Mind map

Urea Cycle and Disorders

Jairo Esteban Sanguino Spanish

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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 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
        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
        This occurs by three ways
        Metabolizing Glutamine
        Glutamate Dehydrogenase (GDH)
        Small intestine
        Glutaminase
        Mucisa Epithelial Tissue
        Bacterial Urease
        Large Intestine
        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
        And ammonia produced is transported to
        Liver
        Here
        Glutaminase
        Takes Glutamine
        Generates
        Glutamate
        Ammonia
        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
        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
        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
        Other point, is that appears
        After of birth
        Hiperammonemia
        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
        Fumarate
        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
        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
        In deficiency of this transporter
        Various amino acids, are elevated
        Citrulline
        Phenylalanine
        Threonine
        Tyrosine
        Methionine
        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
        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
        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
Citrulline
- L-citrulline, it's an important supplement
  - Safely
    - Patients with deficiency of
      - OCT
      - CPSI
- 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
  - 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
  - Acts like regulator of ARG synthesis
    - To avoid excessive Ureagenesis
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
      - 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.
        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
- 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
- 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
    - And exist other exams
      - Urinary Ortic levels
      - Ezyme Activity Analysis
      - Aminoacid Analysis
      - Genetic Analysis
  - ARG deficency
    - Elevated Concentrations
      - Arginine
  - ASL deficency
    - Elevated Concentrations
      - Argininsuccinic

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Description: Mind Map on Urea Cycle and Disorders, created by Jairo Esteban Sanguino on 15/11/2020.
Created by: Jairo Esteban Sanguino · Nov 2020
Updated: Nov 16, 2020
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Urea Cycle and Disorders

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