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Digestion And Metabolism > One Carbon Metabolized > Flashcards

One Carbon Metabolized Flashcards

1
Q

How is serotonin metabolized?

A
  • Serotonin is synthesized in the gut, platelets & CNS
  • Synthesized from tryptophan
  • Serotonin is metabolized to 5-hydroxyindole acetic acid (5-HIAA) by MAO
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2
Q

What is the significance of tetrahydrobiopterin ?

A
  • Coenzyme required for many amino acid hydroxylation reactions
  • Reactions requiring tetrahydrobiopterin:
  1. Phenylalaninehydroxylase(convertsPhetoTyr)
  2. Tyrosinehydroxylase(convertsTyrtoDOPA)
  3. Tryptophan hydroxylase (converts Trp to 5-hydroxy tryptophan)
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3
Q

Describe the clinical significance of PKU II

A

• Deficiency of dihydrobiopterin synthesis or dihydrobiopterin reductase (BH2/BH4)

• Much more severe CNS symptoms
- Decreased neurotransmitter synthesis- serotonin, and the catecholamines: (dopamine, norepinephrine, epinephrine)

• Treatment includes dietary Phe restriction and providing dietary biopterin and precursors of the neurotransmitters
- This is difficult because of Blood Brain Barrier

• Treatment also includes Saproterin as structural analogue of BH4 - Difficulties remain though because of Blood Brain Barrier

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4
Q

What is the biochemical defect in PKU II?

A

Dihydrobiopterin (BH2) or dihydrobiopterin reductase(NADPH) is deficient

BH4 is needed for ring hydroxylation reaction:

  1. Conversion of PHE to TYR
  2. Formation of L-DOPA (catecholamine precursor)
  3. Formation of serotonin (melatonin precursor)
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5
Q

Summarize the impact of PKU II

A

Tyrosine cannot create L-Dopa, nor catecholamines

Still has mousey smell from phenylpyruvuc acid in urine

  1. Decreased melanin synthesis
  2. Tyrosine becomes an essential amino acid
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6
Q

Describe tetrahydrobiopterin deficiency

A

Deficiency of dihydrobiopterin synthesis or dihydrobiopterin reductase results in hyperphenylalaninemia & decreased synthesis of neurotransmitters (catecholamines, serotonin).
• Results in delayed mental development and seizures

  • Management includes addition of dietary tetrahydrobiopterin
  • Provision of neurotransmitters precursors in the diet
  • Dietary Phe restriction
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7
Q

Describe elevated phenylakanine (and its keto derivatives) as a clinical sign

A 
Elevated phenylalanine (and its keto derivatives) as a clinical sign
• Seen as elevated phenyllactate, and elevated phenylpyruvic acid
• Can be due to deficiency of PAH enzyme (PKU-I; Autosomal recessive)

• Can be due to deficiency of BH4 (PKU-II)

  • Due to inability to form it
  • Or due to inability to reduce BH2 to BH
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8
Q

What is the biological influence of S-adenosyl methionine?

A
  • Synthesized from methionine
  • It is a methyl group donor in
  • Epinephrine Synthesis of
  • Creatine Synthesis of
  • Choline Formation (phosphatidylcholine, and acetylcholine)
  • Methylation of DNA and histone (recall genetics; epigenetic gene regulation)
  • After donating its methyl group, SAM is converted to homocysteine
  • Homocysteine can have two fates
  • Conversion to Cysteine (requires PLP) (transsulfuration pathway)
  • Conversion back to methionine (requires B12 and methylfolate)
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9
Q

Give the role of tetrahydrofolate in 1-C pool

A

Sources of 1-carbon units (Amino acids: Glycine, Serine, Histidine)
THF empty. —>

One carbon groups are donated
by catabolism of amino acids

—> 1-Carbon pool (Formyl-THF, Methylene-THF, etc)—>

THF empty. THF acts as a reversible carrier of one carbon groups

—> Products formed using the 1-carbon pool (Purines, Thymidine). Required for DNA & RNA synthesis (cell division)

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10
Q

What are the forms of THF in 1-C pool?

A

• Formyl THF and methylene THF are used as 1- C donors for
synthesis of Purines & pyrimidine (thymidine)

• Methyl THF is used ONLY in one reaction:
- Which is the conversion of Homocysteine to Methionine - Remember this reaction also requires B12 (cobolamine)

• Methyl THF might be considered as the ‘STORAGE’ form of THF - But it is NOT able to function in most reactions
- Methyl THF participates in only one reaction that we are concerned with.

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11
Q

What are the forms of THF ?

A

Different forms of THF with the C-group in various oxidized forms.

Formyl THF methylene THF

Used for synthesis of Purines, Thymidine. Required for DNA & RNA synthesis (cell division)

Methylene THF —> methyl THF (this is irreversible)

In one big reaction:

Homocysteine—> methionine (uses methionine synthase)
Methyl THF —> THF via methylcobalamin (B12)

THF is now empty and it may now reenter the pool of available 1-C carriers by accepting a 1-C group from an amino acid

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12
Q

What are the changes in folate deficiency?

A
  • There is reduction in the 1-C donors, resulting in reduced synthesis of Purine & pyrimidine nucleotides
  • Delay in DNA synthesis resulting in reduced rates of cell division
  • Effects on RBC formation (erythropoiesis) – Macrocytes and Megaloblasts are observed in blood smears
  • Decrease in hemoglobin concentration (macrocytic, megaloblastic anemia)
  • WBC: Polysegmented neutrophils in blood smear
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13
Q

What are the changes in folate deficiency?

A

Red cells in macrocytic anemia are larger than normal

Hypersegmented neutrophil on peripheral blood smear

Blood smear in patients with folate deficiency and vitamin B12 deficiency are similar

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14
Q

What is the impact of the folate deficiency?

A
  • The richest sources of folate are green leafy vegetables
  • Folate deficiency during pregnancy (preconception & first month of conception) is associated with a high risk of neural tube defects (spina bifida) in the fetus
  • Folate deficiency can be present in high risk groups
    • Pregnancy
    • Chronic alcoholics
    • Persons who avoid vegetables in the die
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15
Q

How can a folate deficiency be diagnosed?

A
  • Histidine is metabolized to FIGLU (formiminoglutamate)
  • FIGLU is next converted to glutamate in the presence of folate
  • In folate deficiency, histidine metabolism is limited, and FIGLU accumulates
  • There is increased FIGLU excretion in urine in folate deficiency
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16
Q

Describe vitamin B12 deficiency

A
  • Deficiency of vitamin B12 is characterized by macrocytic anemia and neurological features (tingling sensation in the hands and feet, inability to walk, psychiatric disturbances, urinary incontinence……)
  • Intrinsic factor is released from Parietal cells of stomach (recall parietal cells also secrete HCl). Intrinsic factor binds to vitamin B12.
  • Vitamin B12 is absorbed in terminal ileum as a complex of B12 and the intrinsic factor
17
Q

What are the functions of vitamin B12?

A
  • Animal sources are rich Vitamin B12 • Deficiency might be seen in vegans
  • There are two main reactions which require B12 as a coenzyme:
  1. Methionine synthase (also requires methyl THF)
  2. MethylmalonylCoAmutase
18
Q

What 2 reactions require vitamin B12?

A
  1. Homocysteine—> methionine via methionine synthase

Methyl THF + methylcobalamin (B12)(cofactors)

  1. Methylmalonyl CoA—> Succinyl CoA via methylmalonyl CoA mutase

Cobalamin (B12) (cofactor)

19
Q

Describe vitamin B12. deficiency symptoms

A
  • Patients with Vitamin B12 deficiency have increased levels of methylmalonate in circulation and increased urinary levels of methylmalonate
  • Elevated homocysteine levels are present in B12 and folate deficiency and cannot be used to distinguish folate from B12 deficiency

• Patients with Vitamin B12 deficiency also have deficiency of the usable form of folate (this is Folate trap hypothesis)
- In B12 deficiency, folate levels might be normal or high, but the folate is not usable because it is in the methyl-THF form

20
Q

What is the mechanism of folate trap?

A

• In B12 deficiency, cellular folate is trapped as methyl-THF
- Forms of folate (methylene, formyl THF) may eventually convert to methyl THF

  • Methyl-THF cannot be converted back to the other forms of THF (irreversible reaction)
  • Other forms of THF become deficient resulting in reduced purine and thymidine synthesis and reduction in the rates of cell division (macrocytic anemia)
21
Q

What are the consequences of vitaamin B12 deficiency?

A

-Ineffective DNA synthesis( due to folate trap)—> megaloblastic anemia

-inadequate myelin synthesis —> neurologic damage
Due to SAM deficiency & accumulation of methylmalonate

Hyperhomocysteinemia—> cardiovascular disease

22
Q

What are the risk factors of vitamin B12 deficiency?

A

• Vitamin B12 is stored in liver, deficiency usually takes some time to develop

• Risk factors for developing deficiency
- Strict vegans
- Failure to absorb B12 due to
• Atrophic gastritis (loss of Parietal cells)
• Pernicious anemia (autoimmune destruction of Parietal cells) • Disease of the Ileum (tuberculosis, Crohn’s disease)

23
Q

Compare and contrast folate deficiency and vitamin B12 deficiency

A
  • Folate deficiency
  • Source: Green vegetables
  • Macrocytic, Megaloblastic anemia
  • Increased homocysteine
  • No folate stores – deficiency develops early

• B12 deficiency
• Source: animal
• Macrocytic megaloblastic anemia (folate trap) + Neurological manifestations
• Increased homocysteine +
methylmalonate
• Liver stores B12 – deficiency develops late

Digestion And Metabolism (57 decks)

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