B6 And Homocysteine

MUST DO IL!!!!!!

Objectives

Identify B6 as a vitamin involved in many reactions of amino acid conversion and catabolism

  • essential for transamination, neurotransmitter synthesis, heme synthesis, and cysteine synthesis

Identify pyrodoxal phosphate as the coenzyme formed from vitamin B6

  • essential for transamination, neurotransmitter synthesis, heme synthesis, and cysteine synthesis
  • amino and aldehyde group participate in reaction
  • transamination enzymes:
    • AST
    • Aspartate aminotransferase
    • Glutamate-oxaloacetate transaminase

Identify transamination as a crucial vitamin B6-dependent reaction for conversion of protein to carbohydrate

AST.gif
  • In the ransamination reaction, the B6 dependent AST transforms amino acid aspartate to oxaloacetate, which is a part of the Kreb cycle. It also transforms Glutamate to alpha ketoglutarate, which is also a carbohydrate

Identify alcoholics and patients receiving some medications as being at risk for pyridoxin deficiency as a result of lowered B6 absorption

  • requirement is proportional to dietary protein intake (more protein, more requirement)
  • Drugs such as isoniazid decrease absorption
  • Alcoholics may exhibit: anemia, peripheral neuropathy, weakness, irritability, parasthesia due to deficiency

Recognize that the neurological symptoms of B6 deficiency arise from an impairment of neurotransmitter synthesis

Identify that sideroblastic anemia can result from impaired heme synthesis caused by defective genes or by B6 deficiency

  • Heme synthesis is a condensation reaction
    • Glycine + Succinyl CoA -> ALA synthase (mitochondrial enzyme) -> delta aminolevulinic acid (ALA)
  • Sideroblastic anemia: Iron deposit in the blasts, creating "dots" on the microscope.
  • Iron can't be transported into cells to make heme, because iron can't exit the mitochondria in the first place
  • Blasts have a ringed look
  • Sideroblastic anemia can have genetic and acquired causes
    • Genetic
      • Rare
      • Problem with ALA synthase (heme synthesis)
      • Mitochondrial DNA defects (first step in heme sythensis takes place in mitochondria)
    • Acquired
      • B6 deficiency
      • Alcoholics (B6 deficiency)

Identify B6 as an example of a water-soluble vitamin with documented evidence of toxicity due to overdosing

  • pyridoxin megadosing can lead to toxicity
  • Neurological damage reported with 2-6g/day of B6
  • Mechanisms unknown, but may be due to overwhelming reactions that depends on pyridoxal phosphate, thereby decreasing glutamate levels. (Glutamate is an important neurotransmitter)

Summarize the rationale for dietary supplementation with B6, folate, and B12 to lower cardiovascular risk

homocysteine_metabolism.jpg
  • Patients with hereditary homocystinuria had lots of thrombi and clots
  • epidemiology studies show increased circulating homocysteine is a risk factor for cardivascular disease (possibly due to thrombi formation)
  • Deficiency of folate, B6, or B12 can raise blood homocysteine levels
  • Cysteine eventually produces glutathione, which is a oxidative species scavenger

Main Teaching Points

  • Pyridoxal phosphate (PP) is the coenzyme for vitamin pyridoxin (B6)
  • PP is the coenzyme for many enzymes involved in the transformation of amino acids
  • PP is essential for transaminase function, heme synthesis, neurotransmitter production, and Hcy metabolism
  • Genetic sideroblastic anemia is usually the consequence of defective ALA synthase, the first enzyme in the heme synthetic pathway
  • Acquired sideroblastic anemia usually results from poor B6 supply or absorption
  • "Ringed sideroblasts" in the bone marrow are diagnostic for sideroblastic anemia
  • Sideroblastic anemia results in secondary iron overload from increased intestinal absorption and from blood transfusions
  • B6 supplementation may improve lower-that-normal ALA sythase activity
  • The disposition of Hcy, a potentially-damager amino acid, is dependent on reactions that require B6, B9, and B12
  • Some studies have demonstrated that supplements of B6, B9, and B12 can lower circulating Hcy
  • MTHR polymorphisms are common and contribute to higher-than-normal circulating Hcy levels

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