Lecture 61 Flashcards
Urea Cycle and Urea Cycle Disorders
1
Q
urea cycle overview (aka ornithine cycle)
A
- cycle of biochemical reactions producing urea from ammonia (NH3)
- first metabolic cycle discovered
- takes place primarily in the liver, and to a lesser extent in the kidney
- consists of 5 reactions (1&2 are mitochondrial, 3-5 are cytosolic)
pg 1556
2
Q
urea cycle steps
A
uhh see slide I guess
pg 1557
3
Q
rate-limiting regulated step of urea cycle
A
- enzyme: carbamoyl phosphate synthetase I (CPS-I)
- regulation:
- … by substrate availability (short term) → goal is to remove the toxic free ammonia, so contrasts feedback regulation
- … enzyme induction (long term)
- … allosteric regulation by N-acetylglutamate (NAG) → increases the affinity of CPS-I for ATP
- bicarbonate provides carbon of urea
- free ammonia provides one of the nitrogen atoms of urea
- enzyme has an absolute requirement for N-acetyl-glutamate (NAG) which acts as an allosteric activator (stimulated by high levels of Arg)
pg 1558
4
Q
high protein diet
A
- stimulates urea cycle
- increases transcriptional synthesis of urea cycle enzymes
pg 1559
5
Q
step 2: ornithine transcarbamyolase (OTC)
A
- enzyme: ornithine transcarbomylase (OTC)
- in the mitochondria
- takes ornithine and carbomyl phosphate (high-energy molecule) and makes citrulline
- citrulline transported to cytosol
- deficiency in this enzyme is most common urea cycle defect (X-linked)
pg 1560
6
Q
ornithine and citrulline
A
- AA intermediates, NOT in polypeptide chains
- as citrulline is moved out of the mitochondria, ornithine is moved in
pg 1560
7
Q
steps 3-5 of urea cycle
A
- all steps in the cytosol
- second amino group added from Asp
- common intermediates with TCA cycle (malate, fumarate, oxaloacetate)
- enzyme: arginase → releases free urea which is transported into the bloodstream, filtered by the kidneys, and excreted in the urine
- following completion of the cycle, ornithine is regenerated and transported back into the mitochondria to be reused
pg 1561
8
Q
step 3: citrulline + aspartate to argininosuccinate
A
- utilizes argininosuccinate synthetase (needs ATP)
- amino group of aspartate provides one of the nitrogen atoms of urea
pg 1561
9
Q
step 4: argininosuccinate to L-arginine
A
- utilizes argininosuccinate lyase
- removes fumarate
pg 1561
10
Q
step 5: L-arginine to L-ornithine
A
- utilizes arginase-I which cleaves using water
- urea is removed from arginine
pg 1561
11
Q
serum urea nitrogen (BUN)
A
- normal value between 11-23 mg/dL
- determines how efficiently urea is produced
- if not working, increased ammonia in bloodstream, decreased urea in urine
pg 1561
12
Q
role of kidneys in nitrogen disposal
A
- removal of urea from circulation via filtration
- production of free ammonia via glutaminase reaction in the kidney tubular cells
- free ammonia released in urine as it picks up H+ (NH4+)
- release of H+ contributes to acid-base balance of the body by excreting protons
- ~10% of nitrogen in urine is free ammonia (NH4+) which gives the smell to urine
pg 1562
13
Q
deficiencies of urea cycle enzymes
A
- all present with high-blood NH3 (hyperammonemia → neurotoxicity)
- urea-cycle intermediates before the block accumulate leading to glutamine levels increased in the circulation
- prevents the α-ketoglutarate regeneration by removal of nitrogen from glutamine and free ammonia
- defects in any enzyme lead to elevated glutamine and ammonia levels in the blood
- the extent of the elevation depends on which enzyme is defective
- symptoms similar to drug/alcohol intoxication
pg 1564
14
Q
OTC deficiency
A
- most common inborn urea cycle disorder
- x-linked
- neonatal encephalopathy
- carbamoyl phosphate accumulates and floods pathway for pyrimidine biosynthesis; ornithine also accumulates
- excess orotic acid (intermediate) is excreted in urine; no ill effects, but indicative of problem in urea cycle
pg 1565
15
Q
treatments for urea cycle defects
A
- key: early diagnosis, aggressive treatment to aid in nitrogen removal from the patient
- if enzyme defect is after the synthesis of argininosuccinate, massive arginine supplementation has proved beneficial; helps with regenerating ornithine and continues the cycle → two NH3 excreted as argininosuccinate
pg 1566
16
Q
congenital hyperammonemia
A
- due to genetic defect in any of the enzymes of the urea cycle
- failure to incorporate ammonia into urea leads to high blood ammonia during the first weeks following birth
- high morbidity with neurologic manifestations and high mortality
- symptoms manifest shortly after birth
- if untreated, irreversible damage occurs
pg 1567
17
Q
acquired hyperammonemia
A
- due to ANY liver disease → viral hepatitis, hepatotoxin, alcoholism, cirrhosis, etc
- urea cycle is impaired leading to elevated levels of ammonia in the blood
- elevated blood ammonia is neurotoxic
pg 1567
18
Q
management of hyperammonemia
A
- low-protein diet (↑ ammonia, ↓ urea, ↑ glutamine)
- high dose glucose (IV dextrose)
- hemodialysis (filter ammonia from blood, remove need for urea)
- liver transplant (if SEVERE, completely new urea cycle)
- phenylbutyrate (forms phenylacetylglutamine which contains 2 atoms of nitrogen and is excreted in urine)
glutamine synthetase (“safety bucket”) → produced glutamine from whatever is not converted to urea
pg 1568
