NITROGEN METABOLISM

Question 1

LEAD inactivates what enzymes in heme synthesis?

Answer 1

ALA dehydratase and ferrochelatase​

• ↑ urinary ALA and free erythrocyte porphyrins
• Microcytic, hypochromic anemia with basophilic stippling of RBCs
• Headache, memory loss
• Peripheral neuropathy claw hand, wrist-drop
• Nausea, abdominal pain, diarrhea
• Lead lines in gums, lead deposits in epiphyses

Question 2

Inherited defect of renal tubular amino acid transporter for Cystine, Ornithine, Lysine and Arginine in the PCT of the kidneys

Answer 2

CYSTINURIA​

• Clinical Presentation:
  
  • Excess cystine in urine can lead to precipitation of cystine kidney stones and cause staghorn calculi
• Treatment:
  
  • Acetazolamide to alkalinize the urine

Question 3

FIRST PHASE OF AA CATABOLISM

1. TRANSAMINATION
2. OXIDATIVE DEAMINATION

Answer 3

Question 4

Most common heme defect in Children

Answer 4

Congenital erythropoietic porphyria

Enzyme: Uroporphyrinogen III cosynthase

Question 5

Most severe enzyme defect in the urea cycle

Answer 5

Carbamoyl phosphate synthetase-I deficiency

Question 6

Sphingosine, purines, thymine

Answer 6

Serine

Question 7

• Defect in fumarylacetoacetate hydrolase
• Accumulation of fumarylacetoacetate leads to liver and kidney failure, nervous system disorders, cabbage-like ordor, and increased risk for liver cancer

Answer 7

TYROSINEMIA TYPE I

Question 8

Enzyme deficient in Acute intermittent porphyria

Answer 8

hydroxymethylbilane synthase (uroporphyrinogen I synthase)

• Accumulation of PBG and δ-ALA in the urine
• Episodes of abdominal pain, psychiatric symptoms, peripheral neuropathies
• Urine darkens on exposure to light and air
• Treat with high dose of glucose (mild attack) or hematin (severe attack)

Question 9

Histamine

Answer 9

Histidine

Question 10

UREA CYCLE occurs ONLY to where?

Answer 10

LIVER

o It occurs in both mitochondria and cytosol

Question 11

Carnitine

Answer 11

Lysine

Question 12

STEPS in HEME DEGRADATION

Answer 12

1. Formation of bilirubin

• After approximately 120 days, RBCs are taken up and degraded by the reticuloendothelial system, particularly in the liver and spleen
• Heme → Biliverdin (green) → Bilirubin (red orange)
• Enzyme: Heme oxygenase system of reticuloendothelial cells (relases carbon monoxide)

2. Uptake of bilirubin by the liver

• Bilirubin transported to the liver in the blood by binding to albumin
• In the liver, bilirubin binds to intracellular proteins, particularly to ligandin

3. Formation of bilirubin diglucoronide

• Bilirubin is conjugated to two molecules of glucoronic acid
• Enzyme: Bilirubin glucuronyltransferase
• Deficient in Crigler-Najjar I and II, and Gilbert syndrome

4. Secrection of bilirubin into bile

• Bilirubin diglucuronide is transported into the bile canaliculi and then into the bile
• Susceptible to impairment in liver disease

5. Formation of urobilins in the intestine

• In the gut, bilirubin → urobilinogen (colorless)
• Intestinal bacteria then oxidize urobilinogen → stercolin (brown)
• Some urobilinogen is reabsorbed from the blood and enters the portal circulation
• Remaining urobilinogen is transported by the blood to the kidney, where it is converted to urobilin (yellow)

Question 13

Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine, leading to build up of homogentisic acid

*Homogentisate oxidase converts homogentisic acid to maleylacetoacetate.

Answer 13

ALKAPTONURIA​

• Clinical Presentation:
  
  • Alkapton bodies cause urine to turn black on standing
  • Connective tissue is dark (ochronosis)
  • Benign disease but may have debilitating arthralgias
• Treatment:
  
  • Aimed at reducing pigment deposition
  • Reduce phenylalanine and tyrosine in the diet
  • Vitamin C for older children and adults

Question 14

UREA CYCLE DEFECTS

Answer 14

Question 15

Rate-limiting step of HEME SYNTHESIS

Answer 15

Reaction: Glycine + Succinyl CoA → δ-Aminolevulinic Acid

Enzyme: ALA synthase

Co-factor: Pyridoxine

Question 16

HEME SYNTHESIS

Answer 16

1. δ-Aminolevulinic Acid is synthesized

• This is the rate-limiting step
• Reaction: Glycine + Succinyl CoA → δ-Aminolevulinic Acid
• Enzyme: ALA synthase
• Co-factor: Pyridoxine

2. Porphobilinogen is formed

• Condensation of two molecules of ALA by zinc-containing ALA dehydratase
• Inhibited by heavy metal ions (e.g., lead) that replace the zinc

3. The first porphyrin (uroporphyrinogen) is formed from four PBGs

4. Porphyrins are decarboxylated and oxidized

5. Protoporphyrin IX binds iron, forming heme

• Introduction of iron (as Fe 2+ ) into protoporphyrin IX occurs spontaneously, but the rate is enhanced by ferrochelatase, that is also inhibited by lead
• Vitamin C increases the uptake of iron from the intestinal tract
• Ceruloplasmin is involved in the oxidation of iron

Question 17

enzyme deficient in Porphyria cutanea tarda

* Photosensitivity: cutaneous fragility and blistering of the hands, forearms, and sometimes, the face

Answer 17

uroporphyrinogen decarboxylase (UPD)

Question 18

• Heme, purines, creatine, glutathione
• Conjugated to bile acids, drugs, and other metabolites

Answer 18

Glycine

Question 19

• Blocked degradation of branched amino acids (isoleucine, valine, leucine) due to a deficiency in α-ketoacid dehydrogenase complex​

Answer 19

MAPLE SYRUP URINE DISEASE​

Question 20

Creatine, polyamines, nitric oxide

Answer 20

Arginine

Question 21

TRANSAMINATION

Answer 21

Amino acids transfer their α-amino group to α-ketoglutarate, resulting in the formation of glutamate

Exceptions: lysine, threonine, proline, hydroxyproline

Question 22

Rate-limiting step of UREA CYCLE

Answer 22

NH 3 + CO 2 → Carbamoyl phosphate

Enzyme: Carbamoyl phosphate synthetase I

Allosteric Activator: N-acetylglutamate

Question 23

What are the substrates for UREA CYCLE?

Answer 23

NH3 , aspartate, CO2

Question 24

• Defect in methionine degradation leads to:
  
  • High plasma and urinary levels of homocysteine and methionine
  • Low levels of cysteine
• Most common deficiency: cystathionine β-synthase

Answer 24

HOMOCYSTINURIA

• Clinical Presentation:
  
  • Ectopia lentis (displacement is downward)
  • Faulty bone development and osteoporosis
  • Mental retardation
  • Tendency to form thrombi
  • Myocardial infarction
  • Stroke in children and young adults

Question 25

Coenzyme A, taurine, glutathione

Answer 25

Cysteine

Question 26

Results from ↓ phenylalanine hydroxylase or ↓ tetrahydrobiopterin​

Answer 26

PHENYLKETONURIA

• Tyrosine becomes essential and phenylalanine accumulates
• Clinical presentation:
  
  • Accumulation of phenylketones
    
    • Phenylpyruvate (characteristic odor to the urine)
    • Phenyllactate
    • Phenylacetate
  • Severe mental retardation, failure to walk or talk, seizures
  • Fair skin and eczema
  • Musty body odor

Question 27

Purely Ketogenic AA

Answer 27

“KL”

• Lysine
• Leucine

Question 28

Catecholamine Synthesis

Answer 28

Question 29

OXIDATIVE DEAMINATION OF AA CATABOLISM

Answer 29

Question 30

Defective melanin synthesis from tyrosine, which may be from:

o Absence of the copper-requiring enzyme tyrosinase

o Defective tyrosine transporters

Answer 30

ALBINISM

Question 31

Serotonin, niacin, melatonin

Answer 31

Tryptophan

Question 32

• Catecholamines, thyroid hormones, melanin

Answer 32

Tyrosine

Question 33

BOTH Glucogenic and Ketogenic AA

Answer 33

“WIFY”

• Phenylalanine

• Tyrosine

• Isoleucine

• Tryptophan

Question 34

• Defect in tyrosine aminotransferase, which catalyzes transamination of tyrosine
• Affects the eyes, skin, and mental development

Answer 34

TYROSINEMIA TYPE II​

Question 35

S-adenosylmethionine, creatine, polyamines

Answer 35

Methionine

Question 36

• Methylmalonyl CoA mutase deficiency leads to defect in the conversion of methylmalonyl CoA to succinyl CoA
  
  • Involves the metabolism of amino acids that are converted to propionyl CoA: isoleucine, valine, threonine, and methionine
  • To a lesser extent, odd-chain fatty acid and cholesterol degradation

Answer 36

METHYLMALONIC ACIDEMIA

• Clinical Presentation:
  
  • Seizure, encephalopathy, and stroke at the age of 1 month to 1 year
  • Hypotonia, lethargy, failure to thrive, hepatosplenomegaly, and monilial infections
• Treatment:
  
  • Protein-restricted diet (0.5-1.5 g/kg/d) with L-carnitine and cobalamin supplementation

Question 37

• Defective histidase, which converts histidine to urocanate
• Autosomal recessive disorder
• Earlier cases associated with intellectual disability, but now considered benign

Answer 37

HISTIDINEMIA

Question 38

Most common enzyme defect in the urea cycle

Answer 38

Ornithine transcarbomylase deficiency

Question 39

GABA, glutathione

Answer 39

Glutamate

Question 40

UREA CYCLE

Answer 40

Question 41

TRANSPORT OF AMMONIA FROM PERIPHERAL TISSUES

Answer 41

• THROUGH GLUTAMINE
  
  • In most tissues, glutamate combines with ammonia to form glutamine
  • Enzyme: Glutamine synthetase
  • Glutamine is transported in the blood and may be deaminated to release ammonia in two organs:
    
    • Liver: in response to high protein intake
    • Kidneys: in response to metabolic acidosis
• Enzyme: Glutaminase
• THROUGH ALANINE​
  
  • ​In muscle, pyruvate is transaminated to alanine
  • Alanine is transported to the liver where it is converted back to pyruvate