GLOBIN GENES AND MOLECULAR BIOLOGY OF GLOBIN SYNTHESIS

Globin Gene Organization

The organization of globin genes, including the beta and alpha gene families, is crucial for the synthesis of hemoglobin proteins, which are responsible for transporting oxygen in red blood cells. Here’s an overview of the organization of these gene families:

a) Beta-Globin Gene Family: The beta-globin gene family consists of a cluster of genes that encode the beta chains of hemoglobin. In humans, this gene cluster is located on chromosome 11. The beta-globin gene family includes five functional genes that are arranged in a specific order:

1. ε-Globin Gene (HBG1): This gene is also known as the embryonic globin gene. It is the first gene in the beta-globin gene cluster and is active during the embryonic stage of development.
2. Gγ-Globin Gene (HBG2): This gene is also referred to as the fetal globin gene. It is active during the fetal stage and is gradually silenced after birth.
3. Aγ-Globin Gene (HBG2): This gene is another member of the fetal globin genes and is also active during the fetal stage. It shares a high degree of similarity with the Gγ-globin gene.
4. δ-Globin Gene (HBD): This gene encodes the delta chain of adult hemoglobin (HbA2). It is expressed at low levels in adults.
5. β-Globin Gene (HBB): This is the last gene in the beta-globin cluster and encodes the beta chain of adult hemoglobin (HbA). It is the most abundantly expressed gene in the cluster in adults.

The expression of these genes is tightly regulated during different stages of development. The switch from embryonic to fetal hemoglobin and eventually to adult hemoglobin is crucial for proper oxygen transport.

 

b) Alpha-Globin Gene Family: The alpha-globin gene family is responsible for encoding the alpha chains of hemoglobin. In humans, these genes are located on chromosome 16. The alpha-globin gene family consists of two functional genes:

1. ζ-Globin Gene (HBZ): This gene is also known as the zeta-globin gene. It is expressed during early embryonic development but is eventually silenced.
2. α-Globin Gene (HBA): This gene is responsible for the production of alpha chains of adult hemoglobin (HbA). There are two copies of the alpha-globin gene in the genome, designated as HBA1 and HBA2.

Similar to the beta-globin genes, the expression of alpha-globin genes is also tightly regulated. The imbalance or mutation in alpha-globin genes can lead to disorders like alpha-thalassemia.

Overall, the organization of the globin genes, including the beta and alpha gene families, ensures the proper synthesis of hemoglobin and plays a vital role in oxygen transport throughout the body.

 

Globin Regulation by Iron

Globins are a family of proteins that play a crucial role in binding and transporting oxygen in various organisms, including humans. The regulation of globin biosynthesis, particularly in relation to iron availability, is essential for maintaining proper oxygen-carrying capacity in the body. Iron is a critical component of heme, the prosthetic group found in globins, and its availability directly influences the production of globin proteins.

Iron-Responsive Element-Binding Proteins (IREBPs), also known as Iron Regulatory Proteins (IRPs), are key transcription factors involved in the regulation of globin biosynthesis. These proteins bind to specific RNA structures known as Iron-Responsive Elements (IREs) located in the untranslated regions of messenger RNA (mRNA) molecules. The binding of IRPs to IREs modulates the stability and translation efficiency of target mRNAs.

In the context of globin biosynthesis, IRPs regulate the expression of both heme synthesis and globin genes. When cellular iron levels are low, IRPs bind to IREs present in the mRNA of key iron-related proteins, such as the transferrin receptor (TfR) and the ferritin mRNA. By binding to the IRE in TfR mRNA, IRPs stabilize the mRNA and increase its translation, leading to an increased uptake of iron from the extracellular environment. Simultaneously, IRPs inhibit the translation of ferritin mRNA, reducing the synthesis of ferritin, which is responsible for storing excess iron.

The availability of iron affects heme synthesis, as heme is composed of an iron ion surrounded by a porphyrin ring. When iron levels are low, IRPs promote the translation of aminolevulinate synthase 2 (ALAS2) mRNA, an enzyme involved in the initial step of heme synthesis. This allows for increased heme production, which in turn promotes the synthesis of globin chains.

Furthermore, another critical transcription factor involved in the regulation of globin biosynthesis is the hypoxia-inducible factor (HIF). HIF is activated under conditions of low oxygen levels (hypoxia) and plays a central role in coordinating the cellular response to hypoxic stress. HIF regulates the expression of genes involved in oxygen delivery and utilization, including erythropoietin (EPO), the hormone that stimulates red blood cell production.

HIF directly interacts with the enhancer regions of globin genes, increasing their transcription and promoting the synthesis of globin proteins. The binding of HIF to globin gene enhancers is dependent on the presence of cofactors, such as the transcriptional coactivator p300/CBP and the histone acetyltransferase PCAF. These cofactors assist in modifying the chromatin structure and facilitating the binding of HIF to the globin gene enhancers.

In summary, the regulation of globin biosynthesis is intricately linked to iron availability and hypoxic conditions. Iron-responsive transcription factors, such as IRPs, coordinate the synthesis of globin chains by modulating the stability and translation of key iron-related mRNAs. Additionally, the hypoxia-inducible factor HIF plays a crucial role in enhancing globin gene transcription under hypoxic conditions. Together, these regulatory mechanisms ensure an adequate supply of globin proteins for oxygen transport in response to iron availability and oxygen demand.

 

Heme Regulating Globin Biosynthesis

Heme, a crucial molecule involved in oxygen transport and various cellular processes, plays a key role in regulating globin biosynthesis. Globins are the protein components of hemoglobin, myoglobin, and other heme-containing proteins. The regulation of globin biosynthesis by heme is primarily mediated through a feedback mechanism known as heme regulation.

The synthesis of globin proteins is tightly controlled to maintain the proper balance and functionality of heme-containing proteins in the body. Heme acts as a signaling molecule that monitors the intracellular concentration of heme and modulates the production of globins accordingly. Here’s a general overview of how heme regulates globin biosynthesis:

1. Heme synthesis: Heme is synthesized through a multistep process known as heme biosynthesis. This pathway occurs predominantly in the mitochondria and involves several enzymes. The rate-limiting step of heme biosynthesis is catalyzed by the enzyme 5-aminolevulinate synthase (ALAS). ALAS expression and activity are regulated by the availability of heme. When heme levels are low, ALAS is upregulated, leading to increased heme synthesis.
2. Heme sensing: Heme acts as a sensor of its own concentration. Excess heme binds to specific proteins called heme-regulated eukaryotic initiation factors (eIFs). One of these proteins is heme-regulated inhibitor (HRI). When heme levels are high, heme binds to HRI, causing its inactivation. In turn, HRI is unable to phosphorylate eIF2α (eukaryotic initiation factor 2α), a critical factor in protein synthesis.
3. Globin translation: In the absence of phosphorylated eIF2α, globin translation proceeds, allowing the synthesis of globin proteins. Conversely, when heme levels are low, heme dissociates from HRI, activating it. Active HRI phosphorylates eIF2α, leading to the inhibition of global protein synthesis, including globins. This mechanism ensures that globin synthesis is reduced when heme levels are insufficient, preventing the accumulation of unassembled globin chains.
4. Heme-globin interactions: Once synthesized, globin chains combine with heme to form functional hemoglobin molecules. The binding of heme to globin stabilizes the protein structure and facilitates its proper folding. Heme deficiency or imbalance can result in the accumulation of unassembled globin chains, leading to various pathological conditions known as globin chain disorders, such as thalassemias and unstable hemoglobins.

In summary, heme regulates globin biosynthesis through a feedback mechanism that involves heme sensing, modulation of protein synthesis, and the formation of functional heme-globin complexes. This regulation ensures the appropriate production of globin chains, maintaining the balance and functionality of heme-containing proteins in the body.