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Divergent mechanisms of suicide inactivation for ethanolamine ammonia-lyase

Sandala, Gregory; Smith, David M; Radom, Leo

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Ab initio molecular orbital calculations have been used to study the mechanism of suicide inactivation of ethanolamine ammonia-lyase induced by three different substrate analogues. Analysis of the normal catalytic mechanism with 2-aminoethanol (ethanolamine) as substrate predicts that both the hydrogen-abstraction and hydrogen-reabstraction steps involving the B 12-cofactor are likely to be exothermic. On the other hand, the proposed inactivation mechanism for the first substrate analogue,...[Show more]

dc.contributor.authorSandala, Gregory
dc.contributor.authorSmith, David M
dc.contributor.authorRadom, Leo
dc.date.accessioned2015-12-13T22:52:31Z
dc.identifier.issn0002-7863
dc.identifier.urihttp://hdl.handle.net/1885/81619
dc.description.abstractAb initio molecular orbital calculations have been used to study the mechanism of suicide inactivation of ethanolamine ammonia-lyase induced by three different substrate analogues. Analysis of the normal catalytic mechanism with 2-aminoethanol (ethanolamine) as substrate predicts that both the hydrogen-abstraction and hydrogen-reabstraction steps involving the B 12-cofactor are likely to be exothermic. On the other hand, the proposed inactivation mechanism for the first substrate analogue, glycolaldehyde, leads to a highly stabilized radical that results in a very endothermic (by ca. 90 kJ mol-1) hydrogen-reabstraction step, which is thought to halt the normal function of the enzyme. Curiously, the energy requirements for a catalytically imposed mechanism in the case of the second substrate analogue, 2-hydroxyethylhydrazine (HEH), parallel those for the catalytic substrate, despite the fact that HEH is found to inactivate EAL experimentally. However, further analysis reveals the presence of a lower energy pathway for HEH that leads to the formation of the highly stabilized hydrazinium radical cation. In a manner similar to when glycolaldehyde is the substrate analogue, this results in an endothermicity for the hydrogen-reabstraction step that is prohibitively large. In contrast to these related inactivation mechanisms, the third substrate analogue, 2-aminoacetaldehyde, apparently accomplishes the inactivation of EAL in an entirely different manner. A pathway for the experimentally observed formation of acetic acid and ammonium cation has been identified and appears catalytic in the sense that 5′-deoxyadenosyl radical is regenerated. However, mechanisms to account for the subsequent formation of 4′,5′- anhydroadenosine and degradation of the corrinoid ring of the cofactor have not been elucidated.
dc.publisherAmerican Chemical Society
dc.sourceJournal of the American Chemical Society
dc.subjectKeywords: Acetic acid; Activation analysis; Aldehydes; Amines; Ammonia; Degradation; Substrates; Endothermicity; Energy pathway; Inactivation mechanisms; Molecular orbital calculations; Enzymes; 4',5' anhydroadenosine; acetic acid; adenosine derivative; aldehyde; a
dc.titleDivergent mechanisms of suicide inactivation for ethanolamine ammonia-lyase
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume127
dc.date.issued2005
local.identifier.absfor030799 - Theoretical and Computational Chemistry not elsewhere classified
local.identifier.ariespublicationMigratedxPub9905
local.type.statusPublished Version
local.contributor.affiliationSandala, Gregory, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationSmith, David M, Rudjer Boskovic Institute
local.contributor.affiliationRadom, Leo, College of Physical and Mathematical Sciences, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue24
local.bibliographicCitation.startpage8856
local.bibliographicCitation.lastpage8864
local.identifier.doi10.1021/ja051527k
dc.date.updated2015-12-11T10:51:28Z
local.identifier.scopusID2-s2.0-20944437413
CollectionsANU Research Publications

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