SERPINA7 - serpin family A member 7 |Elisa - Clia - Antibody - Protein

Background

SERPINA7, also known as Thyroxine-Binding Globulin (TBG), is a glycoprotein primarily responsible for the transport of thyroid hormones in the bloodstream. It belongs to the serpin superfamily of proteins, which are typically serine protease inhibitors. However, like SERPINA6, SERPINA7 functions not as a protease inhibitor but as a carrier protein. The thyroid hormones, particularly thyroxine (T4) and to a lesser extent triiodothyronine (T3), are critical for regulating metabolism, growth, and development. SERPINA7 ensures that these hormones are delivered to tissues in a controlled and regulated manner.

Gene and Protein Structure

The SERPINA7 gene is located on the X chromosome at Xq22.2. It encodes a protein that is composed of approximately 395 amino acids, with a molecular weight of around 54 kDa. The structure of SERPINA7 is characterized by its three beta-sheets, eight to nine alpha-helices, and a reactive center loop (RCL), similar to other members of the serpin family. However, its primary function is not to inhibit proteases but to bind thyroid hormones with high affinity.

The glycosylation of SERPINA7 is crucial for its stability and half-life in circulation. Glycosylation sites on the protein enhance its binding to thyroxine (T4) and triiodothyronine (T3), facilitating their transport in the bloodstream.

Biological Function

The primary role of SERPINA7 is to bind and transport thyroid hormones. In the bloodstream, about 70-80% of T4 and 50-60% of T3 are bound to TBG (SERPINA7), with the remaining bound to other proteins like transthyretin and albumin, and only a small fraction existing as free hormones, which are biologically active. The binding of thyroid hormones to TBG serves several critical functions:

1. Hormone Stability: By binding to TBG, thyroid hormones are protected from rapid degradation and excretion, thereby extending their half-life in circulation. This binding also prevents the hormones from diffusing freely into tissues, which could lead to unregulated hormone action.
2. Regulated Delivery: TBG acts as a reservoir of thyroid hormones, releasing them slowly to maintain stable levels of free hormones in the bloodstream. This ensures that tissues receive a consistent supply of thyroid hormones, essential for normal metabolic function.
3. Modulation of Bioavailability: The binding affinity of TBG for thyroid hormones can be influenced by several factors, including changes in pH, temperature, and the presence of certain drugs or hormones. This modulation allows for the fine-tuning of thyroid hormone bioavailability according to the body's physiological needs.

Regulation and Expression

The expression of the SERPINA7 gene and the levels of TBG in the blood are influenced by several factors:

• Estrogens: Estrogen increases the synthesis of TBG in the liver, leading to higher levels of TBG in women, particularly during pregnancy or estrogen therapy. This increase in TBG levels results in higher total thyroid hormone levels, although the free hormone levels remain relatively constant.
• Liver Function: Since TBG is synthesized in the liver, liver diseases can significantly impact TBG levels. For example, in conditions like cirrhosis, TBG levels may be reduced, leading to altered thyroid hormone transport.
• Genetic Variations: Mutations in the SERPINA7 gene can lead to inherited TBG deficiencies or excesses. TBG deficiency can result in lower total thyroid hormone levels, whereas TBG excess can lead to higher total thyroid hormone levels, both of which can complicate the diagnosis of thyroid disorders.

Clinical Significance

Alterations in SERPINA7 levels or function can have significant clinical implications, particularly in the diagnosis and management of thyroid disorders:

1. TBG Deficiency: TBG deficiency can be inherited or acquired. Inherited TBG deficiency is usually due to mutations in the SERPINA7 gene and can be complete or partial. Patients with TBG deficiency typically have low total thyroid hormone levels but normal free hormone levels and are generally euthyroid. However, this condition can be misinterpreted as hypothyroidism, leading to unnecessary treatment.
2. TBG Excess: TBG excess is often seen in situations where estrogen levels are elevated, such as during pregnancy or estrogen therapy. This condition results in high total thyroid hormone levels, but normal free hormone levels. As with TBG deficiency, it is important to recognize this condition to avoid misdiagnosis and overtreatment.
3. Acquired Changes in TBG Levels: Several conditions can lead to acquired changes in TBG levels. For example, liver disease can reduce TBG levels, while conditions such as nephrotic syndrome can increase TBG levels due to increased protein loss. These changes can affect thyroid function tests and complicate the assessment of thyroid status.
4. Thyroid Function Tests: The presence of abnormal TBG levels can complicate the interpretation of thyroid function tests. Since most laboratory assays measure total thyroid hormone levels, altered TBG levels can lead to apparent abnormalities in these tests. For example, high TBG levels can lead to high total T4 levels, while low TBG levels can lead to low total T4 levels, both of which may be misinterpreted as thyroid dysfunction. Therefore, it is important to measure free thyroid hormone levels or use assays that correct for TBG levels to accurately assess thyroid function.
5. Drug Interactions: Certain medications can affect TBG levels and, consequently, thyroid hormone levels. For example, androgens and glucocorticoids can reduce TBG levels, while estrogens can increase TBG levels. Understanding these interactions is important in managing patients on these medications and interpreting thyroid function tests.

Therapeutic Implications

Understanding the function and regulation of SERPINA7 is important for the diagnosis and management of thyroid disorders. For example, in patients with TBG deficiency, it is important to recognize the condition to avoid unnecessary thyroid hormone replacement therapy. Similarly, in patients with TBG excess, particularly during pregnancy, it is important to understand the changes in thyroid hormone levels to avoid overtreatment with antithyroid drugs.

There is currently no specific therapy for TBG abnormalities. However, understanding the role of TBG in thyroid hormone transport and metabolism is important for the appropriate management of patients with thyroid disorders, particularly in the interpretation of thyroid function tests.

Summary

SERPINA7, or Thyroxine-Binding Globulin, plays a crucial role in the transport and regulation of thyroid hormones. By binding and stabilizing thyroxine and triiodothyronine in the bloodstream, it ensures that these hormones are available in a controlled manner for metabolic and developmental processes. Alterations in SERPINA7 levels or function can significantly impact thyroid hormone physiology and complicate the diagnosis and management of thyroid disorders. Understanding the role of SERPINA7 in thyroid hormone metabolism is therefore essential for the accurate assessment and treatment of thyroid-related conditions.