Mindmap
Urea Cycle and Disorders
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Urea Cycle and Disorders
Ammonia represents the excess nitrogen, and it's metabolized to Urea, in the urea cycle
- Nevertheless
- This process is target of several disorders, denominated
- Urea Cycle Disorders (UCDs)
- These pathologies by 50%
- Arise in neonatal period
- But it is also known thatits severity depends on the affected protein
- And another important point, is that
- When one of these pathologies take place
- The priority is to prevent irreversible damage to the brain
- From Excess Ammonia
- The priority is to prevent irreversible damage to the brain
- When one of these pathologies take place
- The disease is caused by congenital defects
- However, in order to undertand them, first
- Nitrogen Metabolism
- Normally, body
- Maintains balanced protein and amino acid turnover
- For Example
- The rate of protein turnover daily, is
- 250-400 g/day
- While, the level of protein intake is much lower
- 50-80 gr/day
- The rate of protein turnover daily, is
- For Example
- Maintains balanced protein and amino acid turnover
- Ammonia produced by gastrointestinal tract
- Represents the largest amount
- Which ends up accumulating
- Portal Vein
- And there, the concentrations are
- 2-5 times higther than in the systemic circulation
- And there, the concentrations are
- Portal Vein
- Which ends up accumulating
- This occurs by three ways
- Metabolizing Glutamine
- Glutamate Dehydrogenase (GDH)
- Small intestine
- Glutaminase
- Mucisa Epithelial Tissue
- Bacterial Urease
- Large Intestine
- Glutamate Dehydrogenase (GDH)
- Metabolizing Glutamine
- Represents the largest amount
- Ammonia is transported in blood as
- Glutamine
- The other route is associated with
- Amino acid Catabolism
- Muscle
- Brain
- Here GDH, repressents
- An importing a way to get Ammonia
- Hence, is regulated by many substances
- Allosteric Activators
- ADP
- L-leucine
- Allosteric Inhibitors
- ATP
- Long-chain Fatty Acids
- Estrogens
- NAD
- Allosteric Activators
- Hence, is regulated by many substances
- An importing a way to get Ammonia
- Amino acid Catabolism
- And ammonia produced is transported to
- Liver
- Here
- Glutaminase
- Takes Glutamine
- Generates
- Glutamate
- Ammonia
- Glutaminase
- Here
- Liver
- Normally, body
- Urea Cycle
- This pathaway takes place in the mitochondria and cytosol
- Start with
- Carbamoylphosphate synthetase CPS1
- Takes
- Ammonia
- Bicarbonate
- This enzyme has several aspects to tell us
- It's the rate limiting enzyme of the cycle
- It needs as allosteric activators
- Mg+2
- N-acetylglutamate (NAG)
- N-acetylglutamate Synthase
- Catalyzes
- Glutamate + Aceyl-CoA
- NAG
- Glutamate + Aceyl-CoA
- Its deficiency is very rare
- And to differentiate from a mutation in the CPS1
- A molecular test is required
- And the most important
- Is that
- Exists an effective treatment available
- That consists in using an analog of NAG
- But, It's pretty important
- A fast and reliablydiagnostic
- But, It's pretty important
- That consists in using an analog of NAG
- Exists an effective treatment available
- Is that
- And to differentiate from a mutation in the CPS1
- Catalyzes
- N-acetylglutamate Synthase
- ATP
- Its deficiency is an autosomal reccessive disorder
- And it's one of the most serve UCDs
- Its prevalence is
- 1/975.000
- EEUU
- 1/800.000
- Japan
- 1/975.000
- Other point, is that appears
- After of birth
- Hiperammonemia
- After of birth
- Carbamoylphosphate
- Ornithine Transcarbamylase
- Citrulline
- Argininosuccinate Stnthetase
- Argininosuccinate
- Argininesuccinate lyase
- Forms
- Arginine
- Arginase 1
- Allows the hydrolysis of arginine to
- Ornithine
- Urea
- Goes to the liver for elimination in the urine
- Deficiency of this enzyme
- It is not caracterized as acute hyperammonemia
- On the other hand, patients sometimes present developmental delay
- Progresive Spasticity
- Seizures
- Hepatomegaly
- On the other hand, patients sometimes present developmental delay
- It is not caracterized as acute hyperammonemia
- Allows the hydrolysis of arginine to
- Arginase 1
- Fumarate
- Arginine
- Defficency of its gen (7-cen-q11.2)
- Causes
- Succinic aciduria
- Argininesuccinate is found in
- Urine
- Cerebrospinal fluid
- In addition is associated
- Liver Disfunction
- Hepatomegaly
- Argininesuccinate is found in
- Succinic aciduria
- Causes
- Forms
- Argininesuccinate lyase
- Already in cytosol, takes
- Citrulline
- Aspartate
- Its aspartate-glutamate carrier
- Which, allows tha aspartate is available
- Since, takes aspartate and transports it to cytosol
- From Mitochondria
- Since, takes aspartate and transports it to cytosol
- In deficiency of this transporter
- Various amino acids, are elevated
- Citrulline
- Phenylalanine
- Threonine
- Tyrosine
- Methionine
- Various amino acids, are elevated
- Which, allows tha aspartate is available
- Its aspartate-glutamate carrier
- Argininosuccinate
- Argininosuccinate Stnthetase
- It takes
- Carbamoylphosphate
- Ornithine
- Here it comes
- Mitochondrial Ornithine Transporter (ORNT1)
- It can transport ornithine from Cytosol
- To Mitochondrial matrix
- But also, can transport citrulline from the mitochondria
- To cytosol
- It can transport ornithine from Cytosol
- Mitochondrial Ornithine Transporter (ORNT1)
- Here it comes
- Its deficiency is the most common
- Allows a residual activity
- By this
- May appear in late periods
- It is the only one of these pathologies that is not autosomal
- May appear in late periods
- By this
- Allows a residual activity
- Citrulline
- Ornithine Transcarbamylase
- Takes
- Carbamoylphosphate synthetase CPS1
- Start with
- It's based in producing urea from ammonia
- To be taken to the kidney for excretion
- Your energy balance consists of:
- Two molecules of ammonia
- To urea
- Requires
- 2 ATP
- 10% of ATP produced in mitochondria
- Is used for this cycle
- 10% of ATP produced in mitochondria
- 2 ATP
- Two molecules of ammonia
- Your energy balance consists of:
- To be taken to the kidney for excretion
- This pathaway takes place in the mitochondria and cytosol
- Nitrogen Metabolism
- However, in order to undertand them, first
- These pathologies by 50%
- Urea Cycle Disorders (UCDs)
- This process is target of several disorders, denominated
- Nevertheless
Citrulline
- L-citrulline, it's an important supplement
- Safely
- Patients with deficiency of
- OCT
- CPSI
- Patients with deficiency of
- Safely
- Bus its applications can be more extensive
- This improves, NO pathway
- And prevents, excessive production of NO
- It has postive effects in protein synthesis
- Trough
- mTOR pathway
- Trough
- Innmunity and Oxidative Stress
- Here its effects are very interesting
- Reduces, circulation levels of
- Leukocytes
- Neutrophils
- It can acts as scavenger
- Oxidative Lipoproteins
- But also, can be a rol of vasoprotection
- It is mediated
- By NO synthesis
- It is mediated
- Acts like regulator of ARG synthesis
- To avoid excessive Ureagenesis
- This improves, NO pathway
- L-citrulline, it's an important supplement
Amonnia Toxicity
- A problem associated with hyperammonemia
- It's that ammonia can crosses
- Blood-brain Barrier
- And this can be accumulate in the blood and also the brain
- And it causes neurological dysfunction
- That Includes
- Tremor
- Ataxia
- Seizures
- Coma
- Death
- That Includes
- However, the mechanism of brain damage is unclear
- But, it's known that in brain, liver and muscle ammonia
- It's metabolized to Glutamine
- And patients with OTC deficiency
- It is thought that intracellular glutamine.
- Is stored by the
- Astrocytes
- This pathway is thought to be one of the main ways in which brain damage occurs.
- Astrocytes
- Is stored by the
- It is thought that intracellular glutamine.
- But in addition it can generate
- Excitotoxic Cell Death
- Drecrease in astrocyte transport
- Increased level of exrtracellular glutmate
- Lost of AMPA receptors
- More activation of NMDA receptors
- It has been seen that accumaltion of Tryptophan
- Can generate
- Abnormality
- Serotoninergic Neurotransmission
- Abnormality
- Can generate
- And patients with OTC deficiency
- It's metabolized to Glutamine
- But, it's known that in brain, liver and muscle ammonia
- Blood-brain Barrier
- It's that ammonia can crosses
- But also it has been that
- Increased potassium concentration
- And activated cotransporter isoform 1 Na+,-K+,-2Cl-
- In neurons without brain edema
- Can be main pathophysiology
- To generate
- Neuronal Disinhibition
- Seizures
- To generate
- Can be main pathophysiology
- Symptoms
- Patients that present
- Hyperammonemia
- Without metabolic acidosis
- With normal glucose level
- Testing for plama ammonia levels
- People during any age, that present
- An unexplained Neurogical in conscioness
- Unusual Neurogical illnes
- Liver failure
- Suspected Intoxication
- Normal levels are:
- Premature Neonates
- < 40 µmol/L
- Term Neonates
- < 150 µmol/L
- Infants and Children
- < 100 µmol/L
- Adolescents and Adults
- < 11-32 µmol/L
- Premature Neonates
- And exist other exams
- Urinary Ortic levels
- Ezyme Activity Analysis
- Aminoacid Analysis
- Genetic Analysis
- People during any age, that present
- ARG deficency
- Elevated Concentrations
- Arginine
- Elevated Concentrations
- ASL deficency
- Elevated Concentrations
- Argininsuccinic
- Elevated Concentrations
- Patients that present
- A problem associated with hyperammonemia
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- Beschreibung
- Mindmap am Urea Cycle and Disorders, erstellt von Jairo Esteban Sanguino am 15/11/2020.
- Erstellt von
- Jairo Esteban Sanguino · Nov 2020
- Aktualisiert
- 16 Nov 2020
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