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1

Urea cycle “ornithine cycle”

Biochemical cycle of multiple reactions which produces urea from ammonia (NH3)
- is the only cycle that can get toxic ammonia out of the body

Developed by Hans Krebs and Kurt henseleit

Takes place primarily in the liver (>80%) and in the kidneys (<20%)

2 mitochondrial reactions and 3 cytosolic steps

**is induced by substrate availability short term (ATP + NH3) and enzyme induction long term (upregulated enzyme levels)

2

What is the allosteric activator of the urea cycle?

N-acetylglutamate (NAG)
- without this substrate, the urea cycle cant move forward
- **stimulated by high protein meals

3

What is the most common urea cycle defect?

An X-linked defect in the enzyme ornithine transcarbamoylase

4

UCD common correlations

*all of them show hyperammonemia, and elevated glutamine levels in the blood circulation*

Hyperammonemia symptoms:
- tremors
- slurring of speech
- somnolence
- vomiting
- cerebral edema
- blurred vision
- coma and death

5

OTC deficency

X-linked deficiency seen in 1:80,000

Always shows elevated ORNITHINE and ORTIC ACID levels in urine

Always presents with neonatal encephalopathy

**causes accumulation of carbonyl phosphate to accumulate in the cytosol of mitochondria and flood the pathway for pyrimidine biosynthesis. Causes carbonyl phosphate to get turned into orotate (ortic acid) via CPS-2 and excreted in the urine

6

How to treat UCDs

1) need to get an early diagnosis

2) neeed to aggressively aid in nitrogen removal from patient

**if enzyme defect is before argininosuccinate production (steps 1-3), give massive arginine supplementation to regenerate ornithine is the only thing you really need to do**

7

Congenital vs acquired hyperammonemia

Congenital:
- due to genetic defects in any enzyme of the urea cycle
- always shows elevated ammonia in the first weeks of life
- high morbidity

Acquired:
- due to ANY liver disease
- always shows elevated ammonia levels later in life usually weeks after liver disease initiates

8

Management of hyperammonemia

1) low-protein diet
- prevents excess protein source

2) high dose glucose (IV dextrose)
- prevents need to breakdown proteins

**#1 and 2 = prevents rise in ammonium levels**

3) hemodialysis

4) phenylbiturate
- is used because it spontaneously combines with glutamate and ammonia groups to form phenylacetylglutamine which is easily excreted in urine

5) liver transplant

***#3-5 get rid of high ammonium levels***

9

Carbamioyl phosphate synthase 1 (CPS-1)

Is the first step and rate-limiting step in the urea cycle
- generates carbonyl phosphate via bicarbonate + free NH3 and 2 ATP.

Short term regulation = substrate availability

Long term regulation = enzyme induction

**activation of N-acetylglutamate (NAG) increases CPS-1 affinity for ATP and allows its activation. NAG is needed to run urea cycle**

10

Where does the carbon and ammonia atoms in urea come from?

Free ammonia (from alanine and glutamate)

bicarbonate ions provide the carbon atom

11

What form does ammonia have to take in order to get out of the mitochondria in the liver?

Citrulline
- created by combining ornithine and carbonyl phosphate via ornithine transcarboxylase enzyme (OTC)


**Citrulline is then converted to aspartate once it it in the cytosol

12

how does NAG get synthesized

Glutamate + acetyl CoA and arginine combine to form NAG via NAG-synthase

**excess NAG gets converted into acetate and glutamate via NAG hydrolase

13

What reaction in the urea cycle produces urea?

Conversion of arginine -> urea and ornithine via Arginase-1 enzyme

14

Why does cerebral edema occur in hyperammonia?

Increased osmotic gradients within the brain tissue causes water to leave into brain tissue

High levels of ammonia and glutamine in astrocytes promote this to occur
- glutaMINE is produced via glutamine synthase in presence of ammonia to try and lower neurotoxicity (this also increases the osmotic gradient and leads to cerebral edema)
- also lowers glutaMATE levels which alters brain function since its a highly used neurotransmitter

15

What is the most common cause of acquired hyperammonemia

Liver disease/ cirrhosis of liver