Banca de DEFESA: JHONATAN DEIVS BARROS ALVES

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : JHONATAN DEIVS BARROS ALVES
DATE: 31/01/2023
TIME: 14:00
LOCAL: Departamento de Química
TITLE:

COMPUTATIONAL MODELING OF THE MECHANISM OF ACTION OF THE TRANS-SIALIDASE ENZYME OF THE PARASITE TRYPANOSOMA CRUZI

KEY WORDS:

TcTS, Trypanosoma cruzi Trans-Sialidase, ping-pong mechanism, a-2,3-sialyl-lactose, QM/MM.

PAGES: 97
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Físico-Química
SPECIALTY: Química Teórica
SUMMARY:

Trypanosoma cruzi (T. cruzi or Tc) is the unicellular protozoan parasite that causes Chagas disease. Considering the evolutionary cycle in the host, it is clear that, regardless of the form of Tc transmission, the Trypomastigote form needs to penetrate the host cell to complete its evolutionary cycle. Trypanosoma cruzi Trans-Sialidase (TcTS), an enzyme from Trypanosoma cruzi, is an example of a relevant biological catalyst for the development of the disease caused by this parasite. The essential substrate for TcTS is sialic acid (SA). The enzyme Trans-Sialidase of Trypanosoma cruzi (TcTS) removes an SA unit, initially linked to a glycoside present on the surface of the host cell, transferring the SA to another glycoside on the surface of the parasite cells, which allows the parasite to go unnoticed of our immune system and be internalized by the host cell. The already consolidated and accepted mechanism for the functioning of the TcTS follows the classic “ping-pong” model, in which the donor leaves the active site for the acceptor to enter. However, according to this hypothesis, a water molecule could easily attack the sialyl-enzyme intermediate before acceptor binding, resulting in inefficient sugar transfer. An alternative mechanism proposed by Oliveira et al. (2014), involving a ternary intermediate, defines the donor and acceptor that bind to the enzyme at the same time. The authors found evidence that, after binding of the donor (α-2,3-sialyl-lactose), a structural rearrangement occurs that opens a gap capable of holding the acceptor unit, allowing a direct mechanism without the need for the exit of the donor for the transfer. In this work, MD simulations were carried out to study the opening of the cavity close to the active site, as well as the extent to which enzymatic activity is affected by the entry of a glucose molecule into the catalytic site of TcTS, together with sialyllactose, by QM. /MM. The results suggest that the mechanism does not follow the commonly accepted ping-pong model, due to the existence of the ternary complex.

COMMITTEE MEMBERS:
Presidente - ***.999.014-** - JULIANA ANGEIRAS BATISTA DA SILVA - UFPE
Interno - WAGNER EDUARDO DA SILVA
Externo à Instituição - DIEGO DE PAULA SANTOS