Introduction
Heme is an essential prosthetic group of proteins that is required to perform diverse biological functions. The enzymes that use heme as a prosthetic protein are hemoglobin, myoglobin, cytochromes in the electron transport chain, catalase, and nitric oxide synthase. Heme is predominantly synthesized by erythrocytes in the bone marrow or hepatocytes of the liver. Heme is a complex molecule containing a porphyrin ring and ferrous or ferric ion.
How Is Heme Synthesized?
Heme is synthesized partly within the mitochondria or cytosol portion of the cell. Heme is produced by a process known as porphyrin synthesis. They are different forms of biological hemes. Heme b is the most common form and is found in hemoglobin. Heme a and c are found in cytochrome a and c, respectively, and are involved in oxidative phosphorylation.
What Is Heme Biosynthesis?
Heme biosynthesis is an eight-step enzymatic pathway.
1) The first step occurs in mitochondria; the succinyl Co-A (Succinyl coenzyme A) is condensed from the citric acid cycle or amino acid cycle. They are then combined to produce a key element, 5'-aminolevulinic acid (ALA), in mitochondria facilitated by vitamin B6 enzyme and aminolevulinic acid synthase (ALAS). It is a rate-limiting step.
2) The ALA is formed to leave mitochondria to enter the cytosol. In the cytosol, two ALA molecules are condensed to produce a pyrrole ring compound known as porphobilinogen. The reaction is catalyzed by porphobilinogen synthase, a zinc-requiring enzyme.
3) Followed by the condensation of four porphobilinogen molecules to form linear hydroxymethylbilane. The reaction is facilitated by hydroxymethylbilane synthase.
4) When linear hydroxymethylbilane is closed, they form an asymmetric pyrrole ring termed as uroporphyrinogen III. The reaction is catalyzed by uroporphyrinogen ring III synthases. This is an important step since an incorrect ring formation can result in the formation of protoporphyria.
5) The normal porphyrin ring III and the side chain of uroporphyrinogen III are modified to form coproporphyrinogen III.
6) The coproporphyrinogen III is transported back to mitochondria and decarboxylated to form protoporphyrinogen IX.
7) The protoporphyrinogen IX is oxidized to form protoporphyrin IX.
8) The final step includes iron addition to protoporphyrin IX to form heme.
What Role Does Heme Play in the Body?
Heme is involved in various body functions such as:
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Facilitating oxygen transport in hemoglobin.
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Aids storage in myoglobin (a protein present in striated muscle of vertebrates).
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It is a reservoir for iron.
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Helps with cellular respiration.
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Cellular differentiation and proliferation.
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It is a prosthetic group for cytochrome p450 enzymes.
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In the electron transport chain, it helps with the electron shuttle.
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It regulates antioxidant response to circadian rhythm (natural mechanism regulating the sleep-wake cycle).
What Is the Procedure for Heme Synthesis?
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Erythroid Cells:
The heme is produced for forming hemoglobin. In immature RBC (red blood cell), heme is produced by erythropoietin stimulation. The heme stimulates protein synthesis for globin chain formation. Accumulation of heme in erythroid cells leads to immature RBC maturation and globin chain synthesis. When RBC is matured, the generation of heme and hemoglobin stops. The factor regulating heme biosynthesis in erythroid is intracellular iron.
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Liver:
The heme generation is highly regulated in the liver since excessive concentration can damage hepatocytes. Cytochrome P450 formation in the liver requires heme. ALAS1 present in most hepatocytes leads to cytochrome P450 generation. The enzyme function is increased by drugs. Heme synthesis stops when heme and hemin accumulate in liver cells and are not incorporated in protein.
What Are the Outcomes of Defective Heme Synthesis?
Heme synthesis is a long process requiring steps, substrates, and enzymes. If there is any deficiency of enzymes or substrates, it leads to the accumulation of heme intermediates. The unfinished heme appears in blood, urine, or tissues leading to a clinical disorder known as porphyria.
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Porphyria:
Porphyria can occur due to errors in heme generation in the liver or erythroid. The disease can be of acute or chronic type. The symptoms of porphyria include mental disturbance, photosensitivity, and neurologic dysfunction. Heme intermediates accumulated after hydroxymethylbilane result in increased photosensitivity. Other features of porphyria are abdominal or colic pain, irritated patients, urine color changes, tachycardia (increased heart rate), lung issues, confusion, nausea, and weakness in the lower limb.
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Lead Poisoning:
Lead inhibits two enzymes of ALA dehydratase and ferrochelatase in the heme synthesis pathway by reacting with their zinc cofactor. This causes ALA and protoporphyrin IX to appear in the urine. Individuals with lead poisoning and heme synthesis inhibition experience abdominal pain, vomiting, fatigue, irritability, and developmental anomalies in children.
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Iron Deficiency Anemia:
Iron is added to protoporphyrin IX as a last step in heme synthesis. A deficiency of iron leads to the development of microcytic hypochromic anemia.
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Sideroblastic Anemia:
Mutation or defect in the ALAS enzyme can cause the development of X-linked sideroblastic anemia. In this condition generation of heme and protoporphyrin is reduced. A unique feature of this disease is iron accumulation in mitochondria.
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Hemin:
Hemin is formed when the ferric state of iron is incorporated into protoporphyrin instead of the ferrous state. Hemin reduces ALA synthesis. However, hemin has antimalarial action due to its toxicity towards malarial parasites.
What Are the Types of Porphyria Developing Due to Defective Heme Synthesis?
Porphyria is inherited in an autosomal dominant form. However, lead toxicity causes acquired porphyria due to the inhibition of enzymes.
Three types of porphyria occur due to defective heme synthesis and are:
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Acute Intermittent Porphyria:
Mutations in hydroxymethylbilane cause porphobilinogen accumulation. The symptoms of the disease are severe abdominal pain, vomiting, constipation, behavioral changes, hypertension, and tachycardia. However, there is no photosensitivity, but the patient's urine darkens on exposure to air or sunlight.
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Erythropoietic Porphyria:
A deficiency of the enzyme ferrochelatase, which is responsible for heme formation in the final step, can lead to this disorder. The protoporphyrin IX gets accumulated in erythrocytes. Individuals with this condition experience hepatic dysfunction and photosensitivity. The sun-exposed area becomes swollen and develops itchiness.
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Porphyria Cutanea Tarda:
It is the most frequent type of porphyria that occurs due to deficiency or mutation in uroporphyrinogen decarboxylase. Therefore, it leads to uroporphyrin accumulation in urine. Severe photosensitivity develops, resulting in hyperpigmentation and blister formation in sun-exposed areas. The urine is red wine in color. There is the development of hepatic injury that is exacerbated by alcohol consumption. The condition is managed by avoiding sunlight exposure, taking hydroxychloroquine, or phlebotomy (puncturing the vein with a cannula for blood drawing).
Conclusion
Heme is an essential protein that is important in synthesizing various molecules needed for the body’s function. Heme synthesis is a complex eight-step procedure requiring various enzymes and substrates. Deficiency of any of the enzymes or substrates in the pathway can lead to intermediate heme accumulation and clinical disorders.
