Repression of growth of pathogens on the basis of iron uptake systems

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K05835
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bio-related chemistry
• Research Institution: Hokkaido University
• Principal Investigator: Uchida Takeshi 北海道大学, 理学研究院, 准教授 (30343742)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: タンパク質 / ヘムタンパク質 / 酵素 / 反応機構解析 / 構造解析 / 病原菌

Outline of Final Research Achievements

Iron is an essential element for bacterial growth because it is contained in proteins playing key roles in metabolic processes. Most irons in the human body are present as a heme iron. Therefore, heme is a dominant iron source for most pathogens. In this project the reaction mechanism of a heme-degrading enzyme HutZ from V. cholerae was solved. We found that iron chelators are able to inhibit HutZ by perturbing the proton transfer to heme intermediate. This mechanism suggests that iron chelators are candidates of antibiotics. We further found that heme binds to iron-carrier protein CyaY and PBGD that catalyzes the polymerization of porphobilinogen to form 1-hydroxymethylbilane. Heme binding to CyaY and PBGD resulted in less activity, indicating the presence of heme-induced negative feedback. These were not observed in the corresponding human proteins. Therefore, we can propose that HutZ, CyaY and PBGD are good target for new medicine to repress pathogen growth without side reaction.

Free Research Field

生物無機化学

Academic Significance and Societal Importance of the Research Achievements

今回の発見の一つであるHutZの活性制御機構は、二量体の界面構造の変化を通じて行っているが、ヒトが保有するヘム分解酵素は単量体のタンパク質であり、コレラ菌由来HutZに特有な性質である。そのため、この界面構造を抑制する分子が存在すれば、コレラ菌の鉄獲得機構をのみを選択的に抑制することが可能である。キレート能をもつ小分子がHutZの反応を抑制するなど候補となる分子も発見した。それ以外にも今回発見した多くの事象はコレラ菌などの病原菌がもつタンパク質に特有な性質である。今後は本研究課題により見出された多くの性質を利用するこでで、従来型とは異なる新規な機構の阻害剤の開発につながることが期待される。