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Heme Synthesis and Metabolism

Heme Synthesis and Metabolism 

The heme is an iron-containing compound of the porphyrin type which makes the non-protein part of hemoglobin and some other biological molecules. 

• One oxygen atom attaches to the iron of each heme group, allowing a single hemoglobin molecule to carry four oxygen atoms. 

• Each erythrocyte contains about 250 million hemoglobin molecules. 

Hemoglobin consists of two components: a protein chain (globin) and a heme molecule. 

Heme consists of a protoporphyrin ring into which a ferrous iron atom has been inserted. 

The initial reaction in the heme synthesis pathway is the combination of glycine and succinyl coenzyme A (CoA) to form δ-aminolevulinic acid (ALA), which is catalyzed by the enzyme aminolevulinic acid synthetase (ALA synthetase). 

Pyridoxal 5’-phosphate (derived from pyridoxine, or vitamin B6), is an essential cofactor in the reaction. 

The final step in the pathway is the insertion of the ferrous iron atom into protoporphyrin IX, catalyzed by the enzyme ferrochelatase. 

Defects in various enzymes in the heme synthesis pathway cause the porphyrias; other defects in the heme synthesis pathway result in the sideroblastic anemias. 

The erythrocyte life cycle: extravascular and intravascular hemolysis 

Heme Breakdown 

Erythrocytes are born in the bone marrow. 

After losing their nucleus, they still contain ribonucleic acid (RNA) and continue to synthesize hemoglobin for 4 days (reticulocytes). 

Normally, three of these days are spent in the marrow and the fourth in the circulation. 

After ~120 days, most erythrocytes (90%) are phagocytized and destroyed by the spleen (extravascular hemolysis). 

The hemoglobin is broken down into the heme ring and the globin proteins. 

The iron is removed from the heme ring and either return to the bone marrow to be inserted into new erythrocytes or enters the iron storage pool. 

The tetrapyrrole ring of the heme molecule is opened, with the release of one molecule of carbon monoxide and the production of biliverdin. 

The biliverdin is transformed into bilirubin, which circulates to the liver bound to albumin (unconjugated or indirect bilirubin). 

In hepatocytes, bilirubin is conjugated to glucuronic acid and is excreted into the bile. 

Most of the bilirubin is excreted in the stool, but a small amount is absorbed in the ileum and returns to the liver via the portal vein; this is the source of conjugated (direct) bilirubin in plasma. 

A minority of erythrocytes, normally ~10%, are destroyed in the circulation (intravascular hemolysis). 

The released hemoglobin can meet several different fates: 

• Most hemoglobin complexes with a plasma protein called haptoglobin. The hemoglobin-haptoglobin complex is removed from circulation by hepatocytes. 

In pathologic intravascular hemolysis, the concentration of haptoglobin in the circulation drops and may become insufficient to tie up all of the released hemoglobin. 

• Excess heme can complex with another plasma protein called hemopexin. The heme-hemopexin complexes are then cleared from the circulation by the liver. 

• Free heme, which exceeds the capacity of the hemopexin system, may bind to albumin, forming methemalbumin. This may circulate for several 

days until the liver can synthesize additional hemopexin. 

Iron absorption, transport, and storage 

Iron is necessary for life and potentially life-threatening. Iron is required for hemoglobin and is also present in myoglobin, cytochrome oxidase, and several other enzymes. 

• Deficiency of iron results in anemia, a weakened immune system, and impaired physical and intellectual performance. 

• An excess of iron (hemochromatosis) can result in cirrhosis of the liver, hepatocellular carcinoma, cardiac failure and arrhythmias, diabetes mellitus, hypopituitarism, and arthritis. 

The body iron store is primarily regulated by limiting absorption. 

Iron excretion is relatively fixed, and the body has no means of ridding itself of excess iron. 

Iron Absorption 

Most of the iron absorption occurs in the proximal small intestine, predominantly the duodenum. 

Iron must complete two sequential steps to be absorbed: 

(1) absorption into the mucosal cells lining the gastrointestinal (GI) tract. 

(2) movement across the mucosal cells into the plasma on the other side. 

The mechanisms that regulate the size of the body iron stores. 

1. The store regulator: The store regulator primarily controls the absorption of non-heme iron from the GI tract; absorption is inversely proportional to iron stores. 

2. The erythroid regulator: The erythroid regulator is driven by erythropoiesis; increased erythropoiesis increases iron absorption. 

Dietary Iron 

The average diet provides approximately 10 to 20 mg of iron per day. Normally, about 1 or 2 mg of this is absorbed. 

Iron absorption can be increased approximately fivefold in states of iron deficiency and can be decreased to approximately 0.5 mg per day in conditions of iron excess. 

Dietary iron is of two types: heme iron and non-heme iron. 

Heme iron comes from meat. It represents about 10 to 15% of dietary Iron. 

The heme ring is absorbed intact into the mucosal lining of cells. After the heme has entered the cytoplasm of the mucosal cell, the iron is split off and enters a common pool with nonheme iron. 

Most of the dietary iron is in the non-heme form. 

This comes from vegetables, grains, and cereals. The majority of nonheme iron is in the ferric (Fe3+) state, which must be converted to the ferrous (Fe2+) state to be absorbed. 

Conversion of ferric to ferrous iron requires gastric acid and is facilitated by ascorbic acid. 

Absorption is decreased by iron chelators, such as phytates in grains, tannates in tea and coffee, phosphates, calcium, and zinc. 

Some vegetable proteins also inhibit iron absorption. Egg proteins and cow’s milk also inhibit iron absorption, whereas human breast milk increases it. 

Ascorbic acid facilitates the conversion of ferric to ferrous iron and thus increases absorption; lack of gastric acid (achlorhydria) inhibits absorption because ferric iron cannot be converted to ferrous iron. 

Iron Requirement 

Iron is lost through cells lining the GI tract and through the superficial squamous cells of the skin as they are shed; a small amount of iron is also lost in sweat. 

This obligatory iron loss averages approximately 1 mg per day in adult men and postmenopausal women and approximately 2 mg per day in menstruating women. 

Times of increased iron need include the first 18 months of life (particularly in premature infants), the adolescent growth spurt, and pregnancy. 

A woman loses approximately 750 mg during the 
average term pregnancy: approximately 225 mg of this is taken by the fetus, mostly during the last trimester. 

Iron Transport 

Iron is transported in the plasma bound to transferrin. Transferrin is a plasma protein synthesized by the liver, which has a high affinity for ferric (Fe3+) iron. Each molecule of transferrin can carry up to two iron atoms. 

There are specific cell surface receptors for the iron-transferrin complex on almost all cells; the highest concentration is on developing erythroblasts. 

After iron-transferrin complexes bind to the transferrin receptor, clusters of transferrin receptors with their attached transferrin-iron complexes are phagocytized into the cell. 

The iron is released from the transferrin, the transferrin receptor returns to the cell surface, and the transferrin protein is released into the circulation so it can transport more iron. 

Iron Storage 

The major sites of iron stores are macrophages in the bone marrow and reticuloendothelial cells in the liver (Kupffer’s cells). 

There are two storage forms of iron: ferritin, which stores iron for immediate use or short-term storage, and hemosiderin. Hemosiderin serves as the long-term storage form; iron stored as hemosiderin is not immediately available for use. 

Body Iron Content 

The average adult man contains a total of about 4 g (4,000 mg) of iron. 

Approximately half of this is in red cell precursors and erythrocytes; another quarter is in other tissues; a small amount (3–6 mg) is circulating in the plasma bound to transferrin, and the remainder (approximately1 g) makes up the body iron storage pool. 

The average woman, being slightly smaller, has slightly less iron in red cells, other tissues, and plasma; her iron stores are also much smaller. 

The Iron Cycle 

In the average man, approximately 25 mL of red blood cells, containing about 25 mg of iron, are phagocytized by macrophages of the reticuloendothelial system every day. 

About 20 mg of this iron is rapidly recycled back into hemoglobin for newly formed erythrocytes. 

A few milligrams are transferred to tissue cells, and most of the remainder is transferred to body iron stores.

Approximately 1 mg is lost from the GI tract, skin, and sweat, and an equal amount is absorbed from the diet. 

A woman in her childbearing years must absorb an additional 1 mg daily, on average, to make up for her menstrual blood loss. 

Iron Indices 

Four values are used to describe body iron status: serum iron, serum transferrin or iron-binding capacity, transferrin saturation, and serum ferritin. 

The transferrin saturation is the serum iron as a percent of the total iron-binding capacity.