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MTC Block 2: Post Quiz Material > 5- Amino Acid Metabolism > Flashcards

5- Amino Acid Metabolism Flashcards

1
Q

Metabolism is closely linked to…

A
  • nutrition and the availability of nutrients

- energy formation = vital component of metabolism

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2
Q

Nonessential amino acids (our body can make them)

A
  • synthesized by humans IN THE LIVER
  • used to make other molecules
  • short pathways
  • diet not sufficient
  • required in high quantities because they are converted to other important molecules and protein synthesis of specific proteins
  • Alanine
  • Asparagine
  • Aspartate
  • Glutamate
  • Glutamine
  • Glycine
  • Cysteine
  • Proline
  • Tyrosine
  • Serine

all A, all G, CPTs

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3
Q

Conditionally essential amino acids (our body can make them BUT THEY ARE required to some degree in young growing animals and/or sometimes during illness)

A
  • synthesized by humans IN THE LIVER
  • used to make other molecules
  • short pathways
  • diet not sufficient
  • required in high quantities because they are converted to other important molecules and protein synthesis of specific proteins
  • arginine
  • cysteine
  • glutamine
  • glycine
  • proline
  • tyrosine

remember with
abby can get guns per trump

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4
Q

essential amino acids (our body cannot make them so we need to ingest them)

A
  • Used mainly for protein synthesis (except tryptophan and phenylalanine)
  • long pathways needed to generate them
  • we usually ingest “complete proteins” or mix of proteins that provide all essential amino acids (so we evolutionarily lost ability to make them)
  • histidine
  • isoleucine
  • leucine
  • lysine
  • methionine
  • phenylalanine
  • threonine
  • tryptophan
  • valine

remember these with
PVT . TIM . HALL

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5
Q

sources the body has for amino acids

A
  1. body protein degradation
    - lysosome
    - ubiquitin-proteasome
  2. dietary proteins
    - stomach -> intestine -> uptake -> transport to cells via blood
  3. synthesis of non-essential amino acids from…
    - intermediates of citric acid cycle
    - intermediates of glycolysis
    - other amino acids
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6
Q

fates of amino acids in the body

A
  1. body protein synthesis
  2. catabolism
    - glusos/glycogen
    - urea/co2/h2o
    - ketone bodies, fatty acids
  3. biosynthesis of non-protein nitrogenous tissue constituents
    - porphyrin
    - creatine
    - hormones
    - neurotransmitters
    - purine
    - pyrimadines
    - niacin
    - thyroxine
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7
Q

Intracellular Protein Degradation

A

Both occur within the cell

  1. lysosomal degradation
  2. ubiquitin-proteasome system
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8
Q

Lysosomal degradation

A

non-specific digestion

Location:
-Lysosome (pH 5)

Major enzymes:
-Acid hydrolases, ATP‐independent.

What is degraded:
-primarily extracellular proteins, such as plasma proteins that are taken into the cell by endocytosis, and cell‐ surface membrane proteins that are used in receptor‐mediated endocytosis

Process in brief

  1. Encapsulation into membrane vesicles
  2. Fusion with lysosomes
  3. ATP required for lysosomal proton pump (acidic pH)
  4. Proteolytic degradation at acid pH
  5. Non‐specific digestion
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9
Q

Ubiquitin-Proteasome System

A

specific digestion of targeted proteins

Location:
-Cytosol

Major enzymes:
-Ubiquitin‐conjugating enzymes (E1, E2, E3)

What is degraded:
-mainly endogenous proteins synthesized within the cell; short‐lived & abnormal proteins

Process in brief
1. Protein is tagged with ubiquitin (i.e. ubiquitination)
2. Polyubiquitin chain is degradation signal for the proteasome complex
3. The proteasome unfolds, deubiquitinates, and cuts the target protein into
fragments that are then further degraded to amino acids, which enter the
amino acid pool.
4. This is a specific process (unlike lysosome)

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10
Q

Getting amino acids from dietary protein degradation

A

Three major parts:

  1. Digestion
    - stomach
    - intestine
  2. Absorption
  3. Distribution
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11
Q

Digestion enzyme cascade

A
  1. Proteins

(pepsin)

  1. Polypeptides

(trypsin, chymotrypsin, elastase)

  1. Oligopeptides

(peptidase)

  1. Amino Acids
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12
Q

Digestive proteases

A
  1. Endopeptidases
    - hydrolyze peptide bonds within chains
    - pepsin, trypsin, chymotrypsin, and elastase
  2. Exopeptidases
    - aminopeptidases remove amino acid at N-terminus
    - carboxypeptidases remove amino acid at C-terminus
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13
Q

proenzymes/zymogens

A

inactive form of enzyme that needs to be activated

pepsinogen (acidic environment) pepsin

trypsinogen (enteropeptidase) trypsin

chymotrypsinogen
proelastase 
procarboxypeptidases 
(trypsin)
chymotrypsin
elastase 
carboxypeptidases
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14
Q

Digestion in the stomach

A

Part of Cascade: Protein to Polypeptide

pH: Low (pH ~2)

Major Cell Types:

  • Parietal cells – release HCl
  • Chief (peptic) cells – release pepsinogen

Major steps:

  1. Pepsinogen auto‐activated at low pH -> pepsin
  2. Pepsin active site is exposed
  3. Pepsin cleaves proteins at the peptide bond on N‐terminal side of large hydrophobic amino acids (preferably aromatic amino acids; Phe, Trp, Tyr, Leu)
  4. Large polypeptides result
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15
Q

Digestion in the intestine

Part of Cascade: Polypeptide to Peptide

A

pH: Neutral (pH ~7)

Major Cell Types:
-Pancreatic ductal epithelial cells – secrete bicarbonate
-Pancreatic acinar cells ‐ secrete trypsinogen,
chymotrypsinogen, proelastase all as inactive zymogen precursors

Major steps:
1. Pancreas secretes bicarbonate into the small intestine

  1. Pancreatic secretes these enzymes as zymogens:
    - Trypsinogen
    - Chymotrypsinogen
    - Proelastase
  2. Zymogen Activation
    -Enteropeptidase (Enterokinase) activates trypsinogen to
    trypsin
    -Trypsin activates chymotrypsinogen to chymotrypsin
    -Trypsin activates proelastase to elastase
  3. Enzyme activity: C‐terminal side
    - Trypsin: basic amino acids
    - Chymotrypsin: hydrophobic/aromatic amino acids
    - Elastase: small amino acids
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16
Q

Digestion in the intestine

Part of Cascade: Peptide to amino acid

A

pH: Neutral (pH ~7)

Major Cell Types:

  • Pancreatic acinar cells ‐ secrete carboxypeptidases as zymogens
  • Intestinal epithelial cells ‐ secrete active aminopeptidases

Major steps:

  1. Procarboxypeptidases to carboxypeptidase
  2. Peptidases cleave peptides into di‐ and tri‐peptides and free amino acids
    - Carboxypeptidase ‐ cleavage from C‐terminal end
    - Aminopeptidases ‐ cleavage from N terminal end
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17
Q

Getting amino acids from dietary protein degradation: absorption by intestinal epithelial cells

A

Free amino acids and small peptides are taken up by sodium co-transporters on intestinal epithelial cells

Amino acid transporters

  • on all cells within body
  • responsible for uptake of amino acids from blood and reuptake of amino acids in the renal tubuels
  • they are specific for classes of amino acids
  • if deficient, can lead to disease
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18
Q

Distribution of dietary amino acids

A
  • Intestine to liver via portal vein
  • insulin release stimulates amino acid uptake from body by cells throughout the body

In Liver

  • protein synthesis
  • other molecules

In other tissues

  • protein synthesis
  • other molecules
  • energy use- branched chain amino acids (valine, isoleucine, leucine)
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19
Q

precursors for de novo synthesis of amino acids

A
  • predominately from carbohydrate metabolism (glycolysis and tca cycle)
  • essential amino acids are required by diet
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20
Q

Cystinuria

Occurrence:
In Brief:
Symptoms:
Treatment:

A

Occurrence: 1:7000

In Brief:

  • Dibasic amino acid transporter deficiency (on intestinal cells)
  • basic (+ charge) amino acids cannot be reabsorbed
  • lysine, arginine, ornithine, cysteine
  • lysine and arginine are soluble at pH 5-7
  • cys-cys (Cystine) forms stones in kidney at pH 5-7
  • one of most common inherited diseases, and the most common genetic error of amino acid transport

Symptoms:

  • Blood in the urine
  • Severe pain in the side or the back (almost always on one side)
  • Nausea and vomiting
  • Pain near the groin, pelvis, or abdomen

Treatment:

  • hydration
  • increasing urine pH
  • chelation
  • nephrolithotripsy- surgical removal of kidney stones
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21
Q

Hartnup Disease

Occurrence:
In Brief:
Symptoms:
Treatment:

A

Occurrence: 1:10,000 autosomal recessive

In Brief:

  • Neutral aminoaciduria
  • Neutral Amino Transporter Deficiency
  • Neutral amino acids poorly absorbed in the intestine or reabsorbed by the renal tubules
  • Asparagine, Glutamine, Isoleucine, Phenylalanine, Methionine, Valine, Leucine, Tryptophan, Tyrosine
  • Lack of intestinal tryptophan uptake main cause of symptoms because tryptophan is normally converted into niacin.
  • Niacin is necessary for nicotinamide and NAD+
  • Body can’t make sufficient niacinamide (B‐complex vitamin)

Symptoms:

  • Pellagra‐like symptoms – Dermatitis; photosensitivity
  • Cerebral ataxia – damage to/degeneration of cerebellar nerve cells that control muscles
  • Psychiatric problems, mental retardation

Treatment:

  • high protein diet
  • niacin supplementation
  • avoid sunlight
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22
Q

Fates of free amino acids

A
  1. protein synthesis
    - incorporated into newly synthesized proteins
  2. energy via catabolism
    - removal of ammonia (transamination, oxidative deamination, excretion of urea)
    - breakdown of carbon skeletons (degradation of aa form intermediates that enter into gluconeogenesis and tca cycle)
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23
Q

1 fate of free amino acids: protein synthesis

A

~400g/day of aa used to synthesize new proteins

  • proteins synthesized daily are required to regulate processes like cell division, circadian rhythm proteins, cell regulator proteins, enzyme pathway control enzymes, energy metabolism, gene expression
  • typically short lived proteins
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24
Q

1 fate of free amino acids: energy production

A

-ALL cells have an amino acid pool, but don’t store them long‐term

-Amino acids that are not needed for protein synthesis or production of
amino acid derivatives are degraded for energy production.

  • Fed State: AA degradation –> ~ 10% of energy used
  • Early Fasting: AA from body proteins –> ~ 33% of energy used
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25
Q

overview of aa catabolism

A
  • Removing the α‐amino group is essential for producing energy from any amino acid, and is an obligatory step in the catabolism of all amino acids.
  • Once removed, this nitrogen can be incorporated into other compounds or excreted, with the carbon skeletons being metabolized.

Catabolism required to get energy from AA

  1. Ammonia removed
    - Dehydratases
    - Lyases
    - Aminotransferases
  2. Carbon skeleton breakdown
    - Acetyl CoA
    - Citric acid cycle intermediates
    - Glucose
    - Fatty acids
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26
Q

Removal of nitrogen from amino acids

A

-amino acids destined for energy metabolism must be deaminated (removal of nitrogen group) to yield the carbon skeleton

  • 3 mechanisms for removal of amino group
    1. Transamination
    2. oxidative deamination
    3. non-oxidative deamination

-sequential action of transamination and oxidative deamination of that resulting glutamate provide a pathway whereby the amino groups of most amino acids can be released as ammonia.

GENERAL PATHWAY
-a-amino acid —> a-keto acid

(transamination)

-a-ketoglutarate —> L-glutamate

(oxidative deamination)

-NH3 removed and goes into urea cycle with CO2

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27
Q

NH3 (ammonia) vs. NH4+ (ammonium ion)

A

Because the pKa is 9.3, the concentration of NH4+ at physiologic pH is almost 100 times that of NH3

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28
Q

Transamination

A
  • All amino acids except lysine and threonine have the ability to undergo transamination reactions.
  • The enzymes that catalyze these reactions are known as transaminases or aminotransferases.

Most commonly:

  • α‐ketoglutarate accepts ammonia —> glutamate
  • oxaloacetate accepts ammonia —> aspartate
  • Two major enzymes: “Liver enzymes” (Indicator of liver damage)
    1. alanine aminotransferase-ALT
    2. Aspartate aminotransferase- AST

PLP (pyridoxal phosphate) required

29
Q

alanine aminotransferase-ALT

A
  • ammonia from alanine to α‐ketoglutarate

- Forms glutamate + pyruvate

30
Q

Aspartate aminotransferase- AST

A
  • ammonia from aspartate to α‐ketoglutarate

- Forms glutamate + oxaloacetate

31
Q

Role of Pyridoxal Phosphate (PLP)

A
  • aminotransferases (or transaminases), are capable of removing the amino group from most amino acids and producing the corresponding α‐ keto acid.
  • required cofactor for these reactions.
  • derived from vitamin B6.
32
Q

Oxidative Deamination

A
  • Major enzyme: Glutamate dehydrogenase
  • Glutamate dehydrogenase plays a central role in nitrogen metabolism
  • Liberates free ammonia from glutamate in preparation for excretion
  • The direction of the reaction depends on the relative concentrations of glutamate, α‐ keto glutarate, and ammonia, and the ratio of oxidized to reduced co ‐enzymes.
  • After ingestion of a meal containing protein, glutamate levels in the liver are elevated, and the reaction proceeds in the direction of amino acid degradation and the formation of ammonia
  • The α‐ketoglutarate formed from this reaction can be used in citric acid cycle and for glucose synthesis
33
Q

gateway between free amonia and amino groups of most amino acids

A

multiple roles of glutamate in nitrogen homeostasis allow for this

34
Q

Non-oxidative deamination

A

Basic description:

  • Removal of a molecule of water by a dehydratase – e.g. serine or threonine dehydratase
  • Produces an unstable, imine intermediate that hydrolyzes spontaneously to yield an α‐keto acid and free ammonia
  • Unlike transamination, the amino group is not transferred to α‐ketoglutarate
  • This free ammonia can be present in the blood
Major Enzymes: 
Dehydratases
-Serine dehydratase
-Threonine dehydratase
-Require pyridoxal phosphate as coenzyme.

important molecules are serine, threonine, and histidine

Desulfhydrase

  • Cysteine desulfhydrase
  • Require pyridoxal phosphate as coenzyme.

Lyases
-Histidine

35
Q

Transport of ammonia to the liver after deamination

A
  • ammonia is highly toxic to cells and readily crosses blood‐brain barrier. Thus, its levels in blood are regulated.
  • ammonia is transported to liver in amino acid form
  • Two major routes are available in humans for the transport of ammonia from the peripheral tissues to the liver for its ultimate conversion to urea.

Ammonia transport amino acids

  1. Glutamine
  2. Alanine
36
Q

Ammonia transport mechanisms: Glutamine Synthetase/Glutaminase system

A
  • use by most cells other than muscle
  • combines ammonia (NH3) with glutamate to form glutamine— a nontoxic transport form of ammonia
  • glutamine is transported by the blood to the liver

-once in the liver, glutamine is cleaved by glutaminase to produce
glutamate and free ammonia

-the ammonia goes to the urea cycle

37
Q

Ammonia transport mechanisms: Glucose/Alanine Cycle

A

-Used primarily by muscle
-Transamination of pyruvate (the end product of aerobic glycolysis) to form alanine
ALT
-Alanine is transported by the blood to the liver
ALT
-Once in the liver, alanine is converted to pyruvate by transamination. Pyruvate feeds into gluconeogenesis to make glucose which can enter blood and be used by muscle (glucose‐alanine cycle)
-generates glutamate from α‐ketoglutarate.

Muscle during exercise

  • Glycolysis to pyruvate
  • Proteins degraded to amino acids
  • Amino acids degraded producing ammonia
  • Nucleic acids degraded releasing ammonia

Alanine synthesized from ammonia and pyruvate
-Alanine aminotransferase

Transport of alanine to the liver

In the liver, Alanine fate:

  • ammonia to glutamate to Urea cycle
  • Pyruvate to Gluconeogenesis
38
Q

Inter-organ amino acid exchange in both fed and fasting states

A

FED STATE

  • amino acids released by digestion of dietary proteins travel through the hepatic portal vein to the liver, where they are used for the synthesis of proteins, particularly the blood proteins, such as serum albumin.
  • The carbon skeletons of excess amino acids are converted to glucose or to triacylglycerols. The latter are then packaged and secreted in very low‐density lipoproteins (VLDLs).
  • Amino acids that pass through the liver are converted to proteins in cells of other tissues.

FASTING STATE

  • amino acids are released from muscle protein.
  • Some enter the blood directly. Others are partially oxidized and the nitrogen is stored in the form of alanine and glutamine, which enter the blood.
  • In the kidney, glutamine releases ammonia into the urine and is converted to alanine and serine.
  • In the cells of the gut, glutamine is converted to alanine. Alanine (the major gluconeogenic amino acid) and other amino acids enter the liver, where their nitrogen is converted to urea, which is excreted in the urine, and their carbons are converted to glucose and ketone bodies, which are oxidized by various tissues for energy. RBCs, red blood cells; TCA, tricarboxylic acid.
39
Q

The first reaction in the degradation of most of the protein amino acids involves the participation of:

A

PYRIDOXAL PHOSPHATE

Pyridoxal‐dependent transamination is the first reaction in degradation of all the common amino acids except threonine, lysine, proline, and hydroxyproline.

40
Q

Overview of urea cycle

A
  • Aspartate from citric acid cycle also feeds ammonia to urea cycle
  • The urea cycle describes the series of reactions that occurs mainly in the liver and is used to convert this ammonia to urea, which is then excreted by the kidneys
  • urea is produced by the liver, and then is transported in the blood to the kidneys for excretion in the urine.
  • Ammonia (toxic) to Urea (non‐toxic)
41
Q

Fate of amino acid carbons and nitrogen

A
  • Amino acid carbon can be used either for energy storage (glycogen, fatty acids) or for energy.
  • Amino acid nitrogen is used for urea synthesis.
  • One nitrogen of urea comes from NH4+, the other from aspartate.
42
Q

How does ammonia get to the urea cycle

A

Phases

  1. Delivery of ammonia to liver
  2. Delivery of ammonia to the mitochondria
  3. Delivery of ammonia to the urea cycle which is in the cytosol
    - Alanine (ALT)
    - Aspartate (AST)
  4. Synthesis of urea (happens in the cytosol)
  5. Release of urea into blood
  6. Concentrated and excreted by the kidney
43
Q

sources of ammonia for urea cycle

A
  • All of the reactions are irreversible except that of glutamate dehydrogenase (GDH).
  • Only the dehydratase reactions, which produce NH4+ from serine and threonine, require pyridoxal phosphate as a cofactor.
  • The reactions that are not shown occurring in the muscle or the gut can all occur in the liver, where the NH4+ generated can be converted to urea.
44
Q

The Urea Cycle: Input

A

Glutamine (from extrahepatic, peripheral tissues)
-Liberates free ammonia by action of glutaminase

Alanine (from muscle)
-Converted to pyruvate via alanine aminotransferase (ALT). This also drives conversion of α‐ketoglutarate to glutamate.

Glutamate (from conversion of other amino acids and alanine)
-Liberates free ammonia by action of glutamate dehydrogenase

Aspartate

  • in cytosol, feeds into citric acid cycle
  • in mitochondria, aspartate aminotransferase (AST) drives conversion of oxaloacetate (from citric acid cycle) to aspartate
45
Q

Urea Cycle reactions

A

THIS IS IN THE MITOCHONDRIA

  • ALT and AST shuttles come to mitochondria and become glutamate which then get converted to NH4+
    1. Formation of carbamoyl phosphate from NH4+ (uses 2ATP) —N-Acetylglutamate as allosteric activator
    2. Formation of citrulline with ornithine

THIS IS IN THE CYTOSOL

  1. Synthesis of argininosuccinate using citrulline and aspartate
  2. Cleavage of argininosuccinate to form arginine (fumarate leaves)
  3. Cleavage of arginine to ornithine, which goes back to work with citrulline in step 2 again
46
Q

Urea Cycle Step 1: Formation of Carbamoyl phosphate

A

Carbamoyl Phosphate Synthetase I (CPS1)

  • Absolute regulator – N‐Acetylglutamate (NAG)
  • Bicarbonate (HCO3), ammonia, 2 ATP required
  • NAG = allosteric activator —> binding enhances attraction among substrates

-NAG is produced by N‐Acetylglutamate Synthase (NAGS)

N‐Acetylglutamate Synthase (NAGS)

  • Arginine positive regulator
  • Requires H2O
  • Localized in mitochondria, primary in liver
  • Carbamoyl phosphate is how ammonia is fed into the urea cycle
  • This is a major step during regulation of the urea cycle
  • Arginine influences the urea cycle
47
Q

Urea Cycle Step 2: Formation of Citrulline

A

Carbamoyl Phosphate + Ornithine —> Citrulline
-The carbamoyl portion of carbamoyl phosphate is transferred to ornithine by
ornithine transcarbamoylase (OTC) as the high‐energy phosphate is released as Pi.
-The reaction product, citrulline, is transported to the cytosol.
-Ornithine and citrulline are basic amino acids that participate in the urea cycle, moving across the inner mitochondrial membrane via a cotransporter.

Ornithine is regenerated with each turn of the urea cycle, much in the same way that oxaloacetate is regenerated by the reactions of the citric acid cycle

The ornithine transcarbamoylase reaction occurs in the mitochondria, subsequent reactions of the urea cycle occur in the cytosol

48
Q

Urea Cycle Step 3: Synthesis of Argininosuccinate

A
  • citrulline is activated by ATP
  • Aspartate is added to citrulline
  • argininosuccinate formed
  • this is the thrid and final molecule of ATP consumed in the formation of urea
49
Q

Urea Cycle Step 4: Cleavage of argininocuccinate

A
  • Argininosuccinate is disassembled
  • Products are Arginine + Fumarate
  • The arginine formed by this reaction serves as the immediate precursor of urea.

Fumarate produced in the urea cycle is hydrated to malate, providing a link with several metabolic pathways.

  • e.g., the malate can be transported into the mitochondria via the malate shuttle, re‐enter the tricarboxylic acid cycle
  • Malate can get oxidized to oxaloacetate (OAA), which can be used for gluconeogenesis or can be converted to aspartate via transamination and can enter the urea cycle
50
Q

Urea Cycle Step 5: Cleavage of arginine

A
  • arginase cleaves arginine to ornithine and urea, and occurs almost exclusively in the liver
  • whereas other tissues, such as the kidney, can synthesize arginine by these reactions, ONLY THE LIVER CAN CLEAVE ARGININE (SYNTHESIZE UREA)
51
Q

Fate of Urea

A
  • urea diffuses from liver and is transported in blood to kidneys for filtration and excretion in urine
  • a portion of teh urea diffuses from blood into intestine and is cleaved to CO2 and NH3 by bacterial urease. this ammonia is partly lost in poop and is partly reabsorbed into blood
52
Q

serum urea measurements

A
  • critical in monitoring pts with diff metabolic diseases where metabolism of aa may be affected
  • relies on urease enzyme resulting in ammonia which is detected by phenol (berthelot reaction)
53
Q

Regulation of urea cycle

A
  • In general, the urea cycle is regulated by substrate availability; the higher the rate of ammonia production, the higher is the rate of urea formation.
  • Regulation by substrate availability is a general characteristic of disposal pathways, such as the urea cycle, which remove toxic compounds from the body. This is a type of “feed‐forward” regulation, in contrast to the “feedback” regulation characteristic of pathways that produce functional end products.

On a short time scale —> availability of N‐acetylglutamate

  • N‐Acetylglutamate is synthesized from acetyl coenzyme A and glutamate by N‐acetylglutamate synthase, in a reaction for which arginine is an activator.
  • Therefore, the intrahepatic concentration of N‐acetylglutamate increases after ingestion of a protein‐rich meal, which provides both a substrate (glutamate) and the regulator of N‐acetylglutamate synthesis (arginine). This leads to an increased rate of urea synthesis.
  • During a fast, protein is broken down to free amino acids which are used for gluconeogenesis. The increase in protein degradation during fasting results in increased urea synthesis and excretion, a mechanism to dispose of the released nitrogen.

On a long time scale —> synthesis of urea cycle enzymes

54
Q

energy requiring steps of urea cycle

A

3 ATP REQUIRED IN TOTAL

  • carbamoyl phosphate synthetase 1 uses 2 ATP
  • Argininosuccinate synthetase uses 1 ATP
55
Q

Hyperammonemia (Description)

A
  • Normal: the capacity of the hepatic urea cycle exceeds the normal rates of ammonia generation, and the levels of serum ammonia are normally low (5–35 μmol/L).
  • However, when liver function is compromised, due either to genetic defects of the urea cycle or liver disease, blood levels can rise above 1,000 μmol/L.
  • Hyperammonemia is a medical emergency, because ammonia has a direct neurotoxic effect on the central nervous system (CNS).
56
Q

Causes of Hyperammonemia

A

Two major types:

  1. Aquired hyperammonemia: Liver Disease
    - viral hepatitis
    - reyes syndrome
    - cirrhosis
  2. Congential hyperammonemia
    - Deficiencies in each of the five enzymes in the urea cycle have been found – most common among the genetic causes
    - prevalence: 1:25,000 live births
    - Ornithine transcarbamoylase (OTC) deficiency, which is X‐linked recessive, is the most common of these disorders, predominantly affecting males, although female carriers may become symptomatic.
    - For the other enzymes in the urea cycle, they are autosomal recessive.
    - In each case, the failure to synthesize urea leads to hyperammonemia during the first weeks following birth.
    - Severity depends on mutation
    - Hyperammonemia, sometimes severe, occurs in inborn errors of metabolism other than the urea cycle defects but the pathogenesis for hyperammonemia in some of these conditions is not fully understood.
57
Q

Hyperammonemia Symptoms

A

Symptoms:

  • Tremors
  • Slurring of speech
  • Somnolence (prolonged drowsiness)
  • Vomiting
  • Cerebral edema
  • Blurred vision
  • At high concentrations, ammonia can cause coma and death.

High ammonia in

  • Cells–osmoticeffect‐brain
  • Blood

-Associated with high levels of transport amino acids– glutamine and alanine

  • Level of arginine in blood can tell you:
  • Elevated —> arginase deficiency
  • Low —> CPSI, OTC, or NAGS deficiency
58
Q

Hyperammonemia Treatment

A
  1. Low protein diet
  2. Nitrogen waste medications
    - Benzoate
    - Phenylbutyrate
  3. Other treatments depending on deficient enzyme
    - Citrulline: Ornithine transcarbamoylase deficiency
    - Arginine: Argininosuccinase lyase deficiency
  4. Lactulose – acidifies GI track – protonates ammonia and traps in the stool
  5. Hemodialysis
  6. Liver transplant
59
Q

How do benzoate and phenylbutyrate help treat hyperammonemia?

A
  • The aromatic acids benzoate and phenylbutyrate, administered in the diet, are metabolized and combine with glycine and glutamine, respectively.
  • The products are excreted in the urine. Subsequent synthesis of glycine and glutamine to replenish the pool of these intermediates removes ammonia from the bloodstream.
60
Q

Type I Hyperammonemia, CPSD

A

Enzyme Deficiency: Carbamoylphosphate synthetase I

-with 24h–72h after birth infant becomes lethargic, needs stimulation to feed, vomiting, increasing lethargy, hypothermia and hyperventilation; without measurement of serum ammonia levels and appropriate intervention infant will die: treatment with arginine which activates N‐acetylglutamate synthetase

61
Q

N‐acetylglutamate synthetase deficiency

A

Enzyme Deficiency: N‐acetylglutamate synthetase

-severe hyperammonemia, mild hyperammonemia associated with deep coma, acidosis, recurrent diarrhea, ataxia, hypoglycemia, hyperornithinemia: treatment includes administration of carbamoyl glutamate to activate CPS I

62
Q

Type 2 Hyperammonemia, OTCD

A

Enzyme Deficiency: Ornithine transcarbamoylase

most commonly occurring UCD, only X‐linked UCD, ammonia and amino acids elevated in serum, increased serum orotic acid due to mitochondrial carbamoylphosphate entering cytosol and being incorporated into pyrimidine nucleotides which leads to excess production and consequently excess catabolic products: treat with high carbohydrate, low protein diet, ammonia detoxification with sodium phenylacetate or sodium benzoate

63
Q

Classic Citrullinemia, ASD

A

Enzyme Deficiency: Argininosuccinate synthetase

episodic hyperammonemia, vomiting, lethargy, ataxia, siezures, eventual coma: treat with arginine administration to enhance citrulline excretion, also with sodium benzoate for ammonia detoxification

64
Q

Argininosuccinic aciduria, ALD

A

Enzyme Deficiency: Argininosuccinate lyase (argininosuccinase)

-episodic symptoms similar to classic citrullinemia, elevated plasma and cerebral spinal fluid argininosuccinate: treat with arginine and sodium benzoate

65
Q

Hyperargininemia, AD

A

Enzyme Deficiency: Arginase

-rare UCD, progressive spastic quadriplegia and mental retardation, ammonia and arginine high in cerebral spinal fluid and serum, arginine, lysine and ornithine high in urine: treatment includes diet of essential amino acids excluding arginine, low protein diet

66
Q

Diagnosing Hperammonemia

A
  • The absence of a urea cycle enzyme can result in hyperammonemia or in the buildup of one or more urea cycle intermediates, depending on the enzyme that is missing.
  • Given that most urea cycle steps are irreversible, the absent enzyme activity can often be identified by determining which cycle intermediate is present in especially elevated concentration in the blood and/or urine
  • if you have a build up of something then you know the enzyme that acts on it is deficient
67
Q

impact of metabolic disease on newborn care

A
  • Since the initiation in the United States of newborn screening programs in the 1960s, all states now conduct metabolic screening of newborns, although the scope of screen employed varies among states.
  • The powerful and sensitive technique of mass spectrometry can in a few minutes detect over 40 analytes of significance in the detection of metabolic disorders.
68
Q

which molecule directly donates a nitrogen atom for the formation of urea during the urea cycle?

A

aspartate

69
Q

how does your body prevent ammonia toxicity

A

ammonia is transported as part of amino acids glutamine and alanine to liver for synthesis of urea

MTC Block 2: Post Quiz Material (7 decks)

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