Structural Basis of the Inhibition of L-Methionine γ-Lyase from <i>Fusobacterium nucleatum</i>
<i>Fusobacterium nucleatum</i> is a lesion-associated obligate anaerobic pathogen of destructive periodontal disease; it is also implicated in the progression and severity of colorectal cancer. Four genes (<i>FN0625</i>, <i>FN1055</i>, <i>FN1220</i>, a...
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2023-01-01
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author | Tingting Bu Jing Lan Inseong Jo Jie Zhang Xue Bai Shanru He Xiaoling Jin Lulu Wang Yu Jin Xiaoyu Jin Liying Zhang Hailong Piao Nam-Chul Ha Chunshan Quan Ki Hyun Nam Yongbin Xu |
author_facet | Tingting Bu Jing Lan Inseong Jo Jie Zhang Xue Bai Shanru He Xiaoling Jin Lulu Wang Yu Jin Xiaoyu Jin Liying Zhang Hailong Piao Nam-Chul Ha Chunshan Quan Ki Hyun Nam Yongbin Xu |
author_sort | Tingting Bu |
collection | DOAJ |
description | <i>Fusobacterium nucleatum</i> is a lesion-associated obligate anaerobic pathogen of destructive periodontal disease; it is also implicated in the progression and severity of colorectal cancer. Four genes (<i>FN0625</i>, <i>FN1055</i>, <i>FN1220</i>, and <i>FN1419</i>) of <i>F. nucleatum</i> are involved in producing hydrogen sulfide (H<sub>2</sub>S), which plays an essential role against oxidative stress. The molecular functions of Fn1419 are known, but their mechanisms remain unclear. We determined the crystal structure of Fn1419 at 2.5 Å, showing the unique conformation of the PLP-binding site when compared with L-methionine γ-lyase (MGL) proteins. Inhibitor screening for Fn1419 with L-cysteine showed that two natural compounds, gallic acid and dihydromyricetin, selectively inhibit the H<sub>2</sub>S production of Fn1419. The chemicals of gallic acid, dihydromyricetin, and its analogs containing trihydroxybenzene, were potentially responsible for the enzyme-inhibiting activity on Fn1419. Molecular docking and mutational analyses suggested that Gly112, Pro159, Val337, and Arg373 are involved in gallic acid binding and positioned close to the substrate and pyridoxal-5′-phosphate-binding site. Gallic acid has little effect on the other H<sub>2</sub>S-producing enzymes (Fn1220 and Fn1055). Overall, we proposed a molecular mechanism underlying the action of Fn1419 from <i>F. nucleatum</i> and found a new lead compound for inhibitor development. |
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spelling | doaj.art-a4ffd15e1f524860b4f057df019375c72023-11-30T22:43:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242165110.3390/ijms24021651Structural Basis of the Inhibition of L-Methionine γ-Lyase from <i>Fusobacterium nucleatum</i>Tingting Bu0Jing Lan1Inseong Jo2Jie Zhang3Xue Bai4Shanru He5Xiaoling Jin6Lulu Wang7Yu Jin8Xiaoyu Jin9Liying Zhang10Hailong Piao11Nam-Chul Ha12Chunshan Quan13Ki Hyun Nam14Yongbin Xu15Department of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaInfectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116600, ChinaDepartment of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Gwanak-gu, Seoul 00826, Republic of KoreaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, ChinaDepartment of Life Science, Pohang University of Science and Technology, Pohang 35398, Republic of KoreaDepartment of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, China<i>Fusobacterium nucleatum</i> is a lesion-associated obligate anaerobic pathogen of destructive periodontal disease; it is also implicated in the progression and severity of colorectal cancer. Four genes (<i>FN0625</i>, <i>FN1055</i>, <i>FN1220</i>, and <i>FN1419</i>) of <i>F. nucleatum</i> are involved in producing hydrogen sulfide (H<sub>2</sub>S), which plays an essential role against oxidative stress. The molecular functions of Fn1419 are known, but their mechanisms remain unclear. We determined the crystal structure of Fn1419 at 2.5 Å, showing the unique conformation of the PLP-binding site when compared with L-methionine γ-lyase (MGL) proteins. Inhibitor screening for Fn1419 with L-cysteine showed that two natural compounds, gallic acid and dihydromyricetin, selectively inhibit the H<sub>2</sub>S production of Fn1419. The chemicals of gallic acid, dihydromyricetin, and its analogs containing trihydroxybenzene, were potentially responsible for the enzyme-inhibiting activity on Fn1419. Molecular docking and mutational analyses suggested that Gly112, Pro159, Val337, and Arg373 are involved in gallic acid binding and positioned close to the substrate and pyridoxal-5′-phosphate-binding site. Gallic acid has little effect on the other H<sub>2</sub>S-producing enzymes (Fn1220 and Fn1055). Overall, we proposed a molecular mechanism underlying the action of Fn1419 from <i>F. nucleatum</i> and found a new lead compound for inhibitor development.https://www.mdpi.com/1422-0067/24/2/1651<i>Fusobacterium nucleatum</i>hydrogen sulfideL-methionine γ-lyaseL-cysteine desulfidaseFn1419gallic acid |
spellingShingle | Tingting Bu Jing Lan Inseong Jo Jie Zhang Xue Bai Shanru He Xiaoling Jin Lulu Wang Yu Jin Xiaoyu Jin Liying Zhang Hailong Piao Nam-Chul Ha Chunshan Quan Ki Hyun Nam Yongbin Xu Structural Basis of the Inhibition of L-Methionine γ-Lyase from <i>Fusobacterium nucleatum</i> International Journal of Molecular Sciences <i>Fusobacterium nucleatum</i> hydrogen sulfide L-methionine γ-lyase L-cysteine desulfidase Fn1419 gallic acid |
title | Structural Basis of the Inhibition of L-Methionine γ-Lyase from <i>Fusobacterium nucleatum</i> |
title_full | Structural Basis of the Inhibition of L-Methionine γ-Lyase from <i>Fusobacterium nucleatum</i> |
title_fullStr | Structural Basis of the Inhibition of L-Methionine γ-Lyase from <i>Fusobacterium nucleatum</i> |
title_full_unstemmed | Structural Basis of the Inhibition of L-Methionine γ-Lyase from <i>Fusobacterium nucleatum</i> |
title_short | Structural Basis of the Inhibition of L-Methionine γ-Lyase from <i>Fusobacterium nucleatum</i> |
title_sort | structural basis of the inhibition of l methionine γ lyase from i fusobacterium nucleatum i |
topic | <i>Fusobacterium nucleatum</i> hydrogen sulfide L-methionine γ-lyase L-cysteine desulfidase Fn1419 gallic acid |
url | https://www.mdpi.com/1422-0067/24/2/1651 |
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