NITROGEN METABOLISM Flashcards
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
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
FIRST PHASE OF AA CATABOLISM
- TRANSAMINATION
- OXIDATIVE DEAMINATION
Most common heme defect in Children
Congenital erythropoietic porphyria
Enzyme: Uroporphyrinogen III cosynthase
Most severe enzyme defect in the urea cycle
Carbamoyl phosphate synthetase-I deficiency
Sphingosine, purines, thymine
Serine
- 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
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)
Histamine
Histidine
UREA CYCLE occurs ONLY to where?
LIVER
o It occurs in both mitochondria and cytosol
Carnitine
Lysine
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)
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
UREA CYCLE DEFECTS
Rate-limiting step of HEME SYNTHESIS
Reaction: Glycine + Succinyl CoA → δ-Aminolevulinic Acid
Enzyme: ALA synthase
Co-factor: Pyridoxine
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
enzyme deficient in Porphyria cutanea tarda
* Photosensitivity: cutaneous fragility and blistering of the hands, forearms, and sometimes, the face
uroporphyrinogen decarboxylase (UPD)
- Heme, purines, creatine, glutathione
- Conjugated to bile acids, drugs, and other metabolites
Glycine
- Blocked degradation of branched amino acids (isoleucine, valine, leucine) due to a deficiency in α-ketoacid dehydrogenase complex
MAPLE SYRUP URINE DISEASE
Creatine, polyamines, nitric oxide
Arginine
TRANSAMINATION
Amino acids transfer their α-amino group to α-ketoglutarate, resulting in the formation of glutamate
Exceptions: lysine, threonine, proline, hydroxyproline
Rate-limiting step of UREA CYCLE
NH 3 + CO 2 → Carbamoyl phosphate
Enzyme: Carbamoyl phosphate synthetase I
Allosteric Activator: N-acetylglutamate
What are the substrates for UREA CYCLE?
NH3 , aspartate, CO2
- 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
Coenzyme A, taurine, glutathione
Cysteine
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
- Accumulation of phenylketones
Purely Ketogenic AA
“KL”
- Lysine
- Leucine
Catecholamine Synthesis
OXIDATIVE DEAMINATION OF AA CATABOLISM
Defective melanin synthesis from tyrosine, which may be from:
o Absence of the copper-requiring enzyme tyrosinase
o Defective tyrosine transporters
ALBINISM
Serotonin, niacin, melatonin
Tryptophan
• Catecholamines, thyroid hormones, melanin
Tyrosine
BOTH Glucogenic and Ketogenic AA
“WIFY”
• Phenylalanine
• Tyrosine
• Isoleucine
• Tryptophan
- Defect in tyrosine aminotransferase, which catalyzes transamination of tyrosine
- Affects the eyes, skin, and mental development
TYROSINEMIA TYPE II
S-adenosylmethionine, creatine, polyamines
Methionine
-
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
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
- Defective histidase, which converts histidine to urocanate
- Autosomal recessive disorder
- Earlier cases associated with intellectual disability, but now considered benign
HISTIDINEMIA
Most common enzyme defect in the urea cycle
Ornithine transcarbomylase deficiency
GABA, glutathione
Glutamate
UREA CYCLE
TRANSPORT OF AMMONIA FROM PERIPHERAL TISSUES
- 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
