Iron, B12, Folate Metabolism

Ferri-reductase reduces

Fe3+ to Fe2+ (non heme iron, plant sources)

Fe2+ is absorbed by

Enterocytes in duodenum by DMT1 channel

Fe2+ stored in enterocytes as

Ferritin, Fe3+

Iron moved out of cell with

Ferroportin using hephaestin, goes into transferrin

Hepcidin inhibits

Ferroportin (iron transport out of cells)

Hepcidin induced by

inflammatory cytokines

RBC lifespan

120 days

Ferroportin resistance to hepcidin can cause

Iron overload, cannot block iron transport

Ferrochelatase

Directly inserts ferrous iron (Fe2+) into protoporphyrin IX, inhibited by lead poisoning

Ferrous iron

Fe2+

Ferric iron

Fe3+

dNTP

deoxynucleoside triphosphate, needed to synthesize DNA

Folate and B12 are needed for

dTTP, thymidine synthesis

If DNA synthesis is impaired, the cell

continues to grow but cannot divide

Ineffective DNA replication impacts

Bone marrow (ineffective hematopoiesis), GI tract (glossitis, diarrhea), skin and hair follicles (poor wound healing, hair loss), embryo (birth defects)

Synthetic folic acid needs to be

reduced (DHF to THF)

DHF

dihydrofolate

THF

tetrahydrofolate, reduced and can act as a carrier for one-carbon groups

dUMP converts to

dTMP using 5,10-methylene-THF

dTMP phosphorylates to

dTTP, used in DNA synthesis

10-formyl-THF supports

purine synthesis (adenine and guanine)

Methotrexate blocks

DHF reductase (DHFR), prevents THF production, can’t synthesize dTMP/dTTP

5-methyl-THF

Most reduced carbon form that THF carries, very stable, needs B12 to convert back to THF and restart cycle

Folate trap

If no B12, increase in 5-methyl-THF, impaired DNA synthesis

B12 aka

cobalamin

B12 becomes methyl-B12 after reacting with

5-methyl-THF, which is converted back to THF

Methyl-B12 forms

methionine from homocysteine

B12 deciciency causes

5-methyl-THF and homocysteine buildup

B12 also converts

methylmalonyl CoA (MMA CoA) to succinyl CoA (used for energy/citric acid cycle)

MMA CoA (unstable) converts to

MMA

Pepsinogen

Released by chief cells in stomach, converts to pepsin in acidic environment (stomach acid)

Pepsin

releases B12 from food proteins

Haptocorrin

Binds B12 to protect it

Intrinsic factor (IF)

Secreted by parietal cells, bind B12 after duodenum

Pancreatic proteases

Degrade haptocorrin to free B12, released in duodenum

IF-B12 complex is absorbed in

terminal ileum

After absorption in terminal ileum, B12 dissociates from IF and binds

transcobalamin II, then enters blood through portal vein and is delivered to liver