Investigation by MD simulation of the key residues related to substrate-binding and heme-release in human ferrochelatase
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ORIGINAL PAPER
Investigation by MD simulation of the key residues related to substrate-binding and heme-release in human ferrochelatase Yaxue Wang & Jingheng Wu & Jinqian Ju & Yong Shen
Received: 17 October 2012 / Accepted: 30 January 2013 / Published online: 28 February 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Molecular dynamics (MD) simulations of three models based on the crystal structure of the E343K variant of human ferrochelatase were performed in this study. The “open” and “closed” conformations of the enzyme obtained by simulations are in agreement with the corresponding crystal structures. The snapshots and the structure analysis indicate that alterations of the hydrogen bonds and the positions of E347 and E351 lead to a conformational change in the π-helix. The hydrogen bonded form of residue R164 could be regarded as a signal indicating alteration of the active site conformation. When R164 forms a hydrogen bond with D95, the active site is closed, and when a hydrogen bond is formed with E171, the active site is open. Interestingly, the protoporphyrin with Fe2+ is observed to move noticeably out of the enzyme while the protoporphyrin lacking Fe2+ remains almost fixed. Alterations of the hydrogen bonds between the propionate of the heme and R115, K118 and S303 trigger movement of the heme out of the active site. Residues E347 and E351, which are located on the π-helix and form an acidic path leading to a salt bridge interaction with the propionate of the heme, accelerate the release process. Keywords Human ferrochelatase . Protoporphyrin IX . Heme . Ferrous ion . Molecular dynamics
Electronic supplementary material The online version of this article (doi:10.1007/s00894-013-1789-9) contains supplementary material, which is available to authorized users. Y. Wang : J. Wu : J. Ju : Y. Shen (*) KLGHEI of Environment and Energy Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, 510275, Guangzhou, People’s Republic of China e-mail: [email protected] Y. Wang School of College of Food Science and Engineering, Northwest A&F University, 712100, Yangling, People’s Republic of China
Introduction Ferrochelatase (protoheme ferrolyase, EC 4.99.1.1) is the terminal enzyme in heme biosynthesis and catalyzes the insertion of ferrous ion into protoporphyrin IX to form protoheme IX (heme) [1]. Heme is a cofactor included in hemo- and myoglobins, cytochromes, all aerobic organisms and the majority of anaerobes and facultative organisms. Biosynthesis of heme requires eight enzymatic steps in mammals and most fungi, and nine in plants and most bacteria. Human and bacterial ferrochelatase are highly conserved at the level of tertiary structure although there is less than 10 % conservation at the level of amino acid sequence [2]. Mutations in the human ferrochelatase gene can lead to the disease erythropoietic protoporphyria (EPP) [3, 4]. A symptom of this disease is light-sensitive dermatitis, caused by overproduction of protoporphyrin and its deposition in skin and liver. In so
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