The Ins and Outs of Heme Synthesis: A Comprehensive Overview of the Complex Pathway and its Regulation

all steps of heme synthesis

-delta aminolevulinate synthase (ALAS) catalyzes condensation reaction between succinyl CoA and glycine to form delta aminolevulinate (ALA), gives of CoA and CO2-porphobilinogen synthase catalyzes porphobilinogen synthesis. 2 molecules of ALA required for each porphobilinogen molecule. 8 molecules of ALA are needed to make 4 porphobilinogen for the next step -porphobilinogen deaminase catalyzes a condensation reaction. Four molecules of porphobilinogen are linked to make a linear tetrapyrrole (pre-uroporphyingen). 4 NH4+ are released.-uroporphyrinogen III synthase catalyzes a cyclization of linear tetrapyrrole into uroporphyrinogen III which is an asymmetric ring -methyl and vinyl side chains are formed and alter saturation of ring constituents, ending with protoporphyrin IX.-ferrochelatase (enzyme) chelates ferrous iron into protoporphyrin IX to form heme. Occurs in mitochondria

Heme synthesis is a complex process that occurs in multiple tissues of the body, primarily in the liver and bone marrow. The process involves eight enzymatic reactions and requires several cofactors, including iron and vitamin B6. The overall pathway of heme synthesis can be divided into three stages:

Stage 1: Synthesis of Aminolevulinic Acid (ALA)
– The first and rate-limiting step of heme synthesis involves the production of aminolevulinic acid (ALA) from glycine and succinyl-CoA catalyzed by the enzyme ALA synthase.
– This reaction occurs in the mitochondria of most cells and is regulated by feedback inhibition from heme.
– ALA is the precursor for the remainder of the heme synthesis pathway.

Stage 2: Conversion of ALA to Protoporphyrin IX
– The next four steps of heme synthesis involve the conversion of ALA to protoporphyrin IX.
– ALA is transported out of the mitochondria and undergoes two sequential reactions involving the enzymes porphobilinogen synthase and porphobilinogen deaminase to form porphobilinogen.
– Four molecules of porphobilinogen are then covalently linked by the enzyme uroporphyrinogen III synthase to form uroporphyrinogen III.
– This molecule is converted to coproporphyrinogen III by the enzyme uroporphyrinogen III decarboxylase, followed by the conversion of coproporphyrinogen III to protoporphyrinogen IX by the enzyme coproporphyrinogen III oxidase.
– Protoporphyrinogen IX is subsequently oxidized to protoporphyrin IX by the enzyme protoporphyrinogen oxidase.

Stage 3: Incorporation of Iron and Formation of Heme
– The final three steps of heme synthesis involve the incorporation of iron into protoporphyrin IX and the formation of heme.
– Iron is incorporated into protoporphyrin IX by the enzyme ferrochelatase to form heme.
– Heme is then further processed by enzymes in the liver and spleen to produce bilirubin, which is excreted in the bile.

Overall, heme synthesis is a tightly regulated and complex pathway that requires multiple enzymes and cofactors. Defects in any one of these enzymes can lead to various forms of porphyria, a group of inherited disorders characterized by abnormalities in heme synthesis.

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