FUT3 - fucosyltransferase 3 |Elisa - Clia - Antibody - Protein

Background

Fucosyltransferase 3 (FUT3) is an enzyme within the glycosyltransferase family that is essential for the biosynthesis of specific carbohydrate structures on glycoproteins and glycolipids. FUT3 is responsible for catalyzing the addition of fucose, a hexose sugar, to various glycan substrates through α(1,3)- and α(1,4)-linkages, which are critical for the synthesis of the Lewis antigen family, including Lewis a (Le^a) and Lewis b (Le^b) antigens. These carbohydrate structures are integral components of cell surface glycoconjugates and play essential roles in cell-cell adhesion, recognition, and signaling.

Encoded by the FUT3 gene located on chromosome 19p13.3, FUT3 is primarily expressed in epithelial tissues and leukocytes, especially in the gastrointestinal tract and other mucosal tissues. It is one of several fucosyltransferases in the human genome, with FUT3 being the most involved in the generation of Lewis antigens. The genetic variations in FUT3 are known to result in different phenotypes of Lewis antigens, which are important in blood group determination and are relevant to various diseases, including cancers and inflammatory conditions.

Protein Structure

The structure of FUT3, as with other fucosyltransferases, is designed to support its function in catalyzing the transfer of fucose. Key structural features include:

Catalytic Domain:

• FUT3 contains a catalytic domain characteristic of glycosyltransferase enzymes. This domain is responsible for transferring fucose from the donor molecule, GDP-fucose, to specific acceptor substrates, usually N-acetylglucosamine (GlcNAc) or N-acetyllactosamine.
• The catalytic domain consists of an α/β Rossmann fold, which facilitates binding of GDP-fucose and positions it correctly for transfer to the acceptor substrate.

Binding Sites:

• FUT3 has binding sites for both the donor molecule GDP-fucose and the glycan acceptor. The GDP-fucose binding site has conserved motifs that are essential for recognizing and positioning the fucose donor molecule, ensuring efficient catalysis.
• An acceptor binding site on the enzyme accommodates specific glycoconjugates, allowing FUT3 to specifically add fucose to Lewis-type glycans via α(1,3) and α(1,4) linkages.

Transmembrane Domain:

• FUT3 is a type II transmembrane protein anchored to the Golgi apparatus, where glycosylation of proteins and lipids predominantly occurs. The transmembrane domain allows FUT3 to be retained in the Golgi, ensuring that fucosylation takes place in this compartment.
• The cytoplasmic tail, though short, helps orient FUT3 properly within the Golgi membrane to facilitate access to glycoconjugate substrates during the fucosylation process.

Conserved Residues:

• Several amino acid residues within the catalytic domain are conserved across fucosyltransferases and are essential for enzymatic activity. These residues are involved in binding GDP-fucose and ensuring the correct orientation of the fucose for transfer to the glycan acceptor.

Clasification and Subtypes

FUT3 is classified as an α(1,3/1,4)-fucosyltransferase due to its ability to add fucose in α(1,3) or α(1,4) linkages. This ability distinguishes it from other fucosyltransferases that have specificity for different linkages, such as α(1,2)- or α(1,6)-linkages. The FUT3 gene exhibits polymorphisms that can affect its function and result in different Lewis blood group phenotypes:

Functional and Non-functional Alleles:

• Variations in FUT3 can lead to differences in enzyme function. Non-functional alleles of FUT3 result in the absence of certain Lewis antigens on cell surfaces, giving rise to phenotypes such as the Lewis-negative blood group.

Related Fucosyltransferases:

• FUT3 is related to other fucosyltransferases, such as FUT4 and FUT5, which also contribute to Lewis antigen synthesis. However, FUT3 is unique in its dual specificity for both α(1,3) and α(1,4) linkages, making it particularly important in the synthesis of Lewis a and b antigens.

Function and Biological Significance

FUT3 is crucial for generating Lewis antigens, which serve various roles in cellular interactions and immune responses:

Lewis Antigen Synthesis:

• The primary function of FUT3 is to synthesize Lewis antigens by transferring fucose residues to N-acetylglucosamine moieties on glycoproteins and glycolipids. These antigens are expressed on the surface of epithelial cells and leukocytes and are key mediators of cellular adhesion and recognition.

Role in Blood Group Antigens:

• FUT3 contributes to the Lewis blood group system, which includes Le^a, Le^b, and other variants. These antigens are crucial in blood transfusions and organ transplants due to their immunogenic properties and role in mediating immune recognition.

Cell-Cell Adhesion and Immune Response:

• Lewis antigens generated by FUT3 play an essential role in leukocyte adhesion to the endothelium, facilitating leukocyte trafficking to sites of infection or injury. FUT3-mediated fucosylation enables leukocytes to express selectin ligands, which bind to E- and P-selectins on endothelial cells, allowing immune cells to exit the bloodstream and migrate to target tissues.

Cancer Progression and Metastasis:

• FUT3 expression is upregulated in various cancers, where it promotes tumor cell adhesion to endothelial cells, enhancing the potential for metastasis. Lewis antigens synthesized by FUT3 can also contribute to the immunosuppressive tumor microenvironment, allowing tumor cells to evade immune detection.

Clinical Issues

Aberrations in FUT3 expression and function are implicated in several diseases, particularly due to its role in synthesizing Lewis antigens:

Cancer:

• Increased expression of FUT3 has been observed in cancers such as colon, pancreatic, and gastric cancers. The Lewis antigens produced by FUT3 can facilitate cancer cell adhesion to the endothelium, aiding in metastasis. Moreover, the immune-modulatory functions of these antigens can create an environment that protects tumor cells from immune surveillance.

Inflammatory Diseases:

• FUT3-mediated fucosylation is involved in leukocyte migration to sites of inflammation. Altered FUT3 expression can affect this process, potentially leading to inappropriate immune responses or chronic inflammation.

Lewis Blood Group Deficiency:

• Genetic mutations in FUT3 can result in Lewis antigen deficiency, leading to a Lewis-negative phenotype. This condition is benign but has implications in transfusion medicine, as the absence of Lewis antigens can affect compatibility in blood transfusions and organ transplantation.

Infectious Disease:

• Certain pathogens, including Helicobacter pylori, exploit Lewis antigens for adhesion to host tissues. FUT3 expression in the gastrointestinal tract facilitates the production of these antigens, which can be hijacked by pathogens to enhance colonization and persistence in the host.

Summary

Fucosyltransferase 3 (FUT3) is a critical enzyme in glycosylation, responsible for synthesizing Lewis antigens on cell surfaces. Structurally, FUT3 consists of a catalytic domain with a Rossmann fold, GDP-fucose binding sites, and a transmembrane domain for Golgi localization. As a dual-function enzyme capable of forming both α(1,3)- and α(1,4)-linkages, FUT3 is essential in the production of Lewis a and b antigens, which play significant roles in cell-cell adhesion, immune response, and blood group compatibility.

FUT3’s biological functions are particularly evident in its contributions to immune cell trafficking and response to infection or injury, where it mediates leukocyte adhesion to endothelial cells. Clinically, aberrant FUT3 expression has been linked to several cancers, where it promotes metastasis and immune evasion. Additionally, variations in FUT3 can affect the Lewis blood group phenotype, which is relevant to transfusion medicine. In summary, FUT3 is integral to cell surface antigen expression and plays a vital role in physiological processes ranging from immune responses to cell adhesion and recognition. Its dysregulation is associated with pathological conditions, including cancer and chronic inflammation, making FUT3 an important enzyme with potential therapeutic implications.