Regulation of heme biosynthesis, differences between hepatocyte and erythroid cell, iron metabolism
Heme production takes place in both the mitochondria and the cytosol of cells, and it can also be obtained from dietary sources and transported between cells. Heme is an essential part of many proteins — most notably hemoglobin, but also myoglobin, cytochromes, catalase, peroxidases, and nitric oxide synthase. There are several forms of heme; the most common is heme b found in hemoglobin. Variants like heme a and heme c are found in cytochromes involved in oxidative phosphorylation.
The key enzyme controlling heme synthesis is 5'-aminolevulinic acid synthase (ALA-S), which exists in two forms: ALAS1 (found in all tissues) and ALAS2 (used for synthesis in erythroid cells). ALAS2 is encoded on the X chromosome.
Heme synthesis involves eight enzymatic steps and takes place partly in the mitochondria and partly in the cytosol:
1.The process begins in mitochondria where succinyl-CoA (from the TCA cycle) combines with glycine to form 5'-aminolevulinic acid (ALA). This reaction is catalyzed by ALA synthase (ALAS) and requires vitamin B6 (pyridoxal phosphate). It’s the rate-limiting step of the pathway.
2.ALA then moves to the cytosol, where two ALA molecules join to form porphobilinogen (PBG), catalyzed by ALA dehydratase (porphobilinogen synthase), a zinc-dependent enzyme.
3.Four PBG molecules are then linked into a linear compound called hydroxymethylbilane (HMB) via PBG deaminase (also called hydroxymethylbilane synthase).
4.This linear chain is cyclized into uroporphyrinogen III by uroporphyrinogen III synthase. This step is essential to prevent the formation of incorrect ring structures that could lead to porphyrias.
5.The side chains of uroporphyrinogen III are altered by uroporphyrinogen decarboxylase, converting it to coproporphyrinogen III.
6.Coproporphyrinogen III re-enters the mitochondria, where it is converted to protoporphyrinogen IX by coproporphyrinogen oxidase.
7.Protoporphyrinogen IX is then oxidized to protoporphyrin IX by protoporphyrinogen oxidase.
8.Finally, ferrochelatase catalyzes the insertion of a ferrous iron (Fe²⁺) into protoporphyrin IX to produce heme.
A major part of heme biosynthesis happens in Erythroid cells via ALAS-II.
Iron metabolism:
Iron is absorbed in the intestine by enterocytes in two forms: heme iron via HCP1 and non-heme Fe³⁺, which is reduced to Fe²⁺ by Dcytb and absorbed via DMT1. Inside enterocytes, iron can be stored as ferritin or exported into the bloodstream by ferroportin. Once in the blood, Fe²⁺ is oxidized to Fe³⁺ by hephaestin or ceruloplasmin and binds to transferrin for transport to tissues like the bone marrow, liver, and macrophages. Macrophages recycle iron from old red blood cells and export it via ferroportin, while hepatocytes store iron and regulate systemic iron through the hormone hepcidin. Hepcidin inhibits ferroportin, thus decreasing iron export from cells and reducing serum iron levels to maintain homeostasis.
