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1

What are three keypoints that summarize ammonia metabolism?

1) Ammonia is very toxic, particularly to the central nervous system (CNS). Thus, the concentration of ammonia and ammonium ions in the blood is kept very low. At physiologic pH, it exists mainly as ammonium ion (pKa=9.3, NH4+ = NH3 + H+). Reference serum levels are less than 35 micromol/L
2) Glutamine & glutamate serve as the major ammonia source & ammonia quencher (or sinker), respectively. Therefore ammonia metabolism is regulated by the two key enzymes, glutamine synthetase & glutaminase
3) The expression of glutamine synthetase & glutaminase is organ-specific. For example, intestines, kidneys, & periportal hepatocytes express glutaminase, but not glutamine synthetase. In contrast, brain, muscles, & perivenous hepatocytes express glutamine synthetase but not glutaminase

2

What is the plasma concentration of ammonia at pH 7.3?

1) pH = pKa + log([base]/[acid])
2) 7.3 = 9.3 + log([base]/35])
3) [base] = 0.35 micromol/L

3

What are 4 sources of ammonia?

1) In the liver & kidney, free ammonia can be formed through deamination reaction catalyzed by glutamate dehydrogenase (GDH) or glutaminase
2) In the intestines, ammonia is formed by the action of bacterial urease
3) Free ammonia is generated from the catabolism of purines & pyrimidines
4) Dietary amines & monoamines such as hormones and neurotransmitters give rise to ammonia by the action of amine oxidase

4

How is ammonia transported to the liver via glutamine & alanine?

1) In most tissues glutamine synthetase combines ammonia with glutamate to form glutamine
2) In muscle, GDH & ALT sequentially funciton to form alanine: glucose-alanine cycle

5

What are two types of hepatocytes?

1) Periportal hepatocytes are highly abundant (about 90%) and are a site for urea cycle (have glutaminase)
2) Perivenous hepatocytes constitute less than 10% of hepatocytes & a have a site for glutamine synthesis with ammonia escpaing from periportal hepatocytes (have glutamine synthetase)

6

How is neurotoxic ammonia disposed?

1) Urea is the major disposal form of ammmonia
2) Urea is produced in the liver, & is transported to the kidneys for excretion int hte urine
3) One nitrogen of the urea is derived from free ammonia & the other nitrogen from aspartate. The carbon and oxygen are from CO2

7

Describe the steps of the urea cycle

1) CO2 + NH3 + 2ATP --> Carbamoyl phosphate + 2ADP + Pi (uses carbamoyl phosphate synthetase 1 (CPS1))
2) L-Ornithine + Carbamoyl phosphate --> Citrulline + Pi
3) Citrulline + L-Aspartate + ATP --> Argininosuccinate + AMP + PPi
4) Argininosuccinate --> L-Arginine + Fumarate
5) L-Arginine + H2O --> Urea + L-Ornithine

8

What are two reactions in the urea cycle that occur in the mitochondria?

1) Synthesis of carbamoyl phosphate by carbamoyl phosphate synthetase 1 (CPS1)
2) Formation of citrulline by ornithine transcarbamoylase (OTC)

9

What are two differences between CPS1 and CPS2?

1) CPS1 functions in the mitochondrial matrix, while CPS2 functions in the cytosol
2) CPS1 uses ammonia as a substrate, while CPS2 uses an amino acid (glutamine) as a substrate

10

What substrate in the urea cycle leaves the mitochondrial matrix and is used in the cytosol?

Citrulline

11

What substrate in the urea cycle leaves the cytosol and is used in the mitochondrial matrix?

L-Ornithine

12

What can L-Arginine be used to directly form in the urea cycle?

L-Arginine + NADPH + H+ +O2 --> Citrulline + NADP+ + NO

13

How can the urea cycle be regulated by arginine?

1) Increased levels of arginine promotes positive feedback for the reaction:
Glutamate + Acetyl CoA --> N-Acetylglutamate + CoA (uses N-Acetylglutamate synthetase; this reaction only occurs when there is ample energy in the body - an excess of Acetyl CoA)
N-Acetylglutamate --> Acetate (uses N-Acetylglutamate hydrolase)
2) N-Acetylglutamate is also a positive allosteric regulator of the enzyme Carbamoyl phosphate synthetase 1 (CPS1)

14

What are two types of hyperammonemia?

1) Acquired hyperammonemia; liver disease; viral infection, ischemia, or cirrhosis by alcoholism or biliary obstruction (caused by a lack of blood flow to the liver, resulting in a lack of amino acids and a buildup of excess ammonia)
2) Hereditary hyperammonemia: 1 in 30,000 prevalence (Nearly all 6 of the enzymes used in the urea cycle will be defective)

15

What is N-acetylglutamate synthetase (NAGS) deficiency?

1) Autosomal recessive disorder
2) N-acetylglutamate could also become deficient if acetyl-CoA is not available
3) Very few cases

16

What is Carbamoylphosphate synthetase 1 (CPS1) deficiency?

1) Autosomal recessive
2) Hyperammonemia develops as early as the first day of life. A majority of affected infants die in the neonatal period

17

What is Ornithine transcarbamoylase (OTC) deficiency?

1) X-linked recessive
2) The most common urea cycle defect, with an estimated incidence of 1 case in 14,000p ersons
3) In the absence of the enzyme, accumulated carbamoyl phosphate enters the cytosol and participates in pyrimidine synthesis in the presence of CPS 2 (increased synthesis of orotic acid)
4) Males who have significant residual enzyme activity and females who are heterozygous for OTC deficiency present later with quite variable clinical pictures. As many as 60% of OTC deficiency diagnoses are made in non-neonates. The oldest reported patient was aged 61 years

18

What is Argininosuccinate synthetase (ASS) deficiency?

1) Autosomal recessive
2) Citrulline combines with aspartate to form argininosuccinic acid. The ASS deficiency results in citrullinemia
3) Onset is usually between hours 24 and 72 of life, but late-onset forms have been described in the literature

19

What is Argininosuccinate lyase (ASL) deficiency?

1) Autosomal recessive
2) The second most common urea cycle disorder
3) The lack of this enzyme leads to argininosuccinic aciduria
4) Abnormally fragile hair (trichorrhexis nodosa) in the affected infants as early as age 2 weeks

20

What is Arginase (A1) deficiency?

1) Autosomal recessive
2) Its deficiency results in argininemia, which is the least frequent UCD with relatively mild hyperammonemia
3) Neonates with A1 deficiency are susualy asymptomatic, but can present with progressive spastic diplegia or quadriplegia, inellectual impairment, recurrent vomiting, delayed growth, & seizures

21

How can hyperammonemia be treated?

1) Lactulose: A colonic acidifier to reduce ammonia; oral administration, 10g/d. Lactulose promotes bacteria growth in colon, inducing assimilation of ammonia and also decreasing deamination of nitrogenous compounds
2) Sodium benzoate (250-500 mg/kg/d): Combines with endogenous glycine to form hippuric acid that is cleared by the kidneys
3) Sodium phenylacetate or phenylbutyrate (250-500 mg/kg/d): Conjugates with glutamine to form phenylacetylglutamine, which is excreted in urine
4) Arginine (200-800mg/kd/d): supplies urea cycle with ornithine & N-acetylglutamate and supports the NO synthesis
5) Citrulline (200-400 mg/kg/d): is useful in patients with OTC deficiency

22

Which amino acids yield free ammonia?

Glutamine & Glutamate (transamination)