Nitrogen Metabolism

Question 1

What is the major source of nitrogen?

Answer 1

protein

Question 2

What are the major nitrogen excretory compounds?

Answer 2

• Urea
• Ammonia
• Creatinine
• Uric acid
• Urobilinogen

Question 3

What is nitrogen shuffling?

Answer 3

• AA’s convert to glutamate via transamination (needs PLP)
• Glutamine is main metabolic byproduct in extrahepatic tissues and this is the most prevalent nitrogen carrier in the blood
• Final ammonia sequestration is done by glutamate
• CPSase uses free ammonium to form carbamoyl phosphate feeding into urea cycle

Question 4

A patient comes in and tells you their PMH. It is significant for a deficient membrane transporter in the gut. How would you expect their kidney function to be?

Answer 4

• The transporter proteins in the gut are the same found in the PCT, so active reabsorption will be decreased

Question 5

Where will reabsorption of AA and glucose occur?

Answer 5

PCT

Question 6

What disease has defective transport of neutral amino acids particularly trp?

Answer 6

Hartnup disease

Question 7

What disease has defective transport of dibasic amino acids? What are these amino acids?

Answer 7

• Cystinuria
• Cystine
• Ornithine
• Arginine
• Lysine

Question 8

After spending all weekend in the sun fishing, in an attempt to relieve the stress of medical school, a 26 yo male presents to urgent care with cutaneous hyperpigmentation. They also appear to have a tremor and minor cerebellar ataxia. What type of diet and supplementation would you recommend?

Answer 8

• Tx is directed towards replacing niacin
  
  • High protein diet
  • Nicotinamide supplementation
• This is Hartnup disease, an AR disorder which results in defective aa transport of neutral AA’s particularly Trp.
  
  • ​Trp is a precursor for NAD

Question 9

What is the only way to diagnose Hartnup disease?

Answer 9

Chromatographic analysis of urine samples

Question 10

A mother brings her 4th month old into the pediatrician for the first time. She had a smooth at home birth and neither her or her daughter have seen a doctor. She tells the doctor that her baby doesn’t show interest in much, isn’t reaching for anything, and has slow reflexes in general. She also states that her diapers have an odd musty smell to them. What enzyme is deficient, what causes the musty smell in the urine, and how would you suggest treating this?

Answer 10

• Phe Hydroxylase (PAH)
• Phe gets converted to phenylpyruvate and then to phenyllacetate which causes the musty smell
• Tx would be to limit dietary Phe, supply protein with synthetic formula supplemented with Tyr
• This is PKU

Question 11

Defects in dihydrobiopterin reductase can lead to ___.

Answer 11

Defects in dihydrobiopterin reductase can lead to secondary PKU

Question 12

What is tyrosinemia?

Answer 12

• Elevated blood levels of tyrosine
• Tx is restricted Phe and Tyr diet

Question 13

How do you distinguish PKU from tyrosinemia?

Answer 13

Hypertyrosinemia

Question 14

Tyrosinemia type I?

Answer 14

• Defect in fumarylacetoacetate hydrolase
• Infants have cabage like smell and develop severe liver failure w/o tx
• Most common type used to require liver transplant, now Nitisinone is the tx

Question 15

Tyrosinemia type II?

Answer 15

• Defective tyrosine aminotransferase
• Palmar and plantar hyperkeratosis, corneal lesions and intellectual disablity
• AR and rare

Question 16

Tyrosinemia type III?

Answer 16

• defective 4-HPPD
• results in various neuro deficiets
• Very very rare
• Confirmed by elevated 4-HPPD and hypertyrosinemia

Question 17

What is Alkaptonuria?

Answer 17

• AR defective homogentistate oxidase which is part of the Tyr degradation pathway
• Black urine Black bone disease
• causes homogentisic acid to accumulate
• Homogentisic aciduria, ochronosis, arthritis

Question 18

Distinguish Primary vs secondary hyperuricemia.

Answer 18

• Primary is the overproduction of uric acid
• Secondary is underexcretion of uric acid

Question 19

For gout, Allopurinol is used as a tx. What does this inhibit?

Answer 19

Xanthine oxidase

Question 20

How does ammonia toxicity result in a disruption of ATP production?

Answer 20

• There is a depletion of alpha ketoglutarate which is a major player in the TCA cycle
• A-KG gets converted back into glutamate

Question 21

What does ammonia toxicity do to the body?

Answer 21

• excessive ammonia due to urea cycle disorders or liver failure, highly toxic for brain and CNS
• causes a pH imbalance, swelling of astrocytes leading to cerebral edema and intracranial htn
• TCA is disrupted
• Postsynaptic excitatory proteins are inhibited depressing the CNS
• Depletion of glutamate disrupts formation of GABA
• Mitochondria dysfxn also

Question 22

What amino acid acts nitrogen flow regulator throughout the body, both accepting and donating nitrogen for eventual incorporation into the urea cycle? (Dr. Kinde)

Answer 22

• Glutamate
• Glutamate is the body’s nitrogen flow regulator. All transaminase reactions donate nitrogen from an amino acid substrate to a-ketoglutarate to form glutamate. Glutamate dehydrogenase is the key enzyme that will eventually oxidatively deaminate glutamate to form ammonia for incorporation into the urea cycle. (Dr. Kinde)

Question 23

Defect in ornithine and citrate transporters, seen in the urea cycle, will result in ____.

Answer 23

Defect in ornithine and citrate transporters, seen in the urea cycle, will result in severe hyperammonemia

Question 24

Deficiency in OTC?

Answer 24

• Build up of carbamyl phosphate in the mitochondria
• It spills into the cytosol
• Gets taken into the pyrimidine synthesis pathway
  
  • Orotic aciduria occurs along with hyperammonemia

Question 25

Inheritance of orotic aciduria?

Answer 25

X linked, defect in ornithine transcarbamoylase

Question 26

Where is CPSase I location cycle and activation?

Answer 26

• Urea cycle
• Mitochondrial
• NAG activated

Question 27

CPSase II location cycle and activation?

Answer 27

• Cytosolic
• Pyrimidine synthesis
• PRPP activated

Question 28

What is the rate-limiting step of the urea cycle? (Dr. Kinde)

• ATP-dependent conversion of citrulline and aspartate to arginosuccinate via argininosucccinate synthase
• • Conversion of ammonia to carbamoyl phosphate via carbamoyl phosphate synthetase I and NAG activation
• • Conversion of carbamoyl phosphate and ornithine to citrulline via ornithine transcarbamoylase
• • Cleavage of argininosuccinate to fumarate and arginine via argininosuccinate lyase (argininosuccinase)
    *

Answer 28

• Conversion of ammonia to carbamoyl phosphate via carbamoyl phosphate synthetase I and NAG activation

Question 29

Premature infants may have a deficiency in ____, which results in increased levels of ____ and jaundice.

Answer 29

Premature infants may have a deficiency in UDP-glucuronyl transferase, which results in increased levels of unconjugated bilirubin and jaundice.

Question 30

How do you get a bilirubin assay from a neonate?

Answer 30

• Unconjugated bilirubin isn’t water soluble and cant be direcly assayed
• Solubilize the sample in 50% methanol and react with Diazo reagent
• Difference between the diazo samples in presence and not in presence of methanol willl give amount of indirect

Question 31

What is Gray Baby Syndrome?

Answer 31

• Chloramphenicol toxicity:
  
  • deficiency in UDP-glucuronyl transferase means the drug can’t be metabolized
  • Insufficient renal excretion of the unconjugated drug
• Can lead to circulatory collapse
• Directly interferes with tissue respiration and ox phos
• Occurs when mother takes this close to birth

Question 32

What are some causes of physiologic jaundice in newborns?

Answer 32

• Shorter lifespand of RBC’s
• Increased fetal RBC mass
• Low UGT activity