3. Pernicious anemia is a disease in which the intestine is unable to absorb vitamin B₁2, frequently due to the loss of the generically named "intrinsic factor" produced by the parietal cells of the stomach lining. Intrinsic factor is a glycoprotein that binds to vitamin B₁2 and is required for its uptake in the ilium. Vitamin B₁2 is synthesized only by microbes, and we get it either from digesting animal protein or from our commensal microbiome. Vitamin B₁2 is unique among metabolic cofactors in that it contains the trace element cobalt, coordinated in a corrin ring structure that is similar to the porphyrin ring system in heme. Loss of intrinsic factor, often through autoimmunity, results in the inability to absorb B₁2 and ultimately a loss of red blood cells that results in anemia and can be deadly ("pernicious"). (a) (c) DIETARY B12 ANTIBODIES I VITAMIN B12 INTRINSIC FACTOR PERNICIOUS ANAEMIA NUMBNESS HYDROXYCOBALAMIN ILEUM In pernicious anemia, N5-methyltetrahydrofolate accumulates, and cells run out of tetrahydrofolate. This results in an inability to synthesize nucleotides, preventing DNA replication and the production of red blood cells. Why does N5-methyltetrahydrofolate accumulate in the absence of vitamin B₁2? Write the related reaction using structural formula. Include the enzyme. (b) What other metabolites accumulate and are depleted in this pathway due to the loss of vitamin B12? How might loss of vitamin B₁2 alter gene expression (think about DNA methylation)?

3. Pernicious anemia is a disease in which the intestine is unable to absorb vitamin B₁2, frequently due to the loss of the generically named "intrinsic factor" produced by the parietal cells of the stomach lining. Intrinsic factor is a glycoprotein that binds to vitamin B₁2 and is required for its uptake in the ilium. Vitamin B₁2 is synthesized only by microbes, and we get it either from digesting animal protein or from our commensal microbiome. Vitamin B₁2 is unique among metabolic cofactors in that it contains the trace element cobalt, coordinated in a corrin ring structure that is similar to the porphyrin ring system in heme. Loss of intrinsic factor, often through autoimmunity, results in the inability to absorb B₁2 and ultimately a loss of red blood cells that results in anemia and can be deadly ("pernicious"). (a) (c) DIETARY B12 ANTIBODIES I VITAMIN B12 INTRINSIC FACTOR PERNICIOUS ANAEMIA NUMBNESS HYDROXYCOBALAMIN ILEUM In pernicious anemia, N5-methyltetrahydrofolate accumulates, and cells run out of tetrahydrofolate. This results in an inability to synthesize nucleotides, preventing DNA replication and the production of red blood cells. Why does N5-methyltetrahydrofolate accumulate in the absence of vitamin B₁2? Write the related reaction using structural formula. Include the enzyme. (b) What other metabolites accumulate and are depleted in this pathway due to the loss of vitamin B12? How might loss of vitamin B₁2 alter gene expression (think about DNA methylation)?