG to use up NH4+ in the brain. This depletes the pool of alpha-ketoglutarate which lowers overall ATP level and leads to possibility of unconsciousness
Describe the removal of exces NH4+ from muscle
As muscles run glycolysis through to pyruvate (the a-ketoacid of alanine), the pyruvate can be converted to alanine via ALT. Alanine acts as a nitrogen carrier, bringing it to the liver so that it can enter the urea cycle and be excreted.
Note that transamination is the reaction from pyruvate to alanine. Oxidative deamination is the reaction that is later required to fully remove the amino group (NH3) for entry into the urea cycle –> excretion
The urea cycle primarily occurs in what two organs?
Primarily the liver, but the kidneys to a lesser extent
What are the 2 major sources of urea cycle deficiencies?
Liver disease
Inborn Errors of Metabolism
The urea cycle primarily occurs in the cytosol of hepatocytes, but some steps occur in the mitochondria. Which steps occur in the mitochondria?
Conversion of NH4+ to carbamoyl phosphate (RL step)
Conversion of ornithine to citrulline via ornithine transcarbamoylase and input of carbamoyl phosphate created in RL step
Ammonia toxicity causes what physiological effects?
pH imbalance, and swelling of astrocytes in the brain which leads to cerebral edema and intracranial hypertension
Postsynaptic excitatory proteins are inhibited which depresses CNS function, disruption of GABA due to depletion of glutamate, mitochondrial dysfunction
What happens to the urea cycle in a high protein diet vs. a high carb diet?
High protein diet increases urea production (upregulates urea cycle)
High carb diet decreases urea production (downregulates urea cycle)
