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Introduction

The 1ki4 protein is the thymidine kinase from Herpes simplex virus type I complexed with 5-bromothienyldeoxyuridine. The Herpes simplex virus type I also called HSV1 cause highly contagious infections worldwide. In most cases, it is orofacial herpes but there is also a small proportion of genital infections.

The thymidine kinase is located in human cells and virus cells like in Herpes simplex virus. In the human cells, it exists two forms called TK1 and TK2.

This protein is a phosphotransferase enzyme that catalyses the reaction:

Deoxythymidine + ATP --> Deoxythymidine monophosphate + ADP

Function

The role of kinase is to catalyse protein phosphorylation. To do this, they transmit a phosphate group to the protein in the side chain of an amino acid chains. The phosphate group comes from the hydrolysis of ATP in ADP. This reaction can be in both directions.

The HSV1-TK is involved in the reactivation of Herpes simplex virus. Indeed this protein is involved in the salvage pathway of pyrimidine synthesis. As seen previously, this enzyme allows to transfert the γ phosphate group from ATP to the deoxythymidine to generate deoxythymidine monophosphate.Image:Reaction.jpeg

Structural highlights

Disease

The HSV1-TK is located in Herpes simplex type I virus and causes orofacial infections.

Most of the time the orofacial herpes is asymptomatic and and carriers of the infection are unaware of it. Symptoms are vesicular lesions or painful open wounds (burning, itching…) inside the mouth.

HSV1 is transmitted mainly by contact with mucous membranes because of the presence of viral particles in wounds, saliva… It can also be transmitted to the genital sphere during oral sex, which causes genital herpes. In rare cases, the mother can transmit the virus to the new-born during the childbirth. In immunocompromised people, symptoms may be more severe and more frequent.

After the first infection, wounds can reappear, and the frequency depends on person. Antivirals are used to reduce the viral load of people infected but they do not cure the infection. However, a mutation in the HSV1-TK protein causes the resistance of the virus against antivirals in immunocompromised patients.

Therapeutic application

The first suicide gene system developed for a therapeutic gene use, uses the thymidine kinase from Herpes simplex type I virus.

The aim was to develop a gene encoding an enzyme that performs an activity normally absent in the target cells of the therapy. This enzyme would then allow the synthesis of toxic compounds.

Aciclovir (ACV) and Ganciclovir (GVC) are 2 nucleosides analogues of guanosine. These are metabolized by HSV1-TK to a monophosphoryl compound which is then transformed into di and tri phosphate metabolites by cellular kinases. Then, ACV-TP and GVC-TP are incorporated into DNA during the elongation causing the death of infected cells by apoptosis. They also inhibit the viral replication. Death of cells is also triggered when they are treated with GVC when there has been an upstream transfection of the HSV1-TK gene outside a viral infection.

Structural highlights

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.