Structure of the Pre-reaction Complex of Alpha-(1,3)-fucosyltransferase of Helicobacter pylori

ZEMANÍK, Július a Petr KULHÁNEK. Structure of the Pre-reaction Complex of Alpha-(1,3)-fucosyltransferase of Helicobacter pylori. In XXII. Meeting of Biochemists and Molecular Biologists. 2023. ISBN 978-80-280-0409-5.

Základní údaje

Originální název

Structure of the Pre-reaction Complex of Alpha-(1,3)-fucosyltransferase of Helicobacter pylori

Název anglicky

Structure of the Pre-reaction Complex of Alpha-(1,3)-fucosyltransferase of Helicobacter pylori

Autoři

ZEMANÍK, Július a Petr KULHÁNEK

Vydání

XXII. Meeting of Biochemists and Molecular Biologists, 2023

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Další údaje

Typ výsledku

Prezentace na konferencích

Utajení

není předmětem státního či obchodního tajemství

Organizační jednotka

Přírodovědecká fakulta

ISBN

978-80-280-0409-5

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Anotace

V originále

Helicobacter pylori is a severe human pathogen associated with gastrointestinal disorders such as gastric inflammation, ulcers, and cancer. However, primary treatment of H. pylori infections has become increasingly more challenging due to the emergence of antibiotic resistance. As a result, there is a growing need for novel antibacterial agents (1). In this presentation, we focus on H. pylori alpha-(1,3)-fucosyltransferase FutA, an attractive pharmacological target for developing such agents. This inverting glycosyltransferase is an essential enzyme in the biosynthesis of Lewis antigens. It is hypothesised that these antigens mask the bacteria from the host’s immune system, enabling long-term infections (2). Consequently, novel antibacterial agents inhibiting FutA could expose H. pylori to the immune system and help clear the infection. Unfortunately, the pre-reaction complex of FutA with both substrates in a suitable conformation is currently unknown, hindering further research. To resolve this limitation, we have employed state-of-the-art methods of computational chemistry. Standard docking simulations failed due to a wide cleft in the active site, which presumably closes upon substrate binding. Therefore, we had to use advanced techniques, such as simulated annealing and molecular dynamics, to dock the substrates. They have allowed the refolding of unstructured parts of the enzyme to accommodate both substrates better. Moreover, the obtained complexes are better shielded from bulk water, an assumed requirement of the glycosylation mechanism. Since the correct orientation of the acceptor in the active site is disputed, we have performed simulations for both previously proposed orientations. In this presentation, we show the latest results of these advanced simulations.

Česky

Helicobacter pylori is a severe human pathogen associated with gastrointestinal disorders such as gastric inflammation, ulcers, and cancer. However, primary treatment of H. pylori infections has become increasingly more challenging due to the emergence of antibiotic resistance. As a result, there is a growing need for novel antibacterial agents (1). In this presentation, we focus on H. pylori alpha-(1,3)-fucosyltransferase FutA, an attractive pharmacological target for developing such agents. This inverting glycosyltransferase is an essential enzyme in the biosynthesis of Lewis antigens. It is hypothesised that these antigens mask the bacteria from the host’s immune system, enabling long-term infections (2). Consequently, novel antibacterial agents inhibiting FutA could expose H. pylori to the immune system and help clear the infection. Unfortunately, the pre-reaction complex of FutA with both substrates in a suitable conformation is currently unknown, hindering further research. To resolve this limitation, we have employed state-of-the-art methods of computational chemistry. Standard docking simulations failed due to a wide cleft in the active site, which presumably closes upon substrate binding. Therefore, we had to use advanced techniques, such as simulated annealing and molecular dynamics, to dock the substrates. They have allowed the refolding of unstructured parts of the enzyme to accommodate both substrates better. Moreover, the obtained complexes are better shielded from bulk water, an assumed requirement of the glycosylation mechanism. Since the correct orientation of the acceptor in the active site is disputed, we have performed simulations for both previously proposed orientations. In this presentation, we show the latest results of these advanced simulations.

Anglicky

Helicobacter pylori is a severe human pathogen associated with gastrointestinal disorders such as gastric inflammation, ulcers, and cancer. However, primary treatment of H. pylori infections has become increasingly more challenging due to the emergence of antibiotic resistance. As a result, there is a growing need for novel antibacterial agents (1). In this presentation, we focus on H. pylori alpha-(1,3)-fucosyltransferase FutA, an attractive pharmacological target for developing such agents. This inverting glycosyltransferase is an essential enzyme in the biosynthesis of Lewis antigens. It is hypothesised that these antigens mask the bacteria from the host’s immune system, enabling long-term infections (2). Consequently, novel antibacterial agents inhibiting FutA could expose H. pylori to the immune system and help clear the infection. Unfortunately, the pre-reaction complex of FutA with both substrates in a suitable conformation is currently unknown, hindering further research. To resolve this limitation, we have employed state-of-the-art methods of computational chemistry. Standard docking simulations failed due to a wide cleft in the active site, which presumably closes upon substrate binding. Therefore, we had to use advanced techniques, such as simulated annealing and molecular dynamics, to dock the substrates. They have allowed the refolding of unstructured parts of the enzyme to accommodate both substrates better. Moreover, the obtained complexes are better shielded from bulk water, an assumed requirement of the glycosylation mechanism. Since the correct orientation of the acceptor in the active site is disputed, we have performed simulations for both previously proposed orientations. In this presentation, we show the latest results of these advanced simulations.

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Návaznosti

MUNI/C/0054/2023, interní kód MU

Název: Studium reakčních mechanismů bakteriálních glykosyltransferáz pomocí molekulového modelování Investor: Masarykova univerzita, Studium reakčních mechanismů bakteriálních glykosyltransferáz pomocí molekulového modelování, Podpora vynikajících diplomových prací