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How does catalase release nitric oxide? A computational structure-activity relationship study.

ABSTRACT: Hydroxyurea (HU) is the only FDA approved medication for treating sickle cell disease in adults. The primary mechanism of action is pharmacological elevation of nitric oxide (NO) levels which induces propagation of fetal hemoglobin. HU is known to undergo redox reactions with heme based enzymes like hemoglobin and catalase to produce NO. However, specific details about the HU based NO release remain unknown. Experimental studies indicate that interaction of HU with human catalase compound I produces NO. Presently, we combine flexible receptor-flexible substrate induced fit docking (IFD) with energy decomposition analyses to examine the atomic level details of a possible key step in the clinical conversion of HU to NO. Substrate binding modes of nine HU analogs with catalase compound I were investigated to determine the essential properties necessary for effective NO release. Three major binding orientations were found that provide insight into the possible reaction mechanisms for producing NO. Further results show that anion/radical intermediates produced as part of these mechanisms would be stabilized by hydrogen bonding interactions from distal residues His75, Asn148, Gln168, and oxoferryl-heme. These details will ideally contribute to both a clearer mechanistic picture and provide insights for future structure based drug design efforts.

SUBMITTER: Vankayala SL

PROVIDER: S-EPMC3893047 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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How does catalase release nitric oxide? A computational structure-activity relationship study.

Vankayala Sai Lakshmana SL Hargis Jacqueline C JC Woodcock H Lee HL

Journal of chemical information and modeling 20131028 11

Hydroxyurea (HU) is the only FDA approved medication for treating sickle cell disease in adults. The primary mechanism of action is pharmacological elevation of nitric oxide (NO) levels which induces propagation of fetal hemoglobin. HU is known to undergo redox reactions with heme based enzymes like hemoglobin and catalase to produce NO. However, specific details about the HU based NO release remain unknown. Experimental studies indicate that interaction of HU with human catalase compound I prod ...[more]

PMID: 24087936

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Project description:Pseudomonas aeruginosa (PA) is a common bacterial pathogen, responsible for a high incidence of nosocomial and respiratory infections. KatA is the major catalase of PA that detoxifies hydrogen peroxide (H2O2), a reactive oxygen intermediate generated during aerobic respiration. Paradoxically, PA displays elevated KatA activity under anaerobic growth conditions where the substrate of KatA, H2O2, is not produced. The aim of the present study is to elucidate the mechanism underlying this phenomenon and define the role of KatA in PA during anaerobiosis using genetic, biochemical and biophysical approaches. We demonstrated that anaerobic wild-type PAO1 cells yielded higher levels of katA transcription and expression than aerobic cells, whereas a nitrite reductase mutant ?nirS produced ?50% the KatA activity of PAO1, suggesting that a basal NO level was required for the increased KatA activity. We also found that transcription of the katA gene was controlled, in part, by the master anaerobic regulator, ANR. A ?katA mutant and a mucoid mucA22 ?katA bacteria demonstrated increased sensitivity to acidified nitrite (an NO generator) in anaerobic planktonic and biofilm cultures. EPR spectra of anaerobic bacteria showed that levels of dinitrosyl iron complexes (DNIC), indicators of NO stress, were increased significantly in the ?katA mutant, and dramatically in a ?norCB mutant compared to basal levels of DNIC in PAO1 and ?nirS mutant. Expression of KatA dramatically reduced the DNIC levels in ?norCB mutant. We further revealed direct NO-KatA interactions in vitro using EPR, optical spectroscopy and X-ray crystallography. KatA has a 5-coordinate high spin ferric heme that binds NO without prior reduction of the heme iron (Kd ?6 ?M). Collectively, we conclude that KatA is expressed to protect PA against NO generated during anaerobic respiration. We proposed that such protective effects of KatA may involve buffering of free NO when potentially toxic concentrations of NO are approached.

Dataset Information

How does catalase release nitric oxide? A computational structure-activity relationship study.

Publications

How does catalase release nitric oxide? A computational structure-activity relationship study.

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