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...

Full description

Bibliographic Details
Main Authors: 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
Format: Article
Language:English
Published: MDPI AG 2023-01-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/24/2/1651
_version_ 1797441100925894656
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.
first_indexed 2024-03-09T12:19:05Z
format Article
id doaj.art-a4ffd15e1f524860b4f057df019375c7
institution Directory Open Access Journal
issn 1661-6596
1422-0067
language English
last_indexed 2024-03-09T12:19:05Z
publishDate 2023-01-01
publisher MDPI AG
record_format Article
series International Journal of Molecular Sciences
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
work_keys_str_mv AT tingtingbu structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT jinglan structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT inseongjo structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT jiezhang structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT xuebai structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT shanruhe structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT xiaolingjin structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT luluwang structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT yujin structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT xiaoyujin structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT liyingzhang structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT hailongpiao structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT namchulha structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT chunshanquan structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT kihyunnam structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi
AT yongbinxu structuralbasisoftheinhibitionoflmethionineglyasefromifusobacteriumnucleatumi