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Identification of oxidative modifications of hemopexin and their physiological relevance

ABSTRACT: This research provides novel insights into the underlying mechanism whereby the cyto- and neuro-protective heme binding protein hemopexin can be inactivated by reactive nitrogen species generated during the heme- and cytokine- driven inflammation that accompanies hemolysis. Nitration of amino acids is generally considered a selective and specific effect reflecting biological events. As we describe in a summary in the next paragraph, three tyrosine resides are preferentially targeted that reside in the heme binding site of apo-hemopexin. Hemopexin deficiency states develop in clinical sepsis and such modifications of hemopexin that we have identified and describe could also provide evidence-based guidance to physicians when heme toxicity is driving pathology to assess the timing and extent of hemopexin replenishment therapies and the patient responses to such treatment.

INSTRUMENT(S): LTQ

ORGANISM(S): Oryctolagus Cuniculus (ncbitaxon:9986) Rattus Norvegicus (ncbitaxon:10116) Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr. Ann Smith

PROVIDER: MSV000080394 | MassIVE | Tue Dec 13 15:13:00 GMT 2016

SECONDARY ACCESSION(S): PXD005560

REPOSITORIES: MassIVE

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Project description:Stone1996 - activation of soluble guanylate cyclase by nitric oxide This features the two step binding of NO to soluble Guanylyl Cyclase as proposed by Stone JR, Marletta MA. Biochemistry (1996) 35(4):1093-9 . There is a fast step binding scheme and a slow step binding scheme. The difference lies in the binding of a NO to a non-heme site on sGC, which may not necessarily be the same site of binding during the initial binding. The rates have been directly used models. This model is described in the article: Spectral and kinetic studies on the activation of soluble guanylate cyclase by nitric oxide. Stone JR, Marletta MA. Biochemistry 1996 Jan; 35(4): 1093-1099 Abstract: The soluble form of guanylate cyclase (sGC) is the only definitive receptor for the signaling agent nitric oxide (.NO). The enzyme is a heterodimer of homologous subunits in which each subunit binds 1 equiv of 5-coordinate high-spin heme. .NO increases the Vmax of sGC up to 400-fold and has previously been shown to bind to the heme to form a 5-coordinate complex. Using stopped-flow spectrophotometry, it is demonstrated that the binding of .NO to the heme of sGC is a complex process. .NO first binds to the heme to form a 6-coordinate nitrosyl complex, which then converts to a 5-coordinate nitrosyl complex through one of two ways. For 28 +/- 4% of the heme, the 6-coordinate nitrosyl complex rapidly (approximately 20 s-1) converts to the 5-coordinate complex. For the remaining 72 +/- 4% of the heme, the conversion of the 6-coordinate nitrosyl complex to a 5-coordinate nitrosyl complex is slow (0.1-1.0 s-1) and is dependent upon the interaction of .NO with an unidentified non-heme site on the protein. The heme (200 nM) was completely converted to the 5-coordinate state with as little as 500 nM .NO, and the equilibrium dissociation constant of .NO for activating the enzyme was determined to be < or = 250 nM. Gel-filtration analysis indicates that the binding of .NO to the heme has no effect on the native molecular mass of the protein. Correlation of electronic absorption spectra with activity measurements indicates that the 5-coordinate nitrosyl form of the enzyme is activated relative to the resting 5-coordinate ferrous form of the enzyme. This model is hosted on BioModels Database and identified by: BIOMD0000000198. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Identification of oxidative modifications of hemopexin and their physiological relevance

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