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#‼️BIOCHEMISTRY - PLE TOPNOTCH 2020 > NITROGEN METABOLISM > Flashcards

Flashcards in NITROGEN METABOLISM Deck (41)
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1

LEAD inactivates what enzymes in heme synthesis?

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

2

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

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

3

FIRST PHASE OF AA CATABOLISM

1. TRANSAMINATION

2. OXIDATIVE DEAMINATION

4

Most common heme defect in Children

Congenital erythropoietic porphyria

Enzyme: Uroporphyrinogen III cosynthase

5

Most severe enzyme defect in the urea cycle

Carbamoyl phosphate synthetase-I deficiency

6

Sphingosine, purines, thymine

Serine

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

TYROSINEMIA TYPE I

8

Enzyme deficient in Acute intermittent porphyria

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)

9

Histamine

Histidine

10

UREA CYCLE occurs ONLY to where?

LIVER

o It occurs in both mitochondria and cytosol

11

Carnitine

Lysine

12

STEPS in HEME DEGRADATION

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)

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.

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

 

14

UREA CYCLE DEFECTS

15

Rate-limiting step of HEME SYNTHESIS

Reaction: Glycine + Succinyl CoA → δ-Aminolevulinic Acid

Enzyme: ALA synthase

Co-factor: Pyridoxine

16

HEME SYNTHESIS

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

17

enzyme deficient in Porphyria cutanea tarda

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

uroporphyrinogen decarboxylase (UPD)

18

• Heme, purines, creatine, glutathione

• Conjugated to bile acids, drugs, and other metabolites

Glycine

19

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

MAPLE SYRUP URINE DISEASE​

 

20

Creatine, polyamines, nitric oxide

Arginine

21

TRANSAMINATION 

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

Exceptions: lysine, threonine, proline, hydroxyproline

22

Rate-limiting step of UREA CYCLE 

NH 3 + CO 2 → Carbamoyl phosphate

Enzyme: Carbamoyl phosphate synthetase I

Allosteric Activator: N-acetylglutamate

23

What are the substrates for UREA CYCLE?

NH3 , aspartate, CO2

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

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

 

25

Coenzyme A, taurine, glutathione

Cysteine

26

Results from ↓ phenylalanine hydroxylase or ↓ tetrahydrobiopterin​

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

27

Purely Ketogenic AA

"KL"

• Lysine

• Leucine

28

Catecholamine Synthesis

29

OXIDATIVE DEAMINATION OF AA CATABOLISM

30

Defective melanin synthesis from tyrosine, which may be from:

o Absence of the copper-requiring enzyme tyrosinase

o Defective tyrosine transporters

ALBINISM